Download Neuro-Opthalmology (Developments in Ophthalmology, Vol. 40)

Neuro-Ophthalmology
Developments in
Ophthalmology
Vol. 40
Series Editor
W. Behrens-Baumann, Magdeburg
NeuroOphthalmology
Neuronal Control of Eye Movements
Volume Editors
Andreas Straube, Munich
Ulrich Büttner, Munich
39 figures, and 3 tables, 2007
Basel · Freiburg · Paris · London · New York ·
Bangalore · Bangkok · Singapore · Tokyo · Sydney
Andreas Straube
Ulrich Büttner
Department of Neurology
Klinikum Grosshadern
Marchioninistrasse 15
DE–81377 Munich
Department of Neurology
Klinikum Grosshadern
Marchioninistrasse 15
DE–81377 Munich
Library of Congress Cataloging-in-Publication Data
Neuro-ophthalmology / volume editors, Andreas Straube, Ulrich Büttner.
p. ; cm. – (Developments in ophthalmology, ISSN 0250-3751 ; v. 40)
Includes bibliographical references and indexes.
ISBN 978-3-8055-8251-3 (hardcover : alk. paper)
1. Neuroophthalmology. I. Straube, Andreas. II. Büttner, U. III. Series.
[DNLM: 1. Eye Movements–physiology. 2. Ocular Motility Disorders. 3.
Oculomotor Muscles–physiology. 4. Oculomotor Nerve-physiology. W1
DE998NG v.40 2007 / WW 400 N4946 2007]
RE725.N45685 2007
617.7⬘32–dc22
2006039568
Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents® and
Index Medicus.
Disclaimer. The statements, options and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The appearance of advertisements in the
book is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness,
quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property
resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and
dosage set forth in this text are in accord with current recommendations and practice at the time of publication.
However, in view of ongoing research, changes in government regulations, and the constant flow of information
relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for
any change in indications and dosage and for added warnings and precautions. This is particularly important when
the recommended agent is a new and/or infrequently employed drug.
All rights reserved. No part of this publication may be translated into other languages, reproduced or
utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying,
or by any information storage and retrieval system, without permission in writing from the publisher.
© Copyright 2007 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland)
www.karger.com
Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel
ISSN 0250–3751
ISBN: 978–3–8055–8251–3
Contents
VII List of Contributors
IX Preface
Büttner, U.; Straube, A. (Munich)
1 Anatomy of the Oculomotor System
Büttner-Ennever, J.A. (Munich)
15 Eye Movement Recordings: Methods
Eggert, T. (Munich)
35 Vestibulo-Ocular Reflex
Fetter, M. (Karlsbad)
52 Neural Control of Saccadic Eye Movements
Catz, N.; Thier, P. (Tübingen)
76 Smooth Pursuit Eye Movements and Optokinetic Nystagmus
Büttner, U.; Kremmyda, O. (Munich)
90 Disconjugate Eye Movements
Straumann, D. (Zurich)
110 The Eyelid and Its Contribution to Eye Movements
Helmchen, C.; Rambold, H. (Lübeck)
132 Mechanics of the Orbita
Demer, J.L. (Los Angeles, Calif.)
V
158 Current Models of the Ocular Motor System
Glasauer, S. (Munich)
175 Therapeutic Considerations for Eye Movement Disorders
Straube, A. (Munich)
193 Subject Index
Contents
VI
List of Contributors
Prof. Dr. med. U. Büttner
Department of Neurology
Klinikum Grosshadern
Marchioninistrasee 15
DE–81377 Munich (Germany)
Prof. Dr. med. Jean Büttner-Ennever
Institute of Anatomy
Ludwig-Maximilian University
Pettenkoferstrasse 11
DE–80336 Munich (Germany)
Dr. N. Catz
Department of Cognitive Neurology
Hertie Institute for Clinical Brain
Research
Hoppe-Seyler Strasse 3
DE–72076 Tübingen (Germany)
Prof. Dr. med. J.L. Demer
Jules Stein Eye Institute
100 Stein Plaza
David Geffen School of Medicine at
UCLA
Los Angeles, CA 90095-7002,
Calif. (USA)
Dr. Ing. T. Eggert
Department of Neurology
Klinikum Grosshadern
Marchioninistrasee 15
DE–81377 Munich (Germany)
Prof. M. Fetter
SRH Clinic Karlsbad-Langensteinbach
Department of Neurology
Guttmannstrasse 1
DE–76307 Karlsbad (Germany)
VII
PD Dr. Ing. S. Glasauer
Department of Neurology
Klinikum Grosshadern
Marchioninistrasse 15
DE–81377 Munich (Germany)
Prof. Dr. med. A. Straube
Department of Neurology
Klinikum Grosshadern
Marchioninistrasse 15
DE–81377 Munich (Germany)
Prof. Dr. med. Ch. Helmchen
Department of Neurology
University Hospitals
Schleswig-Holstein
Campus Lübeck
Ratzeburger Allee 160
DE–23538 Lübeck (Germany)
Prof. Dr. med. D. Straumann
Neurology Department
Zurich University Hospital
Frauenklinikstrasse 26
CH–8091 Zurich (Switzerland)
Dr. O. Kremmyda
Department of Neurology
Klinikum Grosshadern
Marchioninistrasse 15
DE–81377 Munich (Germany)
Prof. Dr. med. P. Thier
Department of Cognitive Neurology
Hertie Institute for Clinical Brain
Research
Hoppe-Seyler Strasse 3
DE–72076 Tübingen (Germany)
PD Dr. H. Rambold
Department of Neurology
University Hospitals
Schleswig-Holstein
Campus Lübeck
Ratzeburger Allee 160
DE–23538 Lübeck (Germany)
List of Contributors
VIII
Preface
Each of us performs thousands of eye movements every day without being
aware of how the brain controls them. The oculomotor system is one of the best
understood motor systems not only with regard to premotor centers in the central
nervous system, but also with regard to the peripheral muscles moving the eye.
This has been made possible by intensive multidisciplinary research, including
ophthalmologists, neurologists and basic scientists, and is reflected in comprehensive textbooks [i.e. Leigh RJ, Zee DS: The Neurology of Eye Movements.
New York, Oxford University Press, 2006]. Based on these studies, some basic
features of the oculomotor system were formulated and put to use in clinical practice: (1) All extraocular motoneurons are involved in all eye movements and
innervate basically functionally similar muscles. (2) The pulling directions of the
muscles are determined by central commands. (3) There are at least 5 different
types of eye movements, i.e. saccades, smooth pursuit eye movements, vestibuloocular reflex (VOR), vergence and optokinetic nystagmus. Furthermore, there are
special neuronal circuits involved in fixation of an object. The premotor centers
for these eye movements have different locations in the central nervous system.
However, experimental evidence gathered over recent years strongly suggests that none of these basic rules are correct and they have to be modified. (1)
Twitch and nontwitch motor fibers of eye muscles have different distributions in
the eye muscle. They are innervated by different motoneurons with distinct locations in the oculomotor nuclei, and furthermore they receive different inputs from
premotor structures in the brainstem [see the chapter by Büttner-Ennever]. Thus,
there are different classes of motoneurons, which serve different functions. (2) It
also becomes increasingly clear that mechanical properties of the connective tissues (pulleys including Tenon’s capsule) in the orbit are important, particularly for
IX
the implementation of 3-D eye movements, and that a pure central neuronal
implementation for eye movements is probably not sufficient [see the chapter by
Demer]. (3) Specifically for cortical structures, it has been shown that one area
can be involved in the control of several types of eye movements, the frontal eye
field being the best investigated structure. It could be shown that the frontal eye
field is not only involved in saccade control [see the chapter by Catz and Thier],
but also in smooth pursuit eye movement [see the chapter by Büttner and
Kremmyda] and vergence [see the chapter by Straumann] control. The functional
meaning of these interactions in one premotor location has yet to be determined.
For undisturbed vision, particularly during natural head movements, the
VOR is of uttermost importance. In this sense, the VOR is the basic machinery
of all eye movements, providing a foundation on which other eye movements
operate. The VOR after a head movement has a latency of only 10 ms, whereas
an eye movement response to a visual stimulus occurs much later, after 100 ms.
Modern tests now allow clinicians to detect even discrete vestibular deficits in
all directions of head movements [see the chapter by Fetter].
The progress in neuro-ophthalmology reveals complex interactions of oculomotor signals at all levels. To understand this complexity, models based on
Control Theory have been proven to be very beneficial, and often deficits can
only be correctly interpreted by the use of such models [see the chapter by
Glasauer]. The latter also allow predictions and can provide the basis for new
surgical procedures and other interventions. In order to test the models, precise
measurements of the eye movements have to be made. Methods for recording
eye movements have greatly improved over the last years, particularly for
recording 3-D eye movements [see the chapter by Eggert].
The main aim in clinical practice is therapy [see the chapter by Straube].
For some disorders, drug therapy has been shown to be quite efficient (i.e. for
downbeat nystagmus), and some therapies are starting to be based on the understanding of the neuronal interactions and their transmitters. For others, the
search for specific and affective drugs is continuing.
This book presents the current state of research and clinical studies in this
important and relevant field. It is aimed at ophthalmologists who want to
become familiar with the latest developments in oculomotor research. Certainly,
the chapters related to the oculomotor periphery [see the chapters by Demer and
Büttner-Ennever] will also have some impact on the surgical approach for treating eye movement disorders (i.e. strabismus). The book is also aimed at basic
scientists with interest in clinical aspects of oculomotor disorders. A continuing
multidisciplinary approach will hopefully lead to further improvement of diagnostic methods and the development of new therapeutic options.
Ulrich Büttner and Andreas Straube, Munich
Preface
X
Straube A, Büttner U (eds): Neuro-Ophthalmology.
Dev Ophthalmol. Basel, Karger, 2007, vol 40, pp 1–14
Anatomy of the Oculomotor System
Jean A. Büttner-Ennever
Institute of Anatomy, Ludwig-Maximilian University, Munich, Germany
Abstract
The sensory and motor control of eye muscles are considered in this chapter. Eye muscles differ from skeletal muscles in several ways. One is the absence of muscle spindles and
Golgi tendon organs in the eye muscles of some species, and their poor development in others. Second, eye muscles have an inner ‘global layer’, and the outer ‘orbital layer’, each containing different types of muscle fiber. Third, eye muscles contain not only twitch muscle
fibers with a single endplate zone (SIFs), but also nontwitch muscle fibers with multiple
endplate zones (MIFs), which are otherwise absent from mammalian muscles. There are
cuffs of nerve terminals, called palisade endings, around the myotendinous junctions of
global layer MIFs. Palisade endings are unique to eye muscles, and have been found in all
mammalian species investigated up to now. The function of palisade endings is uncertain, but
it is possible that they are ‘sensory receptors’. Motoneurons innervating the eye muscles lie
in the oculomotor, trochlear and abducens motor nuclei, and are contacted by several relatively independent premotor networks, which generate different types of eye movements
such as saccades, vestibulo-ocular reflexes, optokinetic responses, smooth pursuit convergence or gaze-holding. In each motor nucleus, the motoneurons can be divided into two distinct sets: the first set innervating SIF muscle fibers and receiving inputs from all oculomotor
premotor networks, and the second set innervating the MIFs and receiving premotor afferents from the gaze holding, convergence or smooth pursuit premotor networks, but not from
the saccadic and vestibulo-oculomotor networks. We suggest that the SIF motoneurons and
muscles are more suited to driving eye movements, and the MIF motoneurons and muscles to
setting the tonic tension in eye muscles. Furthermore the ‘palisade ending – MIF unit’ may
be part of a sensory feedback system in eye muscles, which should be considered in association with the causes and treatment of strabismus.
Copyright © 2007 S. Karger AG, Basel
Skeletomotor function depends on a chain of activity involving (a) sensory
receptors in muscles, (b) their central connections, (c) the diverse central premotor inputs onto motoneurons, (d) the properties of the muscles that are targeted. Similarly, oculomotor function depends on the activity of sensory
receptors in eye muscles, their central connections with the premotor pathways
that drive the activity of extraocular motoneurons, and finally the contraction
properties of the eye muscles.
However, eye muscles are fundamentally different from skeletal muscles in
many ways [1]: they are responsive to different metabolic and neuromuscular
diseases; their myosin retains some characteristics seen only in the early stages
of the embryological development of skeletal muscles, and hence they contain
different muscle fiber types than skeletal muscles. In many species, eye muscles lack the classical sensory receptors, such as muscle spindles and Golgitendon organs, the receptors which would provide the central nervous system
with sensory feedback signals, a fundamental principle of skeletal muscle control [2, 3]. Additional neural structures unique to eye muscles could provide a
sensory feedback signal, but it is clear from the differences between eye and
skeletal muscles that their sensorimotor control will follow a different pattern.
A great deal is known about the motor and premotor control of eye muscles,
perhaps even more than of skeletal muscles. In this chapter, we will consider
how the properties of eye muscles and their neural connections contribute to the
sensorimotor control of eye movements, discussing first properties of eye muscles, then their sensory receptors, the central connections of different types of
extraocular motoneurons, and finally we will suggest how these pathways and
structures might together contribute to different types of eye movements.
Properties of Extraocular Muscles
Eye muscles have 2–3 separate morphological subdivisions (fig. 1a),
which have independent developmental features [4]. There is a C-shaped outer
‘orbital’ layer of small diameter fibers, with high mitochondrial content, a welldeveloped microvascular system and oxidative enzymes, all correlating with a
high level of continuous muscle activity. The orbital layer inserts onto Tenon’s
capsule or ‘pulleys’, a ring of fibroelastic connective tissue that forms sleeves
around the individual eye muscles, and is fully discussed by Demer [this vol,
pp 132–157]. The inner ‘global’ layer contains muscle fibers of a larger diameter;
it extends the full length of the muscle and inserts on the sclera of the globe.
A third thin muscle layer outside the orbital layer has been described in some
species, including human [5], and is called the marginal layer.
Morphological, histochemical and immunological studies have characterized six different types of muscle fibers in mammalian extraocular muscles,
and their properties are fully reviewed by Spencer and Porter [1]. They distinguish between (1) the orbital singly innervated fiber type (orbital SIF), and (2)
the orbital multiply innervated fiber type (orbital MIF); in the global layer, four
Büttner-Ennever
2
Orbital layer with
muscle spindles
Pulleys
Global layer with
palisade endings
Muscle
P
MIF fibre
MIF
Tendon
Global layer
a
MIF motoneuron
50␮m
b
Fig. 1. a Diagram of an extraocular muscle showing how muscle spindles tend to lie in
(and adjacent to) the orbital layer; while the global layer is characterized by MIFs which
extend throughout the length of the muscle and carry palisade endings at their tips in the
myotendinous junction. b Light microscopic photograph of the tip of a MIF at the distal
myotendinous junction of a human lateral rectus muscle (see rectangle in a). The MIF is
identified by the presence of a palisade ending (P) surrounding the tip of the muscle fiber.
Note the axon (arrow) passing into the collagen bundles of the tendon on the left.
muscle types are found: (3) the global red SIF, (4) the global white SIF, (5) the
global intermediate SIF, and lastly (6) the global MIF. These fiber types can be
divided morphologically and physiologically into two fundamentally different
categories – the singly innervated muscle fibers and multiply innervated muscle
fibers, that is SIFs and MIFs which are shown diagrammatically in figure 2.
The SIFs are also called ‘twitch’ fibers, since they undergo an all-or-nothing
contraction on the activation of their centrally lying endplates. Skeletal muscles
contain only SIF, or twitch, fibers, with the exception of perhaps tensor tympani
and vocal muscles [6]. Thus MIFs are highly unusual in mammals. In mammals, the extraocular muscles contain 10–20% of MIF muscle fibers, with the
exception of levator palpebrae. These striated muscle fibers are innervated at
several places along their length, as apposed to having a single endplate zone
like the SIFs (fig. 2). On activation of the nerve fibers to MIFs, the small grapelike clusters of endplates, ‘en grappe’ nerve endings, generate a local contraction which is not propagated throughout the muscle fiber, but remains local to
the nerve terminal [6–11]. The MIFs are often referred to as nontwitch muscle
fibers. They are a regular component of the skeletal muscles in amphibians,
reptiles and fish, where a spectrum of different types of nontwitch fiber can be
found, with graduated properties [6]. The contraction of nontwitch muscle
fibers is slower than in all other muscle types, but they can maintain the tension
for long periods at less energy cost than a twitch fiber, due to the slow turnover
Anatomy of the Oculomotor System
3
‘En plaque’
endplate zone
PROXIMAL
TENDON
SIF
DISTAL
TENDON
‘En grappe’
endplates
Palisade
ending
MIF
?
SIF
motoneuron
MIF
motoneuron
Fig. 2. Diagram of motoneurons innervating SIFs and MIFs of an extraocular muscle.
Note the endplate zone in the central part of the muscle with ‘en plaque’ endings on the SIF,
the ‘en grappe’ endings distally and proximally on the MIF, and the palisade endings associated with the MIFs (only of the global layer).
of the myosin-actin bonding. The function of MIFs in extraocular muscles is
still unclear, but experiments on frogs suggest that they respond in a highly
tonic fashion [12]. The MIFs appear to be primitive or immature fiber types,
and they are unlike any type of skeletal muscle fiber. They also have many features in common with intrafusal muscle fibers of muscle spindles [13].
Sensory Receptors in Extraocular Muscles
Muscle Spindles
All skeletal muscles possess muscle spindles, so it is curious that in
extraocular muscles some animals have them, and others lack them: no muscle
spindles have been found in the eye muscles of submammalian species [14].
Many mammalian species do not have muscle spindles in their eye muscles:
most monkey species including Macacca fascicularis, dogs, cats, rats, guinea
pigs and rabbits do not have muscle spindles, whereas they have been found in
humans, some types of monkey, mice and all ungulates (artiodactyls) [15–18].
The later studies show that the spindles are associated with the orbital layer, or
the transition zone of the orbital layer with the global layer; but they are not
associated with the global layer (fig. 1a). Furthermore, the density of muscle
Büttner-Ennever
4
spindles in human eye muscles is extremely high and is comparable to the density of muscle spindles in hand lumbrical and short neck muscles [16].
Extraocular muscle spindles appear poorly preserved in comparison to
those in skeletal muscle, even to the point that some authors have raised the
question of whether or not they are functional [3, 19–22]. Most extraocular
muscle spindles lack an expansion of the equatorial zone; they contain fibers of
the nuclear chain type, but no nuclear bag fibers are present. Extraocular muscle spindles also have many anomalous fibers which pass through the muscle
spindle capsule without any intrafusal modification. An exception to this is
seen in sheep (ungulates) where the extraocular spindles are very well developed, and they appear very similar to the skeletal spindles [18]. It has long been
known that MIFs are morphologically very similar to the nuclear bag fibers of
muscle spindles [13]; in sheep, branches from extraocular MIFs enter the muscle spindles and build nuclear bag fibers [23].
The erratic occurrence of muscle spindles in eye muscles cannot be
explained today. Recent research on skeletal muscle spindles shows that their
occurrence can be a highly dynamic process. For example, their incidence is
critically dependent on the timing of the sensory innervation of the developing
spindles, on the presence of neurotrophins, and of specific genetic transcription
factors [24–27]. Similar studies on extraocular muscle spindles could help
explain their variability, particularly in view of the persistence of embryological
characteristics in adult eye muscles.
Palisade Endings
The global layer possesses an unusual feature unique to eye muscles; it has
palisade endings at the myotendinous junctions, both proximally and distally
(figs. 1b and 2) [3, 15, 28, 29]. Palisade endings, or palisade-like endings, have
been found in almost all species that have been investigated [30]. Several
authors have suggested that palisade endings could be the source of sensory
afferent signals [2, 3, 31, 32]. The vast majority of the palisade terminals make
contact with collagen fibers, and only a few are associated with muscle fibers
[33, 34]. But this is a controversial topic [35]. A recent demonstration in cats
that palisade endings are cholinergic structures argues in favor of their motor
function [34]. In man, palisade endings with both sensory-like neurotendinous
contacts and a few motor-like neuromuscular contacts have been found, and
some of the authors daringly proposed that palisade endings might combine
sensory and motor function [33, 36, 37].
Palisade endings form a cuff of nerve branches around the muscle fiber tip,
like a palisade fence (fig. 1b); but they contact only one type of muscle fiber,
the MIFs of the global layer [3, 36, 38, 39]. The term ‘innervated myotendinous
cylinders’ is used to describe the palisade endings along with their fibrous
Anatomy of the Oculomotor System
5
capsule. The palisade terminals arise from nerve fibers that enter the muscle at
the central nerve entry zone, run the length of the muscle into the tendon and
then turn back 180⬚, to contact the tip of the muscle fibers (fig. 2).
The uncertainty concerning the sensory or motor nature of palisade endings
is compounded by the conflicting evidence on the location of their cell soma. If
the palisade endings are sensory, their ganglion cell body should be in the trigeminal ganglion or in the mesencephalic trigeminal nucleus, whereas if the endings
are of a motor origin then they would have cell bodies associated with the oculomotor nucleus. Tozer and Sherrington [29] as well as Sas and Schab [40] provided
evidence for their location in the extraocular motor nerves or their nuclei, a result
more compatible with either a motor role for the palisade endings, or perhaps an
aberrant pathway for the afferent axons [3, 41]. The results of other studies point
to the trigeminal ganglion as the location of palisade ending soma [42], and imply
a sensory function. At present, considerable evidence points towards a sensory
function of palisade endings, but without knowledge of their afferent pathways or
evidence for their function, no conclusions can be made.
Golgi Tendon Organs
Golgi tendon organs are very rarely found in eye muscles, but they have
been reported in the tendons of extraocular eye muscles artiodactyls, that is in
sheep, camel, pig and calf [3, 43, 44]. They exhibit structural features not seen
in skeletal Golgi-tendon organs, and several different types have been described
[44]. Of particular interest in the context of this paper are Golgi tendon organs
(only found in sheep). They all lie in one specific layer of the sheep eye muscle,
the outer marginal layer. Zelená and Soukup [45] studied the development of
Golgi tendon organs, and made the exciting suggestion that palisade endings
may represent immature Golgi tendon organs. This hypothesis fits well with the
demonstration of embryological (or immature) myosin types in the eye muscles,
and suggests that eye muscle development may have been arrested at an early
developmental stage, and hence the appearance of ‘immature Golgi tendon
organs’, i.e. palisade endings.
In summary, it seems that each eye muscle layer has its own individual type
of receptor, muscle spindles are associated with the orbital layer, palisade endings with the orbital layer and, albeit only in sheep, Golgi tendon organs with
the outer marginal layer. An important question to answer now is whether these
receptors all deliver a sensory feedback signal to the central nervous system.
Does the central nervous system need them all, or will one type suffice? If palisade endings are proprioceptors, then they could deliver the sensory feedback
signals in species without muscle spindles; and since palisade endings are
found in all species so far investigated, they could be the major sensory receptor, i.e. proprioceptors, for eye muscles.
Büttner-Ennever
6
Central Pathways
The trigeminal nerve or the ocular motor nerves are the only two pathways
available for primary sensory afferents from eye muscles to access the brainstem; however, the route that the sensory afferents take is not clear.
Anastomoses between these two nerves in retro-orbital regions have been
demonstrated, so that it is possible that both pathways are involved. The location of the cell bodies (i.e. pseudounipolar ganglion cells) of the eye muscle primary sensory afferents is also a subject of disagreement, and has been reviewed
by both Ruskell [3] and Donaldson [2]. Some studies suggest that they lie in the
mesencephalic trigeminal nucleus, others the trigeminal ganglion, and some
report finding cells labeled in both structures after tracer injections into eye
muscles. Furthermore, ganglion cells are regularly reported to lie between the
fascicles of the ocular motor and trigeminal nerves, and could possibly belong
to the eye muscle proprioceptors [46, 47].
In spite of the uncertainty of the anatomy of the sensory pathways,
responses to eye muscle stimulation have been reported in numerous central
nuclei [2, 3]; these include the spinal and mesencephalic trigeminal nucleus,
superior colliculus, the vestibular nuclei, the cerebellum, nucleus prepositus
hypoglossi, the lateral geniculate nucleus and the visual cortex. How the activity in these central nuclei affects eye movements, or rather motoneurons, is not
known, but afferent signals from extraocular muscles have been shown to affect
orientation selectivity in the visual cortex, binocularity, stereoacuity, spatial
localization, and under some conditions eye movements [2, 48–51].
Motor and Premotor Pathways Controlling Eye Muscles
Motoneurons in the oculomotor nucleus (III) innervate the ipsilateral
medial and inferior rectus (MR, IR) and the inferior oblique (IO) and contralateral superior rectus (SR); those in the trochlear nucleus (IV) control the contralateral superior oblique (SO), and motoneurons in the abducens nucleus (VI)
drive the lateral rectus muscle (LR). The mammalian III also includes motoneurons which innervate the levator palpebrae superioris; they lie in a slightly separate subgroup in caudal III, called the central caudal nucleus. Although at least
six different types of muscle fiber have been described in extraocular muscles,
only one type of extraocular motoneuron was recognized in III, IV and VI until
recently. Recordings from awake monkeys showed that motoneurons responded
during all types of eye movement providing a so-called ‘final common pathway’.
Neuroanatomical experiments to determine the exact localization of MIF
or nontwitch motoneurons with the motor nuclei were undertaken in the
Anatomy of the Oculomotor System
7
monkey [52]. Injections of a simple retrograde tracer were placed in the muscle
belly within the central endplate zone of the SIFs (fig. 2). The tracer was taken
up by SIF endplates and some MIF endplates. There was retrograde filling of the
classical motoneuron subgroups throughout III, or in IV or VI. Alternatively,
when the injection was placed at the distal tip of the muscle the tracer involved
only MIF ‘en grappe’ motor endplates. Thus, only the (global) MIF motoneurons were retrogradely filled. In fact, these experiments labeled mainly the
global MIFs since the orbital MIFs did not extend into the distal tendon (fig.
1a) [see also the chapter by Demer, this vol, pp 132–157]. The MIF motoneurons lay around the periphery of the classical III, IV and VI boundaries and did
not intermingle with the SIF motoneurons. In VI, the LR MIFs surrounded the
medial aspect of the nucleus; the SO MIFs lay in a dorsal cap over IV; in III the
MIFs of MR and IR gathered into a small group on the dorsomedial boarder of
III (C group), while those of SR and IO lay around the midline between the two
halves of the III (S group). It is important to note that the extraocular MIF and
SIF motoneurons do not intermingle. In terms of neuroanatomy, when neuronal
cell groups lie separately it is often a sign that they receive different afferent
inputs. This is indeed the case, as is described in the next sections.
Premotor Circuits
Pioneering studies of the oculomotor system in 1960s and 1970s resulted in
the realization that there were several relatively independent premotor circuits
carrying vestibular, saccadic, smooth pursuit or vergence signals. They were
modeled, recorded, lesioned and traced and shown to generally converge on the
oculomotor system at the level of the motoneurons in the oculomotor, trochlear
or abducens nuclei [53]. Clinical studies confirmed that saccadic circuits
through the pontine and mesencephalic reticular formation could be lesioned,
leading to the loss of gaze to the ipsilateral side, but other eye movements such
as vestibular reflexes, optokinetic responses or convergence remained intact.
This concept is diagrammatically represented in figure 3. One exception is the
optokinetic system which converges on the vestibular nuclei and uses the
vestibulo-ocular pathways to drive optokinetic eye movements. The motoneurons generate motor responses, some with more tonic activity, others with more
phasic properties; but up to now electrophysiological recordings showed that the
motoneurons respond with every type of eye movement [54–56]. This concept –
a final common pathway – has become widely accepted, although detailed studies described below show that this concept is not yet complete [57, 58].
With the anatomical identification of the MIF motoneurons it became clear
that the concept of a final common pathway is an oversimplification, because
two very different sets of motoneurons were found to innervate the extraocular
muscles. Recent tract tracing experiments have now shown that the MIF
Büttner-Ennever
8
RIMLF
PPRF*
SC
Vestibular
n.
1
Saccades
2
VOR
3
OKN
4
Smooth
pursuit
5
Vergence
6
Gaze holding
Motoneuron
Accessory
optic n.
Vestibular n.
y-group
marginal zone
Retina
Flocculus
region
Pontine
n.
Visual
cortex
Perioculomotor
MRF
Eye muscle
Interst.n.Cajal
n. prepositus*
Vestibular
n.
Flocculus
region
Fig. 3. Several relatively independent neural networks of the brain converge at the level
of the extraocular motoneurons to drive the eye muscles. The simplified diagram of these networks shows the premotor structures involved in five different types of eye movements and in
gaze holding. MRF ⫽ Mesencephalic reticular formation; OKN ⫽ optpkinetic responses;
PPRF ⫽ paramedian pontine reticular formation; RIMLF ⫽ rostral interstitial nucleus of the
MLF; SC ⫽ superior colliculus; VOR ⫽ vestibulo-ocular reflex.
motoneurons in the oculomotor nucleus receive different afferent inputs than the
SIF motoneurons. This was done in two ways. Firstly, by tracing projections to
the oculomotor nucleus, for example from the pretectum, which targeted the
C and S groups of MIFs, but not the classical SIF motoneuron subgroups [59].
A very elegant approach to this system was the use of rabies virus, which is a
retrograde transsynaptic tracer, and when injected into the muscle belly it retrogradely labeled all the premotor structures shown in figure 4 [60]. The injection
of the virus into the distal tip of LR, avoiding the SIF endplate zone and labeling
only MIF terminals, retrogradely filled pathways mainly associated with gaze
holding or convergence, but did not fill the saccadic and vestibulo-ocular pathways. The premotor inputs to the LR MIF motoneurons came from areas not
previously recognized as premotor: the medial mesencephalic reticular formation and the supraoculomotor area, as well as areas associated with the neural
integrator, like nucleus prepositus hypoglossi and the parvocellular parts of the
medial vestibular nucleus. This difference in premotor inputs to SIFs and MIFs
is shown diagrammatically in figure 4.
Anatomy of the Oculomotor System
9
Saccadic pathways
MIF
motoneuron
SIF
motoneuron
Vestibular pathways
Optokinetic pathways
Smooth pursuit pathways
Smooth pursuit pathways
Convergence pathways
Convergence pathways
Gaze holding pathways
Gaze holding pathways
MIF
(nontwitch muscle fibers)
Gaze holding/eye alignment?
SIF
(twitch muscle fibers)
Eye movement
Fig. 4. The diagram is based on the results of transsynaptic tract tracing experiments
[60], and shows that the MIF motoneurons receive afferents from premotor neural networks
associated with smooth pursuit eye movements, convergence and gaze holding, but not from
the networks generating saccades or the vestibulo-ocular reflex. In contrast, the SIF motoneurons receive inputs from saccadic and VOR pathways, and possibly the other networks too.
The difference in connectivity of MIFs and SIFs means a difference in function, and it is suggested that the SIFs may drive fast eye movements, while MIFs control muscle tension.
It is not easy to identify MIF motoneurons physiologically, possibly
because they are smaller than SIF motoneurons, or because they do not gather
together to form large identifiable groups, but rather lie around the perimeter of
the motor nuclei in thin sheets. Thus, the differences between SIF and MIF
motoneuron activity suggested by anatomical experiments have not yet been
confirmed by physiological recordings.
A Proprioceptive Hypothesis
Given that we now have recognized the identity and location of at least
some of the MIF motoneurons innervating tonic nontwitch muscle fibers, and
found them to possess very different properties than the SIF motoneurons, we
must now ask what role they play in oculomotor control [32, 52]. The MIF muscle
fibers of the global layer extend throughout the length of the eye muscle [61],
contract more slowly than SIFs, are fatigue resistant [6], and are driven by ton-
Büttner-Ennever
10
ically firing units [12, 62, 63]. It is not clear how much they contribute to the
tension of eye muscles in natural conditions; but experimentally exposing eye
muscle to succinyl choline, which causes the contraction of MIFs alone, causes
tension changes, and indicates that MIF could contribute to tension in the eye
muscle [64]. As discussed earlier in this chapter, MIFs are coupled with palisade endings at their tips in the myotendinous junction. Since palisade endings
are putative sensory receptors, the MIF-palisade combination has been compared to an immature Golgi tendon organ [45], or an inverted muscle spindle,
where the MIF represents an overgrown nuclear bag fiber and the palisade ending its displaced primary sensory endings [65]. It is possible that this structure
could provide a sensory or proprioceptive feedback signal to the central nervous system, and its afferent signal would be modulated by the activity of the
MIF motoneurons. It is still too early to decide what role MIF motoneurons
play in the control of eye movements, but currently evidence supports the idea
that the SIF or twitch motoneurons primarily drive the eye movements, whereas
the MIF or nontwitch, or tonic motoneurons participate in determining tonic
muscle activity, as in eye alignment, vergence and gaze holding.
Conclusions
Current evidence supports the concept that MIF motoneurons carry a tonic
eye position signal, and the SIF, or twitch, motoneurons an additional phasic
signal driving the actual eye movements. The role of MIFs and palisade endings
is still speculation. However, they are constant features of human eye muscles,
and they draw attention to the myotendinous junction. In the light of the MIFpalisade proprioceptive hypothesis, it is possible that the myotendinous junction
is a site from which sensory signals can be sent to the central nervous system,
and in turn influence muscle tension and perhaps eye alignment. This hypothesis should be considered seriously in the plans for the surgical operations for
strabismus. In strabismus, the myotendinous junction has been reported to be
the site of muscle damage and abnormal innervation [66–68]. But further investigations and experiments are necessary before there is a full understanding of
these structures in the sensory-motor control of the eye position.
Acknowledgement
This research was supported by the German Research Council (DFG) (Ho 1639/4-1).
Anatomy of the Oculomotor System
11
References
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Spencer RF, Porter JD: Biological organization of the extraocular muscles. Prog Brain Res
2006;151:43–80.
Donaldson IML: The functions of the proprioceptors of the eye muscles. Philos Trans R Soc Lond
B Biol Sci 2000;355:1685–1754.
Ruskell GL: Extraocular muscle proprioceptors and proprioception. Prog Retin Eye Res
1999;18:269–291.
Porter JD, Baker RS, Ragusa RJ, Brueckner JK: Extraocular muscles: basic and clinical aspects of
structure and function. Surv Ophthalmol 1995;39:451–484.
Wasicky R, Zhya-Ghazvini F, Blumer R, Lukas JR, Mayr R: Muscle fiber types of human extraocular muscles: a histochemical and immunohistochemical study. Invest Ophthal Vis Sci
2000;41:980–990.
Morgan DL, Proske U: Vertebrate slow muscle: its structure, pattern of innervation, and mechanical properties. Physiol Rev 1984;64:103–138.
Chiarandini DJ, Stefani E: Electrophysiological identification of two types of fibres in rat extraocular muscles. J Physiol 1979;290:453–465.
Jacoby J, Chiarandini DJ, Stefani E: Electrical properties and innervation of fibers in the orbital
layer of rat extraocular muscles. J Neurophysiol 1989;61:116–125.
Nelson JS, Goldberg SJ, McClung JR: Motoneuron electrophysiological and muscle contractile
properties of superior oblique motor units in cat. J Neurophysiol 1986;55:715–726.
Chiarandini DJ, Jacoby J: Dependence of tonic tension on extracellular calcium in rat extraocular
muscle. Am J Physiol 1987;253:C375–C383.
Jacoby J, Ko K, Weiss C, Rushbrook JI: Systematic variation in myosin expression along extraocular muscle fibres of the adult rat. J Muscle Res Cell Motil 1990;11:25–40.
Straka H, Dieringer N: Basic organization principles of the VOR: lessons from frogs. Prog
Neurobiol 2004;73:259–309.
Barker D: The morphology of muscle receptors; in Barker D, Hunt CC, McIntyre AK (eds):
Muscle Receptors. Berlin, Springer, 1974, pp 1–190.
Maier A, DeSantis M, Eldred E: The occurrence of muscle spindles in extraocular muscles of various vertebrates. J Morph 1974;143:397–408.
Cilimbaris PA: Histologische Untersuchungen über die Muskelspindeln der Augenmuskeln. Arch
Mikrosk Anat Entwicklungsgesch 1910;75:692–747.
Lukas JR, Aigner M, Blumer R, Heinzl H, Mayr R: Number and distribution of neuromuscular
spindles in human extraocular muscles. Invest Ophthalmol 1994;35:4317–4327.
Mahran ZY, Sakla FB: The pattern of innervation of the extrinsic ocular muscles and the intraorbital ganglia of the albino mouse. Anat Rec 1965;152:173–184.
Blumer R, Konakci KZ, Brugger PC, Blumer MJF, Moser D, Schoefer C, et al: Muscle spindles and
Golgi tendon organs in bovine calf extraocular muscle studied by means of double-fluorescent labeling, electron microscopy, and three-dimensional reconstruction. Exp Eye Res 2003;77:447–462.
Bruenech JR, Ruskell GL: Myotendinous nerve endings in human infant and adult extraocular
muscles. Anat Rec 2000;260:132–140.
Bruenech JR, Ruskell GL: Muscle spindles in extraocular muscles of human infants. Cell Tissue
Organs 2001;169:388–394.
Ruskell GL: The fine structure of human extraocular muscle spindles and their potential proprioceptive capacity. J Anat 1989;167:199–214.
Blumer R, Lukas JR, Aigner M, Bittner R, Baumgartner I, Mayr M: Fine structural analysis of
extraocular muscle spindles of a two-year-old human infant. Invest Ophthalmol 1999;40:55–64.
Harker DW: The structure and innervation of sheep superior rectus and levator palpebrae extraocular eye muscles. II. Muscle spindles. Invest Ophthalmol Vis Sci 1972;11:970–979.
Walro JM, Kucera J: Why adult mammalian intrafusal and extrafusal fibers contain different
myosin heavy-chain isoforms. Trends Neurosci 1999;22:180–184.
Sekiya S, Homma S, Miyata Y, Kuno M: Effects of nerve growth factor on differentiation of muscle spindles following nerve lesion in neonatal rats. J Neurosci 1986;6:2019–2025.
Büttner-Ennever
12
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
Kucera J, Cooney W, Que A, Szeder V, Stancz-Szeder H, Walro J: Formation of supernumerary
muscle spindles at the expense of Golgi tendon organs in ER81-deficient mice. Dev Dyn
2002;223:389–401.
Fan G, Copray S, Huang EJ, Jones K, Yan Q, Walro J, et al: Formation of a full complement of cranial proprioceptors requires multiple neurotrophins. Dev Dyn 2000;218:359–370.
Dogiel AS: Die Endigungen der sensiblen Nerven in den Augenmuskeln und deren Sehnen beim
Menschen und den Säugetieren. Arch Mikrosk Anat 1906;68:501–526.
Tozer FM, Sherrington CS: Receptors and afferents of the third, fourth and sixth cranial nerves.
Proc R Soc London Ser 1910;82:451–457.
Eberhorn AC, Horn AKE, Eberhorn N, Fischer P, Boergen KP, Büttner-Ennever JA: Palisade endings in extraocular eye muscles revealed by SNAP-25 immunoreactivity. J Anat 2005;205:307–315.
Weir CR, Knox PC, Dutton GN: Does extraocular muscle proprioception influence oculomotor
control? Br J Ophthalmol 2000;84:1071–1074.
Büttner-Ennever JA, Horn AKE, Graf W, Ugolini G: Modern concepts of brainstem anatomy:
from extraocular motoneurons to proprioceptive pathways. Ann N Y Acad Sci 2002;956:75–84.
Lukas JR, Blumer R, Denk M, Baumgartner I, Neuhuber W, Mayr R: Innervated myotendinous
cylinders in human extraocular muscles. Invest Ophthal Vis Sci 2000;41:2422–2431.
Konakci KZ, Streicher J, Hoetzenecker W, Haberl I, Blumer MJF, Wieczorek G, et al: Palisade
endings in extraocular muscles of the monkey are immunoreactive for choline acetyltransferase
and vesicular acetylcholine transporter. Invest Ophthalmol Vis Sci 2005;46:4548–4554.
Büttner-Ennever JA, Konakci KZ, Blumer R: Sensory control of extraocular muscles. Prog Brain
Res 2006;151:81–93.
Richmond FJR, Johnston WSW, Baker RS, Steinbach MJ: Palisade endings in human extraocular
muscle. Invest Ophthal Mol Vis Sci 1984;25:471–476.
Konakci KZ, Streicher J, Hoetzenecker W, Blumer MJF, Lukas JR, Blumer R: Molecular characteristics suggest an effector function of palisade endings in extraocular muscles. Invest
Ophthalmol 2005;46:155–165.
Mayr R: Funktionelle Morphologie der Augenmuskeln; in Kommerell G (ed):
Augenbewegungsstörungen: Neurologie und Klinik. München, JF Bergmann, 1977, pp 1–15.
Alvarado-Mallart RM, Pincon Raymond M: The palisade endings of cat extraocular muscles: a
light and electron microscope study. Tissue Cell 1979;11:567–584.
Sas J, Schab R: Die sogenannten ‘Palisaden-Endigungen’ der Augenmuskeln. Acta Morph Acad
Sci (Hungary) 1952;2:259–266.
Gentle A, Ruskell GL: Pathway of the primary afferent nerve fibres serving proprioception in
monkey extaocular muscles. Ophthal Mic Physiol Opt 1997;17:225–231.
Billig I, Buisseret -Delmas C, Buisseret P: Identification of nerve endings in cat extraocular muscles. Anat Rec 1997;248:566–575.
Ruskell GL: Golgi tendon organs in the proximal tendon of sheep extraocular muscles. Anat Rec
1990;227:25–31.
Blumer R, Lukas JR, Wasicky R, Mayr R: Presence and morphological variability of Golgi tendon
organs in the distal portion of sheep extraocular muscle. Anat Rec 2000;258:359–368.
Zelená J, Soukup T: The development of Golgi tendon organs. J Neurocytol 1977;6:171–194.
Nicholson H: On the presence of ganglion cells in the third and sixth nerves of man. J Compar
Neurol 1924;37:31–36.
Palmieri G, Bo Minelli L, Acone F, Corriero A, Sanna M, Gazza F, et al: Further observations on
the presence of ganglion cells in the oculomotor nerves of mammals and fish: number, origin and
probable functions. Anat Histol Embryol 1999;28:109–113.
Donaldson IML, Long AC: Interactions between extraocular proprioceptive and visual signals in
the superior colliculus of the cat. J Physiol 1980;298:85–110.
Donaldson IML, Knox PC: Afferent signals from the extraocular muscles affect the gain of the
horizontal vestibular-ocular reflex in the alert pigeon. Vision Res 2000;40:1001–1011.
Knox PC, Weir CR, Murphy PJ: Modification of visually guided saccades by nonvisual afferent
feedback signal. Invest Ophthal Mol Vis Sci 2000;41:2561–2565.
Weir CR, Knox PC: Modification of smooth pursuit initiation by a nonvisual, afferent feedback
signal. Invest Ophthalmol 2001;42:2297–2302.
Anatomy of the Oculomotor System
13
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
Büttner-Ennever JA, Horn AKE, Scherberger H, D’Ascanio P: Motoneurons of twitch and nontwitch extraocular muscle fibers in the abducens, trochlear, and oculomotor nuclei of monkeys.
J Comp Neurol 2001;438:318–335.
Büttner U, Büttner-Ennever JA: Present concepts of oculomotor organization. Prog Brain Res
2006;151:1–42.
Keller EL, Robinson DA: Abducens unit behavior in the monkey during vergence movements.
Vision Res 1972;12:369–382.
Dean P: Motor unit recruitment in a distribution model of extraocular muscle. J Neurophysiol
1996;76:727–742.
Fuchs AF, Kaneko CR, Scudder CA: Brainstem control of saccadic eye movements. Annu Rev
Neurosci 1985;8:307–337.
Miller JM, Bockisch CJ, Pavlovski DS: Missing lateral rectus force and absence of medial rectus
co-contraction in ocular convergence. J Neurophysiol 2002;87:2421–2433.
Ling L, Fuchs AF, Phillips JO, Freedman EG: Apparent dissociation between saccadic eye movements and the firing patterns of premotor neurons and motoneurons. J Neurophysiol 1999;82:
2808–2811.
Wasicky R, Horn AKE, Büttner-Ennever JA: Twitch and non-twitch motoneuron subgroups of the
medial rectus muscle in the oculomotor nucleus of monkeys receive different afferent projections.
J Comp Neurol 2004;479:117–129.
Ugolini G, Klam F, Doldan Dans M, Dubayle D, Brandi A-M, Büttner-Ennever JA, et al:
Horizontal eye movement networks in primates as revealed by retrograde transneuronal transfer of
rabies virus: differences in monosynaptic input to ‘slow’ and ‘fast’ abducens motoneurons. J
Comp Neurol 2006;498:762–785.
Mayr R, Gottschall J, Gruber H, Neuhuber W: Internal structure of cat extraocular muscle. Anat
Embryol 1975;148:25–34.
Dieringer N, Precht W: Functional organization of eye velocity and eye position signals in
abducens motoneurons of the frog. J Comp Physiol 1986;158:179–194.
Lennerstrand G: Motor units in eye muscles; in Lennerstrand G, Bach-Y-Rita P (eds): Basic
Mechanisms of Ocular Motility and Their Clinical Implications. Oxford, Pergamon Press, 1975,
pp 119–143.
Bach-Y-Rita P, Alvarado J, Nichols K, McHolm G: Extraocular muscle fibres: ultrastructural identification of iontophoretically labeled fibers contracting in response to succinylcholine. Invest
Ophthalmol Vis Sci 1977;16:561–565.
Steinbach MJ: The palisade ending: an afferent source for eye position information in humans; in
Lennerstrand G, Ygge J, Laurent T (eds): Advances in Strabismus Research: Basic and Clinical
Aspects. London, Portland Press, 2000, pp 33–42.
Corsi M, Sodi A, Salvi G, Faussone-Pellegrini MS: Morphological study of extraocular muscle
proprioceptor alterations in congenital strabismus. Ophthalmologica 1990;200:154–163.
Domenici-Lombardo L, Corsi M, Mencucci R, Scrivanti M, Faussone-Pellegrini MS, Salvi G:
Extraocular muscles in congenital strabismus: muscle fiber and nerve ending ultrastructure
according to different regions. Ophthalmologica 1992;205:29–39.
McNeer KW, Spencer RF: The histopathology of human strabismic extraocular muscle; in
Lennerstrand G, Zee DS, Keller EL (eds): Functional Basis of Ocular Motility Disorders. Oxford,
Pergamon Press, 1981, pp 27–37.
Prof. Dr. med. Jean A. Büttner-Ennever
Institute of Anatomy, Ludwig-Maximilian University
Pettenkoferstrasse 11
DE–80336 Munich (Germany)
Tel. ⫹49 89 5160 4851, Fax ⫹49 89 5160 4857
E-Mail [email protected]
Büttner-Ennever
14
Straube A, Büttner U (eds): Neuro-Ophthalmology.
Dev Ophthalmol. Basel, Karger, 2007, vol 40, pp 15–34
Eye Movement Recordings: Methods
Thomas Eggert
Department of Neurology, LMU Munich, Munich, Germany
Abstract
The development of oculomotor research is closely related to the development of the
technology of eye movement recordings. The first part of this chapter summarizes some cornerstones of the history of eye movement recordings from the 18th century until today and
explains the technical principles of the early antecedents of modern recording devices. The
four most common recording techniques (electro-oculogram, infrared reflection devices,
scleral search coil, and video-oculography) are then compared with respect to the most
important system parameters: spatial resolution, temporal resolution, the capability to simultaneously record the multiple degrees of freedom of the eye, the setup complexity, system
specific artifacts, and invasiveness. These features determine the suitability of these devices
in particular applications.
Copyright © 2007 S. Karger AG, Basel
Visual perception provides us with the illusion of a visual world that is
continuously available within the complete field of fixation. Subjectively we
are unaware of using saccadic eye movements to scan our visual environment
with a small fovea (diameter about 5⬚) because we perceive a stable visual
world. Similarly, we do not directly perceive the stabilizing eye movements we
make, such as the vestibular ocular reflex or the optokinetic reflex. Therefore,
before the actual dynamics of eye movements could be discovered, careful
examination was needed. In particular, the development of eye movement
recording techniques played a crucial role in this research. Some historical cornerstones of this development will be summarized in the first part of this chapter. References to the history of eye movement research and recording
techniques from the 18th and 19th centuries are mainly based on the work of
Wade et al. [1] and Wade and Tatler [2], who provided excellent reviews of this
field. The second part of this chapter will focus on three methods that are still
relevant today.
a
b
Fig. 1. Huey’s [10] lever device to record horizontal eye movements. a Eye movements
made during reading were recorded with this technique; from Huey [11]. b The tracing on the
smoked drum was photographed and then engraved; from Wade et al. [1].
History of Eye Movement Recording
Very early qualitative descriptions of eye movements originated at the
beginning of the 18th century [3]. More accurate descriptions, based on the
observation of afterimages, were made at the end of the 18th century. Using this
method, Wells [4] described the slow and fast phases of vestibular nystagmus.
The occurrence of saccades during reading was first reported by Javal [5] and
Lamare [6], who used a rubber tube connected to the conjunctiva and both ears.
With this device, each eye movement caused a sound that was heard. Hering [7]
used a similar acoustic device in combination with the technique of afterimages. The first attempts to record eye movements were made at the end of the
19th century. Ahrens [8], Delabarre [9], and Huey [10, 11] used devices consisting of a lever attached to a plaster eyecup. A bristle at the end of the lever
recorded the eye movements on the smoked drum of a kymograph. A schematic
outline of the system used by Huey [11] and an original recording are shown in
figure 1. This method had the fundamental drawback that the inertial forces
between apparatus and eye could injure the eye mechanically. The device was
also too heavy for the large accelerations occurring during saccades. To overcome this problem, Javal [12] suggested recording the reflection of a light beam
from a little mirror attached to the conjunctiva, a method that was not successfully applied before von Romberg and Ohm [13] used it to measure ocular torsion. This technique was, however, still too invasive to be adopted by many
researchers.
Eggert
16
A more elegant approach that avoided mechanical contact with the eye was
chosen by Dodge and Cline [14]. They developed the first photographic method
and recorded the corneal reflection of a bright vertical line on a moving photographic plate. This system can be considered an early antecedent of the modern
system that uses light reflections from the cornea and the lens to measure the
orientation of the eye without having any contact with it. These so-called double
Purkinje image (DPI) eye trackers [15] reach very high resolution (⬍0.017⬚),
accuracy (0.017⬚), and bandwidth (500 Hz) (DPI Eyetracker Gen 5.5, Fourward
Technologies, Inc., Buena Vista, Va., USA). However, their accuracy is much
lower during the high accelerations and decelerations of saccades, because the
lens is not rigidly but elastically connected to the eyeball. This causes the large
dynamic overshoot of saccade traces recorded with DPI eye trackers [16]. The
very high accuracy of the DPI eye tracker during steady fixation is due to the
fact that they use the angular differences between light reflections which are
insensitive to small translations between the eye and the tracker. The complex
mechanics involved in DPI trackers make these devices very expensive
(monocular: USD 60,000; binocular USD 115,000).
The electro-oculogram (EOG) was developed as another means to avoid
any mechanical contact with the eye. The history of the EOG was described by
Brandt and Büchele [17]. Schott [18] and Meyers [19] measured electrical
potentials with skin electrodes attached near the eye. They erroneously assumed
that changes of the measured potentials were mainly related to electrical activity of the eye muscles. Mowrer et al. [20] discovered that the EOG is primarily
caused by the electrical dipole between cornea and retina, which moves with the
eye. Jung [21] applied this method to record horizontal and vertical components
of the eye position simultaneously. This signaled a remarkable progress, since
previous recording techniques had been restricted to one movement direction
only. Moreover, the EOG is still the only measurement technique that allows to
record eye movements while the eyes are closed. This is of particular interest
for sleep research. The EOG will be described in more detail in the second part.
The second noninvasive measurement technique to become widely used is
based on the intensity of infrared light reflected from the eye. Infrared reflection devices (IRDs) measure the intensity of these reflections by photosensitive
elements placed at different locations in front the eye. The differences between
these measures are used to determine the eye position. The first system of this
type was developed by Torok et al. [22]. A modern variant of the IRD will be
discussed later in the second part. Because fiber optic cables can be used to spatially separate the location where light intensity is collected and the location of
the photodiodes used to measure the intensity, this method was also adopted for
eye movement recordings together with functional magnetic resonance imaging
techniques [23].
Eye Movement Recordings: Methods
17
None of the recording methods mentioned so far were able to quantify all
three rotatory degrees of freedom of the eye simultaneously. Vertical and horizontal movement components could be quantified by the EOG, IRD, or the DPI
tracker, but these devices cannot measure the orientation of the eye around the
axis of view (ocular torsion), which is of special interest when examining the
coordination of the three pairs of eye muscles. Von Romberg and Ohm [13]
measured pure ocular torsion (during straight-ahead fixation) with their mirror
system mentioned above. Howard and Evans [24] give a more detailed review
of the early history of the measurement of ocular torsion. Already in the 19th
century, the technique of afterimages had provided important findings about
ocular torsion during fixation. Ruete [25] described the relation between gaze
direction and ocular torsion and attributed it to his friend Listing (professor of
mathematical physics in Göttingen) [26]. Von Helmholtz [27] discovered most
of the geometric implications of ‘Listing’s law’. This field of research became
of increasing interest when the magnetic search coil technique developed by
Robinson [28] and Collewijn et al. [29] was extended by Collewijn et al. [30]
and Kasper and Hess [31] to cover 3-D movements. The method is based on the
voltages induced in coils by two or three orthogonal, rapidly alternating magnetic fields. The coils are embedded in a soft plastic annulus that adheres elastically to the eyeball. One coil is sufficient to measure gaze direction. Two coils
with different orientations must be molded in the plastic annulus to measure
gaze direction and ocular torsion simultaneously. The search coil method combines high spatial and temporal resolution and is so far the most precise method
for measuring ocular torsion during eccentric gaze. With this technique it
became possible to extend Helmholtz’s 3-D analysis of fixation to the full range
of oculomotor performance [32].
Like other methods based on contact lenses, the search coil technique has
the main disadvantage of being invasive. Therefore, considerable effort was
made to evaluate the 3-D eye position on the basis of photographic images of
the eye. All photographic methods are based on the detection and localization of
eye-fixed markers (pupil, limbus, iris signatures, episcleral blood vessels) in
image coordinates. The eye position with respect to the head can be computed
from these image coordinates if the camera is firmly attached to the head.
Otherwise, head-fixed markers can be used to compensate for relative translations between head and camera. Pioneers in these techniques, Brecher [33],
Miller [34], Howard and Evans [24], detected and localized these markers manually and individually for each image. Howard and Evans [24] described a
method for computing 3-D angular eye positions from the image coordinates of
the markers.
Video-oculography (VOG), defined as the use of these methods for dynamic
measure of eye movements, became feasible with the rapid development of
Eggert
18
computer-based automatic image processing. This progress is mainly reflected
(1) in the frame rates being processed online and (2) in the robustness and the
accuracy of the marker detection algorithms. Both improve with the increase in
computational power. Young et al. [35] detected the image position and orientation of the eye marker online at a frame rate of 60 Hz. Clarke et al. [36] could
process frame rates up to 400 Hz. This temporal resolution is sufficient to cover
the temporal bandwidth of physiological eye movements. The automatic detection and localization of the pupil do not need very complicated image processing, are relatively robust, and do not require very complicated algorithms. Since
the measurement of the 2-D gaze direction in VOG is primarily based on the
localization of the pupil, the 2-D VOG works reliably in head-mounted systems
and with stabilized head positions. To compute the 3-D eye position, the orientation of the iris signature can be used. This signature must be scanned along a
circular path close to the limbus, in order to be insensitive to changes of the
pupil diameter. Direct polar cross-correlation of the iris signature at the actual
eye position with that of a reference position can be used to measure ocular torsion. This works well while gaze is pointing straight ahead, but geometric distortions of the iris occurring at eccentric gaze positions lead to large errors.
Haslwanter and Moore [37] observed errors of up to 8.7⬚ for 20⬚ horizontal and
vertical eccentricities, and developed a method to correctly compensate for
these errors. However, this technique may be difficult to apply in subjects with
little iris structure. To reduce the computational effort and to increase the
precision of VOG, some applications used artificial markers on the eye because
they can be detected and tracked more easily than natural markers like iris signatures or episcleral blood vessels. Young et al. [35], for example, used a human
hair mounted in a soft contact lens sandwich. As already proposed by
Nakayama [38], Clarke et al. [36] applied two high-contrast tincture landmarks
on the limbus.
Principles of Eye Movement Recordings: Advantages and
Disadvantages
The Electro-Oculogram
The simplest method for measuring human eye movements is based on the
feature that the human eye is an electrical dipole. The axis of this dipole and the
optical axis of the human eye are roughly collinear. The retina is more negative
than the cornea. The potential difference of about 6 mV results from the electrical activity of photoreceptors and neurons in the retina. Changes of this potential induced by sudden light stimulus can be used to monitor the electrical
activity of the retina (electroretinogram, ERG). However, the EOG uses the fact
Eye Movement Recordings: Methods
19
that this dipole rotates with the rotation of the eye. This causes small differences
between the electrical potential at the skin surface depending on eye position. A
rightward eye movement will increase the surface potential at the temporal canthus of the right eye, and decrease the surface potential at the temporal canthus
of the left eye. The potential differences are in the range of a few ␮V and can be
measured with a bitemporal electrode configuration. The voltages are usually
referenced to a third electrode that is generally placed at one of the mastoid
processes or on the earlobe [17, 39]. Placing two electrodes bitemporally has
the advantage that the measured voltage is linearly related to the horizontal eye
position within a range of ⫾25⬚. Because eye movements are largely conjugate
under far-viewing conditions, this electrode configuration is frequently used,
even though it does not permit inference about differences between left and
right eye movements. To simultaneously record vertical eye movements, two
additional electrodes must be placed below and above the eye. Vertical EOG
signals are less reliable than horizontal ones due to lid artefacts. SchmidPriscoveanu and Allum [40] observed systematic overestimation of vertical
EOG velocity compared to VOG.
The resolution of both horizontal and vertical EOG signals is limited by
noise. Three different noise sources can be distinguished. (1) Inductive noise
related to electromagnetic fields in the environment is reduced by relating the
measured voltages to the reference electrode; however, it cannot be completely
eliminated due to residual asymmetries between the three electrodes. (2) Thermal
noise is generated by the input resistance of the amplifier and the contact resistance of the skin electrodes. In addition, an increased contact resistance also
changes the voltage divider at the input of the amplifier, which in turn leads to
a further decrease of the signal-to-noise ratio. To lower the contact resistance,
the skin should be cleaned with alcohol or a commercial skin-preparing material. Electrodes should be made of relatively nonpolarizeable material such as
silver-silver chloride or gold. The electrodes should be applied with a conductive paste. (3) Finally, capacitive noise is due to electrical activity of muscles
and neurons. Subjects should be instructed to avoid any movements except eye
movements. Especially the face and chewing muscles should stay as relaxed as
possible. Changes of the dark adaptation level induce slow drifts of the corneoretinal potential which are superimposed on the EOG signal. Since both the
EOG and ERG measure the corneoretinal potential, the standards of ERG
recordings as specified by Marmor and Zrenner (1999) [41] can also be recommended for EOG recordings.
To compare EOG recordings with IRD (see below), we applied both methods simultaneously to measure horizontal saccades between ⫾5⬚ (symmetrical
around the straight ahead position; amplitude: 10⬚). The EOG was recorded
binocularly with the electrodes placed bitemporally. Eye position signals were
Eggert
20
filtered using a low pass filter excluding frequency components above 50 Hz.
Eye position traces were calibrated separately for each saccade and for both
recording systems, based on the mean eye position signals averaged across windows with a duration of 200 ms, starting 300 ms before and 500 ms after the
saccade. The beginning and end of the saccade were defined by the time at
which eye velocity increased above or fell below 10% of the peak velocity of
the saccade. Saccade amplitude was defined as the difference of eye position
between the end and the beginning of the saccade. We observed a mean saccade
amplitude of 9.4⬚, which was systematically smaller than the target amplitude
(10⬚). This saccadic undershoot is typical for reflexive saccades to stepping targets and does not occur with targets that are continuously visible [42]. We did
not find significant differences in eye amplitude between an IRD recording and
the binocular EOG. Schmid-Priscoveanu and Allum [40] evaluated average horizontal slow-phase velocities induced by optokinetic nystagmus, vestibular nystagmus, and smooth pursuit using (subsequent) EOG and IRD recordings. They
observed similar slow-phase velocity estimates.
To measure movements of the right or the left eye only, skin electrodes can
be placed at the temporal and the nasal canthus of one eye. This nasal-temporal
configuration is difficult to handle, because the EOG voltage is influenced by
the electrical activity of eye muscles and eye lids (electromyogram). Whereas
the electromyogram activity of the right and left lateral rectus muscle cancel
each other in the symmetrical bitemporal configuration, this symmetry is not as
perfect in the nasal-temporal configuration. This can cause nonlinearity in the
relation between horizontal eye position and measured voltage, and it may even
cause asymmetries in the velocity gain between nasal and temporal saccades.
We quantified this asymmetry by measuring the same symmetrical saccade paradigm as described above (amplitude 10⬚) with a nasal-temporal EOG of the
right eye. Again a simultaneous IRD recording of the same eye was performed.
Consistent with results obtained with search coil recordings [42], the IRD measurement correctly indicated that abducting saccades have larger amplitudes
than adducting saccades (fig. 2). Therefore, the opposite adducting-abducting
asymmetry indicated by the EOG recording (fig. 2) seems to reflect a systematic error of the nasal-temporal electrode configuration.
We also analyzed the noise characteristic of the EOG using the same nasaltemporal electrode configuration. Representative examples of the resulting
traces are shown in figure 3. The irregular oscillation of the EOG trace reflects
a peak of the spectral power of the EOG signal close to 10 Hz. The root mean
square (RMS) difference between IRD and EOG position signals was 0.26⬚.
Because the changes of the IRD signal during the initial fixation stayed within
⫾0.05⬚, this noise can be almost completely assigned to the EOG signal. This
leads to a resolution of the EOG signal (defined as its 95% confidence interval)
Eye Movement Recordings: Methods
21
140
EOG
IRD
Right eye gain (%)
120
100
80
60
Adducting
Abducting
Fig. 2. Mean gain saccades of the right eye (i.e. the ratio between saccade amplitude
and target amplitude) to symmetric target steps of 10⬚ as measured with monocular EOG and
IRD. The monocular EOG overestimates the amplitude of adducting saccades and underestimates the amplitude of abducting saccades. For IRD recording, a commercial system (IRIS,
Skalar) was used.
of about ⫾0.5⬚. Thus, the EOG cannot reliably be used for movement amplitudes of less than 5⬚, a condition that is fulfilled in many clinical applications.
Infrared Reflection Devices
In contrast to DPI eye trackers, IRDs do not determine the direction of a
light beam reflected from the cornea, but measure the intensity of infrared light
reflected from the eye at certain fixed locations close to the eye. Light intensity
is measured with photo diodes that have a high temporal resolution. The distance between eye and photoreceptors is in the range of 1 cm. At such small distances, the differences in the intensity between the different photodiodes
depend mainly on the position of iris and pupil, which reflect less light than the
sclera. IRDs are very sensitive to relative translations of the photodiodes and
the eye because they do not evaluate the angle, but only the intensity of the
reflection. For an eye radius of 1.25 cm, a translational error of 1 mm will lead
to an eye position error of almost 5⬚. The system must therefore be firmly
attached to the head. IRDs have a much lower noise level than EOG, but they
suffer from eye lid artifacts that critically depend on the position of the photodiodes. These lid artifacts may increase dramatically if the device is not properly adjusted in front of the eye. Lid artifacts are more pronounced for vertical
than for horizontal eye movements. Moreover, the position of the photodiodes is
Eggert
22
6
EOG
IRD
Target
Position (degrees)
4
2
0
⫺2
⫺4
⫺6
0
100
200
300
400
500
Time (ms)
Fig. 3. Recording of a horizontal symmetrical saccade to a target step starting at 5⬚
eccentricity at the right side and ending at 5⬚ eccentricity on the left side. The solid traces
show the horizontal eye position of the right eye simultaneously recorded with the monocular
EOG and IRD. The noise level of the EOG is much higher that of the IRD. The amplitude of
the leftward saccade of the right eye (adducting) is overestimated by the EOG (fig. 2).
also critical for the system linearity. Due to these features, optimal adjustment
of the device requires that the experimenter carefully controls the eye position
signal of the IRD and compares it with the eye movements. A useful method to
control the subject’s eye movements during the adjustment is to manually guide
the head movements of the subject while the subject is fixating a space-fixed
target. System setup may be very difficult or even impossible for subjects with
narrow palpebral fissures. Because of the sensitivity of the overall transfer
function (IRD signal/eye position) to translation, it is recommended to collect
calibration data not only at the beginning or the end of a recording, but at regular time intervals.
We tested the temporal stability of the calibration using a commercial IRD
(IRIS, Skalar, Delft, The Netherlands). Figure 4 shows two sets of calibration
data for one subject, the second was collected 10 min after the first. Targets
were presented at eye level at nine equidistant horizontal positions with eccentricities between ⫾20⬚. The interpolated curves are least square fits of 3rd order
polynomials. The coefficients of the polynomial were computed by minimizing
Eye Movement Recordings: Methods
23
30
Calibration 1
Calibration 2
Target position (degrees)
20
10
0
⫺10
⫺20
⫺30
500
1,000
1,500
2,000
2,500
3,000
Raw units
Fig. 4. Relation between the noncalibrated raw signal of an IRD (raw units of a 12-bit
analog to digital converter; abscissa) and the target position during fixation of that target.
Each symbol corresponds to one fixation. The second set of data is separated from the first
set by a time interval of 10 min. Solid lines indicate the fitted calibration curves (see text).
Differences between the first and the second calibration are mainly due to relative movements between the IRD and the eye caused by slip of the head mount.
the mean squared distance between the IRIS signal during fixations and the fitted curve. The distance is measured along lines parallel to the abscissa of figure
4. The curvature of the calibration curve is more pronounced in the first data set
(fig. 4; deviations from linearity: ⬍4.5⬚) than in the second data set (fig. 4;
deviations from linearity: ⬍2.8⬚). This shows that using a nonlinear calibration
is indeed profitable for accuracy. The difference between the two subsequent
calibrations can largely vary between subjects and amounts up to 10⬚ in the
given example. We conclude that the calibration of an IRD can be substantially
improved by considering temporal drifts of gain, offset, and nonlinearity.
Search Coil
The scleral search coil system measures the voltages in one or two coils
induced by two or three rapidly oscillating magnetic fields. The coils are
molded in a soft contact annulus that is attached to the eyeball. The magnetic
fields are generated by three pairs of large coils, mounted in a cubic frame. The
subject’s head is positioned in its center. The field coils should be large, because
the homogeneity of the magnetic field is crucial for the precision of the measurement. With pairs of square-shaped coils, arranged in a cubic configuration,
the inhomogeneity inside of a central test cube stays below 5% when the edge
Eggert
24
Torsional coil
Directional coil
Fig. 5. Technique for molding two coils with almost orthogonal effective planes in a
single contact annulus. The directional coil is wound in a single plane that is orthogonal to
the viewing axis. The torsional coil is wound in the shape of an ‘eight’. A magnetic field
aligned to the axis of view will induce identical, but opposite voltages in both parts of this
‘eight’. These voltages cancel each other. Therefore, the axis of view is a null direction of the
torsional coil. Consequently, because by definition the vector of any null direction lies in the
efficient plane of a coil, the efficient planes of directional and torsional coils are orthogonal.
length of the test cube approaches one fifth of the edge length of the field coil
[43]. This means that when using field coils with an edge length of 1.5 m, subjects should not move by more than 7 cm. The basic principle of the relation
between induced voltage and coil orientation is the following.
The voltage induced by one of the magnetic fields in the scleral search coil
is proportional to the projection of the coil vector (defined as the vector orthogonal to the effective coil plane) onto the magnetic field vector. Thus, the three
voltages induced by three orthogonal magnetic fields form the vector components of the coil vector expressed in field coordinates. A dual search coil for
recording 3-D eye orientation provides six voltages, corresponding to the two
3-D coil vectors of the directional and the torsional coil (fig. 5). Methods to
compute the 3-D eye orientations from these six signals were described by
Tweed et al. [44]. This simple principle is complicated by a number of potential
sources of errors: (1) cross-coupling of horizontal, vertical, and frontal field
caused by misalignment of the three magnetic fields and the three orthogonal
axes of the head-fixed Cartesian reference frame; (2) inhomogeneity of the magnetic fields; (3) offset voltages related to induction in the connecting line of the
search coil; (4) misalignment between coil vector and gaze vector. To overcome
these problems, search coil recordings require a calibration procedure that is
often based on multiple fixations on targets at various positions. The calibration
parameters are computed by minimizing the errors between the calibrated gaze
vector and target vectors. Systems with only two magnetic fields are usually
calibrated in this way. The disadvantage of this method is that it cannot be used
with oculomotor pathologies that prevent accurate fixation. Systems with three
Eye Movement Recordings: Methods
25
magnetic fields can be objectively calibrated [45], i.e. their calibration does not
rely on accurate fixation of targets at different positions, as most other recording
techniques. The calibration method described by Bartl et al. [45] evaluates the
gain matrix of the 3-D search coil system based on an objective measurement of
the direction of the three magnetic fields. Only a single fixation target is needed
in order to determine the orientation of the coil with respect to the eye.
Another important advantage of 3-field systems over 2-field systems is
that the orientation of the coil vector can be determined without knowledge of
the actual inductance of the scleral search coil. This is because changes in
inductance will have the same proportional effect on all three voltages and can
easily be eliminated by normalization.
With the search coil technique, the inherent system noise of horizontal and
vertical eye position has been estimated to be on the order of 0.5 min of arc
(0.0083⬚) [29]. With a dual search coil and a 3-field system (Remmel Labs,
Ashland, Mass., USA) using a 12-bit analog to digital converter, we measured a
system noise of 0.007⬚ for horizontal and vertical eye positions and 0.025⬚ for
torsional eye position. The system noise was defined as the standard deviation of
the eye position signal from its mean when the coil was objectively fixed in
space. Data were sampled at 1 kHz. The larger system noise of the torsional eye
position is due to the smaller inductivity of the torsional coil (fig. 5). It should be
noted that the actual resolution of the calibrated coil signal depends very much
on the amplifier gain which should make optimal use of the dynamic range of
the recording device (usually analog to digital converters). The system resolution
is a very important parameter; it determines the smallest eye movement that can
be detected. However, to compare the metrics of eye movements between different subjects or with a stimulus- defined requirement the accuracy is more important than the system noise. The system accuracy of search coils depends mainly
on the quality of the calibration. Imai et al. [46] used an artificial eye to evaluate
the coil accuracy. They obtained mean differences between coil measure and the
set angle of the artificial eye of 0.458, 0.948, and 1.628⬚ for horizontal, vertical,
and torsional eye position, respectively. Measurement errors are mainly caused
by instabilities of the current of the field coils, temperature dependences of the
electronic circuits, and metallic parts in the neighborhood of the field coils.
These difficulties, however, can be controlled by careful handling of the system.
Due to its large signal to noise ratio and reliability, the search coil technique has been the generally accepted reference standard for eye movement
recordings for 30 years. However, the disadvantages, connected with the invasiveness of the method, have also been recognized. The search coil not only
measures eye movements, but also affects them. Frens and van der Gest [47]
found that saccades last longer (by about 8%) and become slower (by about 5%)
when subjects wear search coils in both eyes than when they do not. When only
Eggert
26
one search coil was applied, these effects did not reach significance within the
tested population, because the differences between subjects were larger. At least
in some subjects, wearing a search coil in one eye only also prolonged saccade
duration and reduced saccade velocity. It was also shown that the eye torsion,
when evaluated with the search coil, depends on the orientation of exit point of
the connecting line from the search coil. With the nasal exiting orientation of a
commercial eye coil (Skalar), Bergamin et al. [48] observed that ocular torsion
depended more on eye elevation than with a modified exit point that minimized
the contact between wire and eyelids. Changes in static torsion associated with
40⬚ change in elevation were about 2⬚ larger with the commercial search coil
than with the modified eye coil. Differences in intrasaccadic torsion between
the two different coils reached up to 5⬚. These results suggest that contact
between eye lid and coil wire can lead to substantial changes of the coupling
between gaze direction and ocular torsion.
Other disadvantages of the scleral search coil are that wearing the coil may
lead to drying, and temporal deformations of the cornea, and reduced visual acuity in the eye with the search coil. Therefore, the manufacturer of the search coil
limits wearing time to 30 min. Irving et al. [49] observed corneal deformations
of more than 3 dpt in 2 of 6 subjects and visual acuity (Snellen) of less than 6/9
in 2 subjects. These effects appeared as early as 15 min after coil insertion and
dissipated after coil removal. As the number of subjects in this study was small,
it is possible that the frequency of occurrence of such effects is less across the
population. However, in eye movement experiments involving visual tasks, particularly with binocular search coil recordings, visual acuity should be checked.
Even though most authors feel confident that the safety risks of the search coil
are relatively minor [49, 50], the discomfort induced by wearing eye coils makes
it more difficult to work with untrained volunteers. Irving et al. [49] asked subjects to rate the coil-induced discomfort on a scale between none (1) and
‘extreme discomfort’ (5). The mean subject rating on this scale was 3.0 ⫾ 0.3 at
the point of maximum discomfort (immediately before coil removal).
Video-Oculography
Video-based eye movement recordings have become more and more popular because of the rapid progress made in electronic data processing. The
devices have become affordable, the robustness of the algorithms improved, and
the range of applications expanded. Nowadays, commercial companies produce
VOG devices that can be used in an fMRI scanner (MeyeTrack, SMI, Berlin,
Germany). Most fundamental VOG techniques, as defined above, are based on
tracking of the position of eye-fixed markers in a 2-D image. These positions
have to be expressed in head-fixed coordinates. Since head-fixed markers are
difficult to obtain with high precision, one strategy of VOG systems is to attach
Eye Movement Recordings: Methods
27
the video camera as firmly as possible to the head. As long as the system is not
compensated for relative translation between camera and head, the accuracy of
VOG has a problem very similar to that of the IRD. A translation of 1 mm will
result in an error of about 5⬚. Head-fixed devices cause a problem under headfree conditions, because the stability of the head mount is not sufficient.
Because of this problem, actual VOG systems can make highly accurate measurements of eye position, only as long as the head is fixed in space.
Karmali and Shelhamer [51] compared algorithms to compensate for camera
translation by tracking specific landmarks in the surrounding of the eyes that
are supposed to move little with respect to the head. Karmali and Shelhamer
[51] were especially interested in the differences in vertical translation between
the cameras of the left and the right eye. In this study, the best results were
obtained when the upper eyelid was localized using a template matching algorithm together with 20% outlier rejection. On average, the estimate of head
translation differed by less than 1.5 pixels from a manual estimate of head position. Another method of compensating for head translation uses the relative
position of the corneal reflex of an infrared LED (Eyelink II, SR Research,
Osgode, Canada). One difficulty with this method is that using the corneal
reflection adds more noise. For eye movements of about 12–15⬚ the reflection
reaches the edge of the cornea, and can no longer be used for compensation.
Moreover, this approach relies on the topography of the cornea, which varies
between subjects. Therefore, it seems to be useful when compensating for large
translations, but may be unable to provide very high accuracy.
Since the pupil position is detected and evaluated in image coordinates, the
nonlinearity of the VOG systems (in contrast to IRDs) is well defined by the
geometry of the image projection. With parallel projection, the angular eccentricity of the eye can be approximated by the inverse sinus of the ratio of the
eccentricity of the pupil center and the eye radius, both expressed in image
coordinates. The main aim of the VOG calibration is therefore to determine the
location of the center of rotation of the eye and the radius of the eyeball.
Up to now, no objective method has been established to determine these
parameters. This is due to the following difficulties. (1) Pure rotation is an
insufficient mathematical model to describe the actual movement of the eyeball
[52] during large changes of vergence. (2) The pupil is viewed through the
cornea and therefore, the detected pupil center is subject to refractive errors.
Systems that track the limbus position [53] avoid this problem, because the limbus is closer to the eye surface than the pupil. Usual calibration methods do not
explicitly compensate for these effects but use 2-D interpolating functions to
transform the image coordinates of the pupil to 2-D eye position. The parameters of these functions are computed by minimizing the mean squared error in a
similar manner as for the IRD (see above). Van der Geest and Frens [54] used
Eggert
28
Horizontal
30
3.0
Eye position (degrees)
25
Eye position (degrees)
Vertical
3.5
20
15
10
5
2.5
2.0
1.5
1.0
Coil
VOG
0.5
0.0
0
⫺50
0
50
100
Time (ms)
150
⫺0.5
⫺50
0
50
100
Time (ms)
Fig. 6. Simultaneous recordings of an oblique saccade with a search coil and VOG.
Data from Van der Geest and Frens [54].
such a calibration (biquadratic interpolating function) for a 2-D VOG system
(Eyelink version 2.04, SR Research) and compared it with a simultaneous
recording of a 2-D coil system (fig. 6). This VOG system neither tracked the
corneal reflex nor tried to compensate for relative translation between camera
and head. While fixating targets between ⫾20⬚ horizontal and vertical eccentricity, the standard deviation of the difference of gaze position between both
systems was 0.98⬚ for the horizontal errors and 1.05⬚ for the vertical errors.
Since the accuracy of the 2-D search coil was estimated at about 0.5⬚ [46; see
above], Van der Geest and Frens [54] concluded that the ‘…video system
should be treated with care when the accuracy of fixation position is required to
be smaller than 1 deg’. This statement can be generalized for any eye movement
recording system using calibrations based on fixation data because the standard
deviation of the eye position across repeated fixation of the same target position
in healthy subjects is on the order of 1–2⬚ (fig. 4). The accuracy of a calibration
based on fixations is not better than the standard error of the fixation. For
example, nine fixations with a standard deviation of 1.8⬚ lead to a calibration
accuracy of 0.6⬚. The resolution of the 2-D VOG defined by the standard deviation of system noise measured with an artificial eye is about 0.01⬚ (details
provided by SR research). This system noise is typical and is also reached
by other modern VOG devices [55]. Since these values were obtained with
artificial eyes under optimal lighting conditions, system noise should be about
2–5 times higher with human eyes under natural conditions.
Eye Movement Recordings: Methods
29
150
Torsional eye position (degrees)
2
1
0
⫺1
⫺2
0
1
2
3
Time (s)
Fig. 7. Torsional eye position during galvanic vestibular stimulation of a subject
instructed to fixate straight ahead. Two dark artificial markers were applied outside and close
to the limbus. The two traces show the torsional eye position evaluated on the basis of the
image location of the markers (upper trace) or on the basis of a cross-correlation of 16 iral
segments (lower trace). For clarity, the latter has been shifted down by 1⬚. Both methods were
applied offline to the same image data. The noise level of the marker method is about ten
times less than the method based on iris patterns. Data from Schneider et al. [57].
Like the VOG of 2-D gaze direction, measurements of ocular torsion also
reach accuracy values that are similar to those of coil measurements. Using an
artificial eye, Imai et al. [46] reported mean errors of the torsional VOG signal
of 0.52⬚. Occasionally, and in particular for fixations in tertiary gaze positions,
larger deviations (up to 5⬚) of ocular torsion between a VOG and a simultaneous
search coil recording have been observed [56]. Using an artificial eye with a
very clear iris structure, Clarke et al. [55] estimated the inherent system noise
of VOG measurements of ocular torsion at 0.016⬚ (RMS). This value is probably better than torsional noise levels reached with natural iris patterns.
Schneider et al. [57] reported noise levels of about 0.14⬚ (RMS) (fig. 7). They
demonstrated that the noise level of torsional VOG measurements can be substantially lowered by tracking two artificial marks applied outside and close to
the limbus (fig. 7). With this method, the inherent system noise dropped to
0.017⬚ (RMS), which is similar to coil data. Unfortunately, marking the eyeball
with tincture markers requires anesthetizing the eye. Hence, the VOG system’s
main advantage of noninvasiveness is lost when this method is used.
Eggert
30
Table 1. Summary of the main features of EOG, IRD, scleral search coil and VOG
EOG
IRD
Scleral search
coil
VOG
Spatial
resolution
(inherent
system noise
RMS value),
degrees
⬇0.5
⬇0.02
⬇0.01
⬇0.05
Temporal
resolution
(bandwidth), Hz
40
100
500
50–400
Vertical
movements
recordable
possible,
confounded by
eyelid artifacts
possible,
confounded by
eyelid artifacts
yes
yes
Torsional
movements
recordable
no
no
yes, also in
secondary gaze
positions
yes, with some
difficulties in
secondary
gaze positions
Setup time
slow (skin
preparation and
electrode
application)
medium (goggle
adjustment to
minimize
nonlinearity)
slow
very fast
Accurate
fixation needed
for calibration
yes
yes
no
yes
Complexity of
calibration
good linearity
(with bitemporal
configuration)
polynomial
calibration
necessary for
larger
eccentricities
nonlinearity can
be compensated
by model-based
parameter fit
good linearity
Invasiveness
surface
electrodes next
to the eye, no
contact with the
eye, no effects
on vision
head-mounted
device, no
contact with the
eye, moderate
limitations of
field of view
contact lens
attached to the
eye, potential
effects on visual
acuity,
considerable
discomfort
head mounted
device, no
contact with
the eye,
moderate
limitations of
field of view
Eye Movement Recordings: Methods
31
The main features of the eye movement recording devices mentioned in this
chapter are summarized in table 1. Since the EOG is still the only method that
allows measurement of eye movements while the eyes are closed, it remains
important for specialized applications that require this possibility. Modern VOG
systems can measure 2-D gaze direction at spatial resolutions comparable to
those of search coil systems. The accuracy of VOG devices is also comparable to
that of the search coil, but it depends on the ability of the subjects to fixate accurately. System noise and accuracy of ocular torsion is slightly better in search coil
systems than in VOG. The main disadvantage of the search coil is that it is invasive compared with the EOG, IRD, or VOG. Therefore, search coil measurements
are advisable only for relatively short recordings requiring high temporal resolution, high accuracy, and an objective calibration. For most other applications,
VOG seems to provide a good alternative to the search coil technique. Until
recently, the IRD was still a reasonable noninvasive alternative to the search coil,
at least for measuring horizontal (1-D) eye movements. In the meantime, the temporal resolution of VOG improved and is now sufficient to cover the temporal
bandwidth of physiological eye movements. The robustness of the system linearity with respect to displacements between the device and the eye is much better in
VOG than in the IRD. Therefore, the IRD appears to have been outdated by VOG.
References
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Wade NJ, Tatler BW, Heller D: Dodge-ing the issue: Dodge, Javal, Hering, and the measurement
of saccades in eye-movement research. Perception 2003;32:793–804.
Wade NJ, Tatler BW: The Moving Tablet of the Eye: The Origins of Modern Eye Movement
Research. Oxford, Oxford University Press, 2005.
Porterfield W: An essay concerning the motions of our eyes. I. Of their external motions.
Edinburgh Med Essays Obs 1737;3:160–263.
Wells WC: An Essay Upon Single Vision with Two Eyes: Together with Experiments and
Observations on Several Other Subjects in Optics. London, Cadell, 1792.
Javal LE: Essai sur la physiologie de la lecture. Ann Ocul 1879;82:242–253.
Lamare M: Des mouvements des yeux dans la lecture. Bull Mem Soc Fr Ophtalmol 1892;10:354–364.
Hering E: Über Muskelgeräusche des Auges. Sitzungsberichte der kaiserlichen Akademie der
Wissenschaften in Wien. Math Naturwiss Kl Abt III 1879;79:137–154.
Ahrens A: Die Bewegungen der Augen beim Schreiben. Rostock, University of Rostock, 1891.
Delabarre EB: A method of recording eye movements. Am J Psychol 1898;9:572–574.
Huey EB: Preliminary experiments in the physiology and psychology of reading. Am J Psychol
1898;9:575–586.
Huey EB: On the psychology and physiology of reading. Am J Psychol 1900;11:283–302.
Javal LE: Essai sur la physiologie de la lecture. Ann Ocul 1878;80:240–274.
von Romberg G, Ohm J: Ergebnisse der Spiegelnystagmographie. Gräfes Arch Ophtalmol 1944;
146:388–402.
Dodge R, Cline TS: The angle velocity of eye movements. Psychol Rev 1901;8:145–157.
Crane HD, Steele CM: Generation-V dual-Purkinjeimage eyetracker. Appl Optics 1985;24:527–537.
Deubel H, Bridgeman B: Fourth Purkinje image signals reveal eye-lens deviations and retinal
image distortions during saccades. Vision Res 1995;35:529–538.
Eggert
32
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
Brandt T, Büchele W: Augenbewegungsstörungen: Klinik und Elektronystagmographie. Stuttgart,
Gustav Fischer, 1983.
Schott E: Über die Registrierung des Nystagmus und anderen Augenbewegungen vermittels des
Seitengalvanometers. Dtsch Arch Klin Med 1922:140:79–90.
Meyers IL: Electronystagmographie. A graphic study of the action currents in nystagmus. Arch
Neurol 1929;21:901–908.
Mowrer OR, Ruch RC, Miller NE: The corneoretinal potential difference as the basis of the
galvanometric method of recording eye movements. Am J Physiol 1936;114:423.
Jung R: Eine Elektrische Methode zur Mehrfachen Registrierung von Augenbewegungen und
Nystagmus. J Mol Med 1939;18:21–24.
Torok N, Guillemin V, Barnothy JM: Photoelectric nystagmography. Ann Otol Rhinol Laryngol
1951;60:917–926.
Kimmig H, Greenlee MW, Huethe F, Mergner T: MR-eyetracker: a new method for eye movement
recording in functional magnetic resonance imaging. Exp Brain Res 1999;126:443–449.
Howard IP, Evans JA: The measurement of eye torsion. Vision Res 1963;61:447–455.
Ruete CGT: Ocular physiology. Chapter 4. The muscles of the eye. Strabismus 1999;7:43–60;
translated from Lehrbuch der Ophthalmologie, ed 2. Braunschweig, Vieweg, vol 1, 1846,
pp 36–37.
Simonsz HJ: Christian Theodor Georg Ruete: the first strabismologist, coauthor of listing’s law,
maker of the first ophthalmotrope and inventor of indirect fundoscopy. Strabismus 2004;12:
53–57.
von Helmholtz H: Handbuch der Physiologischen Optik. Hamburg, Voss, 1867.
Robinson DA: A method of measuring eye movement using a scleral search coil in a magnetic
field. IEEE Trans Biomed Eng 1963;10:137–145.
Collewijn H, van der Mark F, Jansen TC: Precise recording of human eye movements. Vision Res
1975;15:447–450.
Collewijn H, Steen J, Ferman L, Jansen TC: Human ocular counterroll: assessment of static and
dynamic properties from electromagnetic scleral coil recordings. Exp Brain Res 1985;59:185–196.
Kasper H, Hess BJ: Magnetic search coil system for linear detection of three-dimensional angular
movements. IEEE Trans Biomed Eng 1991;38:466–475.
Straumann D, Zee DS, Solomon D, Kramer PD: Validity of Listing’s law during fixations,
saccades, smooth pursuit eye movements, and blinks. Exp Brain Res 1996;112:135–146.
Brecher GA: Die optokinetische Auslösung von Augenrollung und rotatorischen Nystagmus.
Pflügers Arch Ges Physiol 1934;234:13–28.
Miller EF: Counterrolling of the human eye produced by head tilt with respect to gravity. Acta
Otolaryng (Stockh) 1962;59:479–501.
Young LR, Lichtenberg BK, Arrott AP, Crites TA, Oman CM, Edelman ER: Ocular torsion on
earth and in weightlessness. Ann N Y Acad Sci 1981;374:80–92.
Clarke AH, Steineke C, Emanuel H: High image rate eye movement measurement. A novel
approach using CMOS sensors and dedicated FPGA devices; in Lehmann T (ed):
Bildverarbeitung in der Medizin. Berlin, Springer, 2000.
Haslwanter T, Moore ST: A theoretical analysis of three-dimensional eye position measurement
using polar cross-correlation. IEEE Trans Biomed Eng 1995;42:1053–1061.
Nakayama K: Photographic determination of the rotational state of the eye using matrices. Am J
Optom Physiol Opt 1974;51:736–741.
Dieterich M, Brandt T: Elektronystagmographie: Methodik und klinische Bedeutung. EEG Labor
1989;11:13–30.
Schmid-Priscoveanu A, Allum JHJ: Die Infrarot- und die Videookulographie – Alternativen zur
Elektrookulographie? HNO 1999;47:472–478.
Marmor MF, Zrenner E: Standard for clinical electroretinography (1999 update). Doc Ophthalmol
1999;97:143–156.
Collewijn H, Erkelens CJ, Steinman RM: Binocular co-ordination of human horizontal saccadic
eye movements. J Physiol 1988;404:157–182.
Ditterich J, Eggert T: Improving the homogeneity of the magnetic field in the magnetic search coil
technique. IEEE Trans Biomed Eng 2001;48:1178–1185.
Eye Movement Recordings: Methods
33
44
45
46
47
48
49
50
51
52
53
54
55
56
57
Tweed D, Cadera W, Vilis T: Computing three-dimensional eye position quaternions and eye
velocity from search coil signals. Vision Res 1990;30:97–110.
Bartl K, Siebold C, Glasauer S, Helmchen C, Büttner U: A simplified calibration method for
three-dimensional eye movement recordings using search-coils. Vision Res 1996;36:997–1006.
Imai T, Sekine K, Hattori K, Takeda N, Koizuka I, Nakamae K, Miura K, Fujioka H, Kubo T:
Comparing the accuracy of video-oculography and the scleral search coil system in human eye
movement analysis. Auris Nasus Larynx 2005;32:3–9.
Frens MA, van der Geest JN: Scleral search coils influence saccade dynamics. J Neurophysiol
2002;88:692–698.
Bergamin O, Ramat S, Straumann D, Zee DS: Influence of orientation of exiting wire of search
coil annulus on torsion after saccades. Invest Ophthalmol Vis Sci 2004;45:131–137.
Irving EL, Zacher JE, Allison RS, Callender MG: Effects of scleral search coil wear on visual
function. Invest Ophthalmol Vis Sci 2003;44:1933–1938.
Murphy PJ, Duncan AL, Glennie AJ, Knox PC: The effect of scleral search coil lens wear on the
eye. Br J Ophthalmol 2001;85:332–335.
Karmali F, Shelhamer M: Automatic detection of camera translation in eye video recordings using
multiple methods. Ann N Y Acad Sci 2005;1039:470–476.
Enright JT: Ocular translation and cyclotorsion due to changes in fixation distance. Vision Res
1980;20:595–601.
Wang JG, Sung E: Gaze determination via images of irises. Image Vis Comput 2001;19:891–911.
van der Geest JN, Frens MA: Recording eye movements with video-oculography and scleral
search coils: a direct comparison of two methods. J Neurosci Methods 2002;114:185–195.
Clarke AH, Ditterich J, Druen K, Schönfeld U, Steineke C: Using high frame rate CMOS sensors
for three-dimensional eye tracking. Behav Res Methods Instrum Comput 2002;34:549–560.
Houben MM, Goumans J, van der Steen J: Recording three-dimensional eye movements: scleral
search coils versus video oculography. Invest Ophthalmol Vis Sci 2006;47:179–187.
Schneider E, Glasauer S, Dieterich M: Comparison of human ocular torsion patterns during natural and galvanic vestibular stimulation. J Neurophysiol 2002;87:2064–2073.
Web Links
Hain TC (2005): Eye movement recording devices;
http://www.dizziness-and-balance.com/practice/eyemove.html
Marmor MF, Zrenner E (1999): Standard for clinical electroretinography;
http://www.iscev.org/standards/eog.html
Paulson EJ, Goodman KS (1999): Influential studies in eye movement research;
http://www.readingonline.org/research/eyemove.html
Schneider G, Kurt J (2000): Zur Rolle der Blicksteuerung bei Lesestörungen.
Kapitel 7: Technische Prinzipien zur Messung der Augenbewegungen;
http://www2.hu-berlin.de/reha/eye/Studie2000/tech.pdf
Wooding D (2002): Eye movement equipment database;
http://ibs.derby.ac.uk/cgi-bin/emed/emedsrch.cgi?opr1 ⫽ OR&fld1 ⫽ name&key1a ⫽ *.
Dr. T. Eggert
Department of Neurology, Klinikum Grosshadern
Marchioninistrasse 23
DE–81377 Munich (Germany)
Tel. ⫹49 89 7095 4834, Fax ⫹49 89 7095 4801
E-Mail [email protected]
Eggert
34
Straube A, Büttner U (eds): Neuro-Ophthalmology.
Dev Ophthalmol. Basel, Karger, 2007, vol 40, pp 35–51
Vestibulo-Ocular Reflex
Michael Fetter
Department of Neurology, SRH Clinic Karlsbad-Langensteinbach, Karlsbad, Germany
Abstract
The vestibulo-ocular reflex (VOR) ensures best vision during head motion by moving
the eyes contrary to the head to stabilize the line of sight in space. The VOR has three main
components: the peripheral sensory apparatus (a set of motion sensors: the semicircular
canals, SCCs, and the otolith organs), a central processing mechanism, and the motor output
(the eye muscles). The SCCs sense angular acceleration to detect head rotation; the otolith
organs sense linear acceleration to detect both head translation and the position of the head
relative to gravity. The SCCs are arranged in a push-pull configuration with two coplanar
canals on each side (like the left and right horizontal canals) working together. During angular head movements, if one part is excited the other is inhibited and vice versa. While the
head is at rest, the primary vestibular afferents have a tonic discharge which is exactly balanced between corresponding canals. During rotation, the head velocity corresponds to the
difference in the firing rate between SCC pairs. Knowledge of the geometrical arrangement
of the SCCs within the head and of the functional properties of the otolith organs allows to
localize and interpret certain patterns of nystagmus and ocular misalignment. This is based
on the experimental observation that stimulation of a single SCC leads via the VOR to slowphase eye movements that rotate the globe in a plane parallel to that of the stimulated canal.
Furthermore, knowledge of the mechanisms that underlie compensation for vestibular disorders is essential for correctly diagnosing and effectively managing patients with vestibular
disturbances.
Copyright © 2007 S. Karger AG, Basel
The vestibulo-ocular reflex (VOR) helps to stabilize the retinal image by
rotating the eyes to compensate for movements of the head. An ideal VOR, that
tries to compensate for any arbitrary movement of the head in 3-D space, would
generate eye rotations at the same speed as, but in the opposite direction to, head
rotation independent of the momentary rotation axis of the head. The desired
result is that the eye remains still in space during head motion, enabling clear
vision. The VOR has two different physical properties. The angular VOR, mediated
Sensory input
Central processing
Motor output
Visual
Vestibular
Proprioceptive
Vestibular
nuclear complex
Oculomotor
neurons
Adaptive
processor
(cerebellum)
Fig. 1. Schematic drawing illustrating the VOR.
by the semicircular canals (SCCs), compensates for rotation. The linear VOR,
mediated by the otolith organs (saccule and utricle), compensates for translation.
The angular VOR is primarily responsible for gaze stabilization. The linear VOR
is most important in situations where near targets are being viewed [1, 2].
The VOR has three main components: the peripheral sensory apparatus
(the labyrinth), a central processing mechanism, and the motor output (the eye
muscles) [3]. The sensory input for the generation of the VOR is provided by a
set of motion sensors, which send the information about head angular velocity,
linear acceleration, and orientation of the head with respect to gravity to the
central nervous system (specifically the vestibular nucleus complex and the
cerebellum). In the central nervous system, these signals are combined with
other sensory information (e.g. from the somatosensors) at as early stages as the
vestibular nucleus complex to estimate head orientation. The output of the central vestibular system is sent to the ocular muscles and the spinal cord to serve
the VOR and the vestibulospinal reflex (VSR), the latter generating compensatory body movement in order to maintain head and postural stability, thereby
preventing falls. The information goes also to cortical structures (e.g. posterior
insular vestibular cortex, PIVC) where it is further integrated with visual, proprioceptive, auditory and tactile input to generate a best possible perception of
motion and space orientation [4]. The performance of the VOR and VSR is
monitored by the central nervous system, and readjusted as necessary by adaptive processes with immense capability of repair and adaptation mainly involving cerebellar function (fig. 1) [5].
The Peripheral Sensory Apparatus
The peripheral vestibular system includes the membranous and bony
labyrinths, and the motion sensors of the vestibular system, the hair cells. Each
Fetter
36
labyrinth consists of three SCCs, the cochlea, and the vestibule containing the
utricle and saccule). The geometric arrangement of the SCCs allows for detection of head rotation about any axis in space. They are positioned in three nearly
orthogonal planes in the head and act as angular accelerometers working in a
push-pull arrangement with the other labyrinth (right and left lateral SCC; right
anterior and left posterior SCC; left anterior and right posterior SCC). The
planes of the SCCs are close to the planes of the extraocular muscles, thus
allowing relatively simple neural connections between sensory neurons related
to individual canals, and motor output neurons, related to individual ocular
muscles (fig. 2) [6]. One end of each SCC is widened in diameter to form an
ampulla containing the cupula. The cupula causes endolymphatic pressure differentials, associated with head motion, to be coupled to the hair cells embedded in the cupula. These specialized hair cells are biological sensors that
convert displacement due to head motion into neural firing. When hairs are bent
toward or away from the longest process of the hair cells, firing rate increases or
decreases in the vestibular nerve [7, 8]. The hair cells of the saccule and utricle,
the maculae, are located on the medial wall of the saccule and the floor of the
utricle. The otolithic membranes are structures similar to the cupulae, but as
they contain calcium carbonate crystals called otoconia, they have substantially
more mass than the cupulae. The mass of the otolithic membrane causes the
maculae to be sensitive to gravity. In contrast, the cupulae normally have the
same density as the surrounding endolymphatic fluid and are insensitive to
gravity. By virtue of their orientation, the SCC and otolith organs are able to
respond selectively to head motion in particular directions [9].
Central Processing of Vestibular Signals
The coplanar pairing of canals is associated with a push-pull change in the
quantity of SCC output. With rotation in the plane of a coplanar SCC pair, the
neural firing increases from tonic resting discharge in one vestibular nerve and
decreases on the opposite site. For the lateral canals, displacement of the cupula
towards the ampulla (ampullopetal flow) is excitatory, whereas for the vertical
canals, displacement of the cupula away from the ampulla (ampullofugal flow)
is excitatory (fig. 3).
There are certain advantages to the push-pull arrangement of coplanar
pairing. First, pairing provides sensory redundancy. If disease affects the SCCs
from one member of a pair (e.g. as in vestibular neuritis), the central nervous
system will still receive vestibular information about head velocity within that
plane from the contralateral member of the coplanar pair. Second, such a pairing allows the brain to ignore changes in neural firing that occur on both sides
Vestibulo-Ocular Reflex
37
25º
53º
10
so
sr
mr
III
lr
ir
ir
io
sr
mr
bc
IV
mlf
bc
so
VI
47º
in
lr
ra
la
rh
lh
lp
rp
47º
Fig. 2. The VOR network: corresponding SCCs and the main brainstem connections to
the oculomotor nuclei are shown. lr, sr, ir, mr ⫽ Left, superior, inferior, medial rectus muscle; IO, SO ⫽ inferior, superior oblique muscle; III ⫽ third nerve nucleus with inferior
(ir), superior (sr), medial rectus (mr), and inferior oblique (io) motor neurons; IV ⫽ fourth
nerve nucleus with superior oblique motor neurons (so); bc ⫽ brachium conjunctivum;
VI ⫽ sixth nerve nucleus with lateral rectus (lr) and internuclear (in) motor neurons;
mlf ⫽ medial longitudinal fasciculus; la, lh, lp ⫽ left anterior, horizontal and posterior
SCC; ra, rh, rp ⫽ right anterior, horizontal and posterior SCC. (Courtesy of D.A. Robinson,
Baltimore.)
Fetter
38
Sp/s
Inhibition
R
L
Excitation
Resting
Fig. 3. With rotation toward the left side, the neural firing increases from tonic resting
discharge (shown as horizontal dotted line) in the vestibular nerve of the left lateral canal and
decreases in the vestibular nerve of the right lateral canal. During rotation, the head velocity
corresponds to the difference in firing rate between SCC pairs.
simultaneously, such as might occur due to changes in body temperature or
chemistry.
In the otoliths, as in the canals, there is a push-pull arrangement of sensors,
but in addition to splitting the sensors across sides of the head, the push-pull
processing arrangement for the otoliths is also incorporated into the geometry
of the otolithic membranes. Within each otolithic macula, a curving zone, the
striola, separates the direction of hair cell polarization on each side.
Consequently, head tilt results in increased afferent discharge from one part of a
macula, while reducing the afferent discharge from another portion of the same
macula [10, 11].
There are two main targets for vestibular input from primary afferents: the
vestibular nuclear complex and the cerebellum. The vestibular nuclear complex
is the primary processor of vestibular input, and implements direct, fast connections between incoming afferent information and motor output neurons.
Vestibulo-Ocular Reflex
39
The erebellum is the adaptive processor – it monitors vestibular performance
and readjusts central vestibular processing if necessary [12]. At both locations,
vestibular sensory input is processed in association with somatosensory and
visual sensory input [5].
The vestibular nuclear complex consists of 4 major nuclei (superior,
medial, lateral, and descending) and at least 7 minor nuclei. This large structure, located primarily within the pons, also extends caudally into the medulla.
The superior and medial vestibular nuclei are relays for the VOR. The medial
vestibular nucleus is also involved in the VSR, and coordinates head and eye
movements that occur together. The lateral vestibular nucleus is the principal
nucleus for the VSR. The descending nucleus is connected to all of the other
nuclei and the cerebellum, but has no primary outflow of its own [13]. The
vestibular nuclei are connected via a system of commissures, which for the
most part, are mutually inhibitory. The commissures allow information to be
shared between the two sides of the brainstem and implements the push-pull
pairing of vestibular canals. Extensive connections between the vestibular
nuclear complex, cerebellum, ocular motor nuclei, and brainstem reticular activating systems convey the efferent signals to the VOR and VSR effector organs,
the extraocular and skeletal muscles [14]. The output neurons of the VOR are
the motor neurons of the ocular motor nuclei, which drive the extraocular muscles resulting in conjugate movements of the eyes in the same plane as head
motion (fig. 2).
VOR – Pathology
It is crucial to carefully evaluate the eye movements during clinical examination, as the physiological and anatomical substrate of the ocular motor system is intimately connected with the vestibular system via the VOR. The VOR
is responsible for the nystagmus phenomena seen in patients [15]. Caloric
stimulation provides perhaps the clearest analogy to what the patient with
pathological vertigo and nystagmus experiences. For example, warm stimulation of the left ear increases neural activity from the left lateral SCC and therefore in the left vestibular nerve; it thereby produces not only left-beating
horizontal nystagmus but a sense of turning about the body long axis, toward
the left. Conversely, cold stimulation of the right ear reduces neural activity in
the right lateral SCC, the right vestibular nerve; and by commissural disinhibition it also increases neural activity in the left vestibular nucleus and, therefore, produces left-beating nystagmus and a sense of turning to the left (the
nystagmus always beating toward the side of higher vestibular activity) [16,
17]. In a patient with sudden unilateral loss of peripheral vestibular function
Fetter
40
(such as in vestibular neuritis), the situation is in some way analogous to a cold
caloric stimulus.
An example of vertigo due to pathological unilateral increase in vestibular
activity is benign paroxysmal positioning vertigo (BPPV), the most common
vestibular disorder. With appropriate positioning, there is a sudden brief
increase in activity from one SCC. The result is a sudden intense sense of selfrotation in the plane of the activated canal and a nystagmus beating in this
plane. For example, if a patient with left posterior canal BPPV is rapidly placed
in the provocative left lateral position, there is a sense of self-rotation in a plane
halfway between the roll and the pitch plane toward the patient’s left side with a
vertical – torsional nystagmus beating upward and with the torsional component to the lower ear [18–21].
Practical Aspects for Bedside Clinical Evaluation
An acute unilateral peripheral vestibular lesion reduces or eliminates input
from one or more SCCs and otolith organs on that side. In the acute phase, a
complete lesion abolishes the tonic neuronal discharge (resting activity) in the
vestibular nerve [22]. The resulting loss of accelerometer function on one side
of the head and the imbalance between the tonic inputs on the two sides lead to
both spontaneous nystagmus and decreased and asymmetrical dynamic vestibular responses. Thus, there are both static and dynamic imbalances which need to
be evaluated.
Static Imbalance
Spontaneous nystagmus (with the head still) is the hallmark of an imbalance in the tonic levels of activity mediating SCC-ocular reflexes. When
peripheral in origin, spontaneous nystagmus characteristically is damped by
visual fixation and is increased or only becomes apparent when fixation is
eliminated. Hence, one must look for spontaneous nystagmus behind Frenzel
lenses (magnifying lenses that prevent the patient from using visual fixation to
suppress any spontaneous nystagmus) or during ophthalmoscopy (with the
opposite eye occluded to prevent fixation). The intensity of nystagmus is compared with that observed when the patient is fixing on a visual target.
Nystagmus is sometimes seen or even palpated through closed eyelids. Note
that during ophthalmoscopy the direction of any horizontal or vertical slow
phases is opposite to the direction of the motion of the optic disk.
The nystagmus should also be inspected for dependence on the position of
the eye in the orbit. Nystagmus arising from a peripheral lesion and most central lesions is more intense or may be evident only when the eye is deviated in
Vestibulo-Ocular Reflex
41
the direction of the quick phase (Alexander’s law). With central lesions, however, the opposite sometimes occurs. The axis around which the globe of each
eye is rotating should be evaluated. For example, a pure vertical or a pure torsional nystagmus implies a central disturbance; a mixed horizontal-torsional
nystagmus is typical for a peripheral labyrinthine dysfunction, and a mixed vertical-torsional nystagmus that becomes more vertical on looking toward one
side and more torsional on looking to the other is typical for inappropriate excitation of the posterior SCC causing BPPV [19].
Skew deviation is the hallmark of an imbalance in the tonic levels of activity underlying otolith-ocular reflexes. Skew deviation is a vertical misalignment
of the eyes that cannot be explained on the basis of an ocular muscle palsy.
Patients with a skew deviation complain of vertical diplopia and sometimes torsional diplopia (one image tilted with respect to the other). There may also be a
cyclorotation (ocular counterroll) of both eyes associated with an illusion of tilt
of the visual world. The head may also be tilted, usually toward the side of the
lower eye. Skew deviation, ocular counterrolling, and head tilt constitute the ocular
tilt reaction: vestibulo-ocular and vestibulo-collic components of the righting
reaction in response to the lateral tilt of the head and body [23]. Skew deviation
is best detected with cover testing. With the alternate cover test, one looks for a
vertical corrective movement on switching the cover from one eye to the other
as an index of a vertical misalignment. Skew deviation tends to be relatively
comitant (i.e. the degree of misalignment changes little with different direction
of gaze), though it is not always the case. Ocular counterroll is difficult to
detect clinically without photographic means, but if the amount of counterroll is
large it can be appreciated by the tilt of the imaginary line that connects the
macula and the optic disk. The ocular tilt reaction can occur with lesions anywhere in the otolith-ocular pathway. With peripheral and vestibular nucleus
lesions, the lower eye is on the side of the lesion. The otolith-ocular pathway
crosses at the level of the vestibular nucleus, so that with lesions above the
decussation the higher eye is on the side of the lesion [24–26].
Dynamic Disturbances
The SCC induced VOR can be tested at the bedside by observing the effect
of head rotation on visual acuity and by looking at the eye movements themselves in response to head rotation. Measure the patient’s best corrected visual
acuity using a distance acuity chart with the head still and then with the head
passively rotated at a frequency of about 2 Hz. Normal individuals may lose one
line of acuity during head shaking; patients with a complete loss of labyrinthine
function loose up to five lines and sometimes more. The possible influence of
stimulation of cervical afferents, through the cervico-ocular reflex, when the head
is rotated on the body must also be considered. In normal subjects, especially at
Fetter
42
the relatively high frequencies associated with bedside testing, the cervico-ocular reflex is rudimentary and can be ignored. In patients with loss of the function of the SCCs, however, there may be potentiation of the cervico-ocular
reflex or the use of cervical afferents to trigger preprogrammed compensatory
slow phases or even saccades, independent of inputs from the SCCs [27].
Next, carefully apply brief, high-acceleration head thrusts, with the eyes
beginning about 15⬚ away from the primary position in the orbit and the amplitude of the head movement such that the eyes end near the primary position of
gaze. Instruct the patient to look carefully at the examiner’s nose. Look for a
corrective saccade (usually catch-up) as a sign of an inappropriate compensatory slow phase. When interpreting an abnormal response, one must consider
the potential adaptive readjustment in VOR function that may occur when a
subject habitually wears a spectacle correction. Farsighted individuals (hyperopia) increase their VOR gain owing to the magnification effect of a plus lens;
nearsighted individuals (myopia) decrease their VOR gain owing to the minification effect of a minus lens [28, 29].
Head-shaking nystagmus (HSN) is another way to look for an imbalance
of dynamic vestibular function. First, with Frenzel lenses in place, instruct the
patient to shake the head vigorously about 15–20 times, side to side. Look for
any nystagmus following the head shaking. Normal individuals usually have no
or occasionally just a beat or two of HSN. With a unilateral loss of labyrinthine
function, however, there is usually a vigorous nystagmus with slow phases initially directed toward the lesioned side and then a reversal phase with slow
phases directed oppositely [30]. The initial phase of HSN arises because there is
asymmetry of peripheral inputs during high-velocity head rotations. More
activity is generated during rotation toward the intact side than toward the
affected side [31, 32]. This asymmetry leads to an accumulation of activity during the head shaking [33]. The nystagmus following head shaking reflects the
discharge of that activity again beating towards the healthy side.
Positional Testing
Positional (sustained) and positioning (transient) nystagmus is best elicited
with the patient wearing Frenzel lenses. For positioning nystagmus the head
should be moved to the dependent position as rapidly as possible. The same
positioning maneuver should be repeated to see if the nystagmus becomes
attenuated. If a horizontal nystagmus is elicited with one ear down during positional testing, the patient’s head should be rotated to put the other ear down to
see if the horizontal nystagmus changes direction, as occurs, for example, with
the lateral canal variant of BPPV [15].
A positioning nystagmus is characteristic of BPPV. A transient burst of a
mixed vertical (upbeat)-torsional (the superior pole of the globe beats toward
Vestibulo-Ocular Reflex
43
the side of the dependent ear) nystagmus, usually appearing after a latency of
several seconds and lasting 20–30 s, is characteristic of the inappropriate excitation of the posterior SCC that produces typical BPPV. On reassuming the
upright position, nystagmus due to BPPV may transiently reappear, but it is
usually directed opposite to that in the dependent position. With successive repetitions, the nystagmus usually becomes more difficult to elicit.
With the lateral canal variant, the horizontal nystagmus usually lasts much
longer. The increased duration may reflect the action of the central velocity
storage mechanism, which is much more effective for horizontal than vertical
canal inputs. Lateral canal BPPV occurs with either ear down and may be geotropic (beats toward the ground) or ageotropic (beats away from the ground). It
should be remembered that a small amount of unidirectional horizontal positional nystagmus is observed in many normal subjects. A central lesion is most
likely when a positional nystagmus is purely vertical or purely torsional, or if
there is a significant sustained unidirectional horizontal positional nystagmus
[20].
Positional testing may also exacerbate a spontaneous nystagmus. With
an acute unilateral loss of labyrinthine function, the horizontal component of
the spontaneous nystagmus is increased with the patient lying with the
affected ear down and decreased with the affected ear up. This effect of gravity on the horizontal component of the spontaneous nystagmus is probably
mediated by the otolith-ocular reflex, which normally produces a horizontal
nystagmus in response to linear accelerations associated with translation of
the head. In the case of spontaneous nystagmus due to a vestibular imbalance, the change in the pull of gravity with head tilt produces a horizontal
slow-phase response that either damps or increases the spontaneous nystagmus depending on whether the ear with the hypoactive labyrinth is up or
down, respectively [34].
Valsalva- and Hyperventilation-Induced Nystagmus
Patients with craniocervical junction anomalies, such as the Chiari malformation, perilymph fistulas, and other abnormalities involving the ossicles, oval
window, and saccule may develop nystagmus with the Valsalva maneuver or by
manipulation of the ossicular chain with changes in middle-ear pressure owing
to noise, tragal compression, application of positive and negative pressure to the
tympanic membrane (Hennebert’s sign), or opening and closing the eustachian
tube [35].
Hyperventilation may induce symptoms in patients with anxiety and phobic disorders but usually does not produce nystagmus. Patients with demyelinating lesions on the vestibular nerve (such as that due to a tumor, e.g. an
acoustic neuroma or cholesteatoma), compression by a small blood vessel, or in
Fetter
44
central structures (multiple sclerosis) may show hyperventilation-induced nystagmus [36].
Laboratory Evaluation: Electro-Oculography and Rotational Testing
Vestibular laboratory testing can aid in diagnosis, can be used to document
an abnormality suspected at bedside evaluation, and can aid in devising a treatment plan. The ability to perform serial vestibular evaluations allows an assessment over time of patients who are undergoing treatment for their dizziness or
who are undergoing treatment with a potentially ototoxic medication. Both
electro-oculography (EOG) and rotational testing can provide information that
is helpful for determining if a vestibular abnormality is present and, if so,
whether it is located in the central or peripheral vestibular system. The choice of
subtests that are preformed may vary according to the clinical suspicions of the
physician ordering the test. When a peripheral vestibular abnormality is suspected caloric testing may be helpful, and when a central vestibular abnormality is suspected visual-vestibular interaction tests may prove useful.
Positional testing is performed as part of the EOG battery by placing the
patient in the supine and head-hanging positions, head-right and right-lateral
positions, and head-left and left-lateral positions. However, BPPV may be difficult to record in the vestibular laboratory because EOG is insensitive to torsional eye movements and vertical EOG is plagued by eyeblink and muscle
artifacts and has a low signal/noise ratio. Despite these limitations, patients
with positioning vertigo should have Dix-Hallpike testing, as many patients
with BPPV produce a recordable eye movement whose temporal characteristics
can be objectified. A paroxysmal nystagmus observed during the Dix-Hallpike
maneuver that does not conform to the typical pattern seen with BPPV should
be considered the result of a CNS abnormality until it is proved otherwise.
Examples of such nystagmus include downbeating nystagmus in a head-hanging position and nystagmus that does not fatigue with repeated positioning.
Caloric testing is the mainstay of vestibular laboratory testing. The caloric
response is primarily the result of the convection current caused by the combination of a thermal gradient across the horizontal SCC and placement of the lateral canal in a vertical plane. Although research from microgravity experiments
has indicated that direct thermal effects generate a portion of the caloric
response, the convection current theory still accounts for most of the caloric
response [37]. Warm irrigation of the ear causes excitation of the lateral SCC
and thus induces slow movement of the eyes away from the side of irrigation
with subsequent beating toward the ear being irrigated. The irrigation of the left
ear with cool water induces right-beating nystagmus. Many studies have shown
Vestibulo-Ocular Reflex
45
that the maximum slow component velocity attained after each caloric irrigation is the best determinant of the response of a particular ear to a particular
stimulus [38]. A reduced vestibular response typically indicates a peripheral
vestibular injury. It may include damage to the labyrinth itself, the eighth cranial nerve, or the root entry zone of the vestibular nerve. When an ear is unresponsive to warm and cold irrigation, direct irrigation with ice water may be
helpful. The chief advantage of caloric testing is its ability to stimulate each ear
individually.
The types of rotational vestibular testing that are in common clinical use
include earth-vertical axis rotation and visual-vestibular interaction.
Rotational testing makes use of a natural stimulus to the labyrinth (i.e. rotational acceleration). Besides sinusoidal rotations, rotating a subject at a constant velocity for enough time for the perrotatory nystagmus to decay is widely
used. The rotational chair is then stopped abruptly and the induced postrotatory nystagmus is measured. The main measures of the response to constant
velocity rotation are gain and time constant. The gain is, by definition, the
ratio of the magnitude of the response to the magnitude of the stimulus (maximum eye velocity divided by maximum head velocity). The time constant of
the VOR is a measure of how rapidly vestibular nystagmus decays after an
abrupt stop of the rotation chair [39].
Conventional Rotational Testing
The hallmark of unilateral peripheral vestibular loss is a reduced
vestibular response on caloric testing. With acute peripheral vestibular
lesions, a brisk spontaneous nystagmus may make interpretation of caloric
testing difficult, especially if nystagmus in the same direction is seen
regardless of the side or temperature of the irrigation during bithermal testing. In such cases, ice-water irrigation may be helpful. Ice-water irrigation
of the normal ear should stop the nystagmus in the acute phase and reverse
it in compensated states [40]. Acute unilateral peripheral vestibular lesions
are usually associated with a normal ocular motor screening battery and an
absence of gaze-evoked nystagmus. However, with a severe acute unilateral
peripheral loss there may be asymmetrical pursuit and asymmetrical optokinetic nystagmus as a result of superposition of an intense spontaneous
vestibular nystagmus with visual following. Also, with an acute unilateral
peripheral vestibular lesion, there may be spontaneous nystagmus during
fixation. Rotational testing shortly after an acute unilateral peripheral loss
usually shows severe asymmetry and drastically reduced time constants
[41].
Fetter
46
Fig. 4. Electrical stimulation of a single SCC nerve induces eye movements roughly in
the plane of that canal (shown for stimulation of the right posterior canal). (Courtesy of A.
Boehmer, Zürich.)
Modern Vestibular Testing
Semicircular Canal Function
Routine vestibular testing such as calorics and rotational testing mainly
investigate the function of the lateral SCCs, while the vertical SCCs and
the otoliths are basically ignored. This has changed in recent years. In the last
20 years, there has been a revival of interest in 3-D approaches to the control of eye
movements. This was boosted by the fact that 3-D eye movement analysis has
become practical with the development of the magnetic field search coil technique. New analytical approaches have made the mathematics of eye rotations
and coordinate transformations more tractable and intuitive. Strabismus,
labyrinthine dysfunction and brain disorders leading to nystagmus and other
eye movement disorders are ubiquitous clinical problems and demand a 3-D
approach for their understanding. This is especially true when dealing with
vestibular problems. The vestibular system is intrinsically 3-D trying to stabilize the retinal image in all 3 rotational degrees of freedom. Under pathological
conditions, we often find spontaneous or elicited eye movements with torsional
components. The key for understanding vestibular-induced eye movements has
been found in the early 60s. Since then, we know that electrical stimulation of
single SCC nerves induces eye movements roughly in the plane of the canal
[42, 43] (fig. 4). If more than one canal is stimulated, the different canals combine at least roughly linearly to drive the eyes. Thus, if multiple canals are stimulated, the slow phases should be in a direction that is a weighted vector sum of
Vestibulo-Ocular Reflex
47
the axes of the involved canals. Using this premise, one can stimulate the
vestibular system in numerous ways (low- and high-velocity head movements
in 3-D, 3-D calorics, and diverse methods of inducing positional nystagmus)
and relate the resulting eye movements to the function or dysfunction of single
SCCs [44–46].
Obviously, in humans one cannot stimulate with electrodes the vestibular
nerve and record the resulting eye movements. We therefore tested patients in
whom nature produced a situation where just one SCC is stimulated. These
patients suffered from benign paroxysmal positioning nystagmus. When the
nystagmus induced by positioning the subject in the offending position is measured in 3-D and the average axis of eye rotation is reconstructed and plotted
into a head-fixed reference system together with the anatomical on-directions
of the SCCs it can be shown that the elicited eye movements are closely aligned
with the direction of the offending canal. With this proof that also in humans
eye movements are produced in the plane of the stimulated SCC, it is possible
to deduct which canals are responsible for the direction of eye movements
found during vestibular stimulation when parts of the vestibular sensors are
defective [44, 47, 48].
Otolith Function
Subjective Visual Vertical
The subjective visual vertical (SVV) is a sensitive measure of otolith and
especially utricular function. The bilateral graviceptive input from the otoliths
dominates our perception of verticality. To test for SVV, the subjects sit with
their heads fixed in the upright position and look at an illuminated line (on
computer display or projected with a laser galvanometer system) in complete
darkness. They then have to adjust 10 times separately for each eye the line
from different starting positions to their SVV. In acute peripheral vestibular
lesions, including the utricles, there is an ipsiversive deviation of the SVV of
about 10–15⬚. Likewise, most patients with acute unilateral brainstem infarctions exhibit pathological tilts of static SVV from the true vertical [49].
Click-Evoked Myogenic Potentials
Electromyograms can be recorded from surface electrodes over the sternomastoid muscles and averaged in response to brief (0.1-ms) clicks played
through headphones. In normal subjects, clicks 85–100 dB above 45 dB SPL
(perceptual threshold for normal subjects) evoke reproducible changes in the
Fetter
48
averaged electromyogram beginning at a mean latency of 8.2 ms. The earliest
potential changes, a biphasic positive-negative wave, is generated by afferents
from the ipsilateral sacculus. The potential is abolished in patients with lesions
of the inferior vestibular nerve subserving the sacculus but is preserved in subjects with severe sensorineural hearing loss. It is proposed that the response is
generated by activation of vestibular afferents arising from the saccule, and
transmitted via a rapidly conducting oligosynaptic pathway to anterior neck
muscles [50].
Conclusions
With the new VOR test methods described, a more thorough investigation
of vestibular function at the level of single SCC function and the otoliths has
become possible. Modern techniques are now available such as 3-D eye movement analysis for the evaluation of SCC function, measurement of the SVV for
utricular, and click-evoked myogenic potentials for saccular testing. These new
techniques have the potential to significantly improve our diagnostic capabilities in dizzy patients.
References
1
2
3
4
5
6
7
8
9
10
11
12
Lorente de No R: Vestibulo-ocular reflex arc. Arch Neurol Psychiatr 1933;30:245–291.
Baloh RH, Honrubia V: The vestibular system; in Baloh RH, Honrubia V (eds): Clinical
Neurophysiology of the Vestibular System, ed 2. Philadelphia, FA Davis, 1990, pp 1–17.
Szentágothai J: The elementary vestibulo-ocular reflex. J Neurophysiol 1950;13:395–407.
Grüsser OJ, Pause M, Schreiter U: Localization and responses of neurons in the parieto-insular
vestibular cortex of awake monkeys (Macaca fascicularis). J Physiol (London) 1990;430:
537–557.
Lisberger SG, Miles FA, Zee DS: Signals used to compute errors in monkey vestibuloocular
reflex: possible role of flocculus. J Neurophysiol 1984;52:1140–1153.
Blanks RHI, Curthoys IS, Markham CH: Planar relationships of the semicircular canals in man.
Acta Otolaryngol (Stockh) 1975;80:185–196.
Goldberg JM, Fernandez C: Physiology of peripheral neurons innervating semicircular canals
of the squirrel monkey. I. Resting discharge and response to constant angular acceleration.
J Neurophysiol 1971;34:634–660.
Fernandez C, Goldberg JM: Physiology of peripheral neurons innervating semicircular canals of
the squirrel monkey. II. Response to sinusoidal stimulation and dynamics of the peripheral
vestibular system. J Neurophysiol 1971;34:661–675.
Bach-Y-Rita P: The Control of Eye Movements. New York, Academic Press, 1971.
Suzuki J-I, Tokumasu K, Goto K: Eye movements from single utricular nerve stimulation in the
cat. Acta Otolaryngol 1969;68:350–362.
Fernandez C, Goldberg JM, Abend WK: Response to static tilts of peripheral neurons innervating
otolith organs of the squirrel monkey. J Neurophysiol 1972;6:978–987.
Robinson DA: Adaptive gain control of the vestibulo-ocular reflex by the cerebellum.
J Neurophysiol 1976;39:954–969.
Vestibulo-Ocular Reflex
49
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
Brodal A: Anatomy of the vestibular nuclei and their connections; in Kornhuber HH (ed):
Handbook of Sensory Physiology. The Vestibular System. New York, Springer, 1974, vol VI, part 1.
Büttner-Ennever JA: Vestibular oculomotor organization; in Fuchs AF, Becker W (eds): The
Neural Control of Eye Movements. Amsterdam, Elsevier, 1981.
Dix R, Hallpike CS: The pathology, symptomatology and diagnosis of certain common disorders
of the vestibular system. Ann Otol Rhinol Laryngol 1952;6:987–1016.
Barany R: Physiologie und Pathologie des Bogengangsapparates beim Menschen. Vienna,
Deuticke, 1907.
Sills AW, Baloh RW, Honrubia V: Caloric testing 2. Results in normal subjects. Ann Otol Rhinol
Laryngol 1977;85:7–23.
Schuknecht HF: Cupulolithiasis. Arch Otolaryngol 1969;90:765–778.
Baloh RW, Honrubia V, Jacobson K: Benign positional vertigo. Neurology 1987;37:371–378.
Brandt T: Positional and positioning vertigo and nystagmus. J Neurol Sci 1990;95:3–28.
Brandt T, Steddin S: Current view of the mechanism of benign paroxysmal positioning vertigo:
cupulolithiasis or canalolithiasis? J Vestibular Res 1993;3:373–382.
McCabe BF, Ryu JH, Sekitani T: Further experiments on vestibular compensation. Laryngoscope
1972;82:381–396.
Brandt T, Dieterich M: Central vestibular syndromes in roll, pitch, and yaw planes. Neuroophthalmol 1995;6:291–303.
Dieterich M, Brandt T, Fries W: Otolith function in man: results from a case of otolith Tullio phenomenon. Brain 1989;112:1377–1392.
Halmagyi GM, Brandt T, Dieterich M, Curthoys IS, Stark RJ, Hoyt WS: Tonic contraversive ocular
tilt reaction due to unilateral meso-diencephalic lesion. Neurology 1990;40:1503–1509.
Brandt T, Dieterich M: Skew deviation with ocular torsion: a vestibular brainstem sign of
topographic diagnostic value. Ann Neurol 1993;33:528–534.
Kasai T, Zee DS: Eye-head coordination in labyrinthine-defective human beings. Brain Res
1978;144:123–141.
Halmagyi GM, Curthoys IS, Cremer PD, Henderson CJ, Todd MJ, Staples MJ, D’Cruz DM: The
human horizontal vestibulo-ocular reflex in response to high-acceleration stimulation before and
after unilateral vestibular neurectomy. Exp Brain Res 1990;81:479–490.
Cremer PD, Halmagyi GM, AW ST, Curthoys IS, McGarvie LA, Todd MJ, Black RA, Hannigan
IP: Semicircular canal plane head impulses detect absent function of individual semicircular
canals. Brain 1998;121:699–716.
Hain TC, Fetter M, Zee DS: Head-shaking nystagmus in patients with unilateral peripheral
vestibular lesions. Am J Otolaryngol 1987;8:36–47.
Ewald R: Physiologische Untersuchungen über das Endorgan des Nervus Octavus. Wiesbaden,
Bergmann, 1892.
Baloh RW, Honrubia V, Konrad HR: Ewald’s second law re-evaluated. Acta Otolaryngol 1977;83:
474–479.
Raphan T, Matsuo V, Cohen B: Velocity storage in the vestibulo-ocular reflex arc (VOR). Exp
Brain Res 1979;35:229–248.
Fluur E: Interaction between the utricles and the horizontal semicircular canals. IV. Tilting of
human patients with acute unilateral vestibular neuritis. Acta Otolaryngol 1973;76:349–352.
Singleton GT, Post KN, Karlan MS, Bock DG: Perilymph fistulas: diagnostic criteria and therapy.
Ann Otol Rhinol Laryngol 1978;87:797–803.
Leigh RJ, Zee DS: The Neurology of Eye Movements, ed 2. Philadelphia, F.A. Davis, 1991,
pp 384–385.
Scherer H, Clarke AH: The caloric vestibular reaction in space. Physiological considerations. Acta
Otolaryngol 1985;100:328–336.
Baloh RW, Sills AW, Honrubia V: Caloric testing. 3. Patients with peripheral and central vestibular
lesions. Ann Otol Rhinol Laryngol Suppl 1977;86(suppl 43):24–30.
Baloh RW, Sakala SM, Yee RD, Langhofer L, Honrubia V: Quantitative vestibular testing.
Otolaryngol Head Neck Surg 1984;92:145–150.
Nelson JR: The minimal ice water caloric test. Neurology 1969;19:577–585.
Fetter
50
41
42
43
44
45
46
47
48
49
50
Baloh RW, Honrubia V, Yee RD, Hess K: Changes in human vestibulo ocular reflex after loss of
peripheral sensitivtiy. Ann Neurol 1984;16:222–228.
Cohen B, Suzuki J: Eye movements induced by ampullary nerve stimulation. Am J Physiol
1963;204:347–351.
Suzuki J, Cohen, B: Head, eye, body and limb movements from semicircular canal nerves. Exp
Neurol 1964;10:333–405.
Fetter M, Dichgans J: Vestibular neuritis spares the inferior division of the vestibular nerve. Brain
1996;119:755–763.
Aw ST, Fetter M, Cremer PD, Karlberg M, Halmagyi GM: Individual semicircular canal function
in superior and inferior vestibular neuritis. Neurology 2001;57:768–774.
Aw ST, Haslwanter T, Fetter M, Dichgans J: Three-dimensional spatial characteristics of caloric
nystagmus. Exp Brain Res 2000;134:289–294.
Fetter M, Sievering F: Three-dimensional (3-D) eye movement analysis in patients with positioning nystagmus. Acta Otolaryngol (Stockh) 1995;520:369–371.
Fetter M, Aw ST, Haslwanter T, Heimberger J, Dichgans J: Three-dimensional eye movement
analysis during caloric stimulation used to test vertical semicircular canal function. Am J Otology
1998;19:180–187.
Dieterich M, Brandt T: Ocular torsion and tilt of subjective visual vertical are sensitive brainstem
signs. Ann Neurol 1993;33:292–299.
Colebatch JB, Halmagyi GM, Skuse NF: Myogenic potentials generated by a click-evoked
vestibulocollic reflex. J Neurol Neurosurg Psychiatry 1994;57:190–197.
Prof. Michael Fetter, MD
SRH Clinic Karlsbad-Langensteinbach, Department of Neurology
Guttmannstrasse 1
DE–76307 Karlsbad (Germany)
Tel. ⫹49 7202 610, Fax ⫹49 7202 616180, E-Mail [email protected]
Vestibulo-Ocular Reflex
51
Straube A, Büttner U (eds): Neuro-Ophthalmology.
Dev Ophthalmol. Basel, Karger, 2007, vol 40, pp 52–75
Neural Control of Saccadic Eye Movements
Nicolas Catz, Peter Thier
Department of Cognitive Neurology, Hertie Institute for Clinical Brain Research,
Tübingen, Germany
Abstract
One of the major functions of the central nervous system is the generation of movement
in response to sensory stimulation. The visual guidance of saccadic eye movement represents
one form of sensory-to-motor transformation that has contributed significantly to our understanding of motor control and sensorimotor processing at large. The neural circuitry controlling saccadic eye movements is now understood at a level that is sufficient to link the specific
roles of a number of saccade-related cortical and subcortical areas. In this chapter, we review
the main subcortical areas for controlling saccades, concentrating mostly on the role of the
posterior cerebellar vermis (PV), with the dorsal pontine nuclei and the nucleus reticularis
tegmenti pontis as the major gateway to the PV and the fastigial nucleus as the link between
the PV and the brainstem saccade generator. We argue that the PV is the key structure
enabling saccadic learning and that this contribution is based on the control of saccade duration by a PV Purkinje cell population signal.
Copyright © 2007 S. Karger AG, Basel
One of the major functions of the central nervous system is the generation
of movement in response to sensory stimulation. Saccadic eye movements represent an example of the sensory guidance of movements that has contributed
significantly to our understanding of some of the general principles underlying
the sensory guidance of movement. The eyes have a simple and well-defined
repertoire of movements, and the neural circuitry regulating the production of
saccadic eye movements is now understood at a level that is sufficient to
attribute specific roles to a number of saccade-related cortical and subcortical
areas and to characterize their interactions in the generation of saccades.
Different kinds of saccades can be distinguished. Resetting saccades are a
major component of reflectory optokinetic and vestibular gaze-stabilizing
reflexes. They regularly interrupt the smooth stabilizing movements in order to
move the eyes back towards the center of the orbit, whereupon another period of
slow gaze-stabilizing movements can follow [1]. Rather than contributing to
stabilizing the visual scene, target-directed saccades emphasize particular
objects whose images are foveated in order to improve their scrutiny. The object
serving as target of a saccade may be singled out from a number of others by a
selection process that involves a careful consideration of object features and the
expectations and needs of the observer. Such target-directed saccades are usually referred to as goal directed [2]. Alternatively, the target for a saccade may
be an object appearing unexpectedly, requiring immediate attention and therefore prompting a reflectory orienting saccade. Objects serving as targets of saccades may be defined by visual, auditory or tactile cues. Objects whose location
defines a desired location for the eyes do not have to be present at the time the
saccade is carried out. Rather, fairly precise saccades can be elicited based on
memorized information on the target location (memory-guided saccades).
Antisaccades are a specific example of a spatial dissociation of object location
and saccade goal, resulting from the instruction to invert the vector defining the
object location in order to generate a saccade vector [3–5]. Finally, spontaneous
saccades may be generated in the absence of any guiding sensory cues, defining goals in the external world, solely determined by endogenous goals.
Irrespective of the circumstances causing a saccade, all saccades are fast
ballistic eye movements, reaching maximum velocities up to 500⬚ per second
and more, and are usually completed within tens of milliseconds. Despite their
speed, saccade trajectories tend to be remarkably stereotyped both within and
across individuals. The duration and peak velocity of saccades increases monotonically with the amplitude of the movement in a consistent way, usually
referred to as the ‘main sequence’ [6] (fig. 1).
Saccade latency is defined as the delay between the presentation of the cue
and the onset of the saccade. Latency for saccades varies between 100 and
300 ms, depending on the type of target-directed saccade. Express saccades are
especially fast orienting saccades with latencies of ⬍100 ms [7, 8] that can be
observed if attention is not bound by a fixation point at the time a peripheral
visual target comes up. Like the second type of target-directed eye movements,
smooth-pursuit eye movements [9], also target-directed saccades obey Listing’s
law, minimizing the amount of torsion that accompanies the movements of the
eyes about their horizontal and vertical axes, thereby stabilizing the orientation
of the object image on the retina [10, 11]. The programming and execution of a
saccadic eye movement require different operations which overlap in time,
rather than following in a serial manner. (1) Fixation has to be disengaged, a
process that involves detaching attention from a fixated object and shifting
attention to the new object or the desired spatial location. During fixation, the
saccade machinery is suppressed by tonic inhibition from a cortical-subcortical
network that embraces neurons in the frontal eye fields (FEF and SEF) [12–14],
Neural Control of Saccadic Eye Movements
53
10
5
Target
Eye
0
0
50
100
200
400
200
0
0
Time (ms)
800
70
600
500
400
300
200
100
150
200
250
Time (ms)
80
700
50
b
900
60
50
40
30
20
10
100
0
0
0
c
600
250
Saccade duration (ms)
Peak of velocity (degrees/s)
a
150
Eye velocity (degrees/s)
Eye position (degrees)
15
2
4
6
0
8 10 12 14 16 18 20 22 24 26
Saccade amplitude (degrees)
d
2
4
6
8 10 12 14 16 18 20 22 24 26
Saccade amplitude (degrees)
Fig. 1. Example of 10⬚ horizontal saccade: horizontal position of the eye and target (a)
and horizontal saccade velocity (b) as a function of time. Saccade ‘main sequence’: peak of
saccade velocity (c) and saccade duration (d) as a function of saccade amplitude.
in the superior colliculus (SC; fixation region [15, 16]), and the brainstem
(omnipause neurons; OPNs [17]), inhibition that has to be terminated in order
to facilitate the upcoming saccade. (2) The acquisition of the spatial coordinates
of the target location and their transformation into the spatial coordinates of the
saccade endpoint. This step, as well as the reallocation of spatial attention
alluded to before relies to a large extent on posterior parietal circuits, specifically on saccade representations in the intraparietal cortex such as area lateral
intraparietal sulcus (LIP) [18–20]. (3) The transformation of the saccade vector,
describing the desired change in eye position into a motor command that
unfolds in time and that is responsible for the kinematics features of the
observed saccade. Hence, the motor command, in order to be appropriate, must
be based on a full consideration of the dynamical aspects of the movement. The
elaboration of an appropriate motor command sent to the oculomotor motoneurons (MNs) is the major function of the premotor circuitry in the brainstem,
Catz/Thier
54
interacting closely with the SC and parts of the cerebellum. This review focuses
on the role of the subcortical structures involved in the generation of saccades,
placing special emphasis on the cerebellum and the major precerebellar nuclei.
Readers interested in the cognitive control of saccades and the spatial processing preparing target-directed saccades, largely cortical functions, are referred to
several excellent reviews available on the topic [13, 21].
The Brainstem Saccadic Generator
Oculomotor MNs discharge a burst of action potentials for saccades in
their respective ‘on-direction’ and suppress their discharge during saccades in
the ‘off-direction’. Burst amplitude is correlated with eye velocity and the number of spikes in the burst scales with saccade amplitude. These transient
changes in the discharge of MNs pass over into a tonic level of activity, whose
amplitude depends on eye position. Both the size of the transient change during
the movement as well at the level of the subsequent tonic activity are determined by input from premotor neurons located in mesencephalic, pontine and
medullary regions of the brainstem reticular formation [22]. The burst component of the MN discharge is generated by short-lead burst neurons (fig. 2).
Burst neurons for horizontal saccades are located in the paramedian pontine
reticular formation (PPRF) next to the abducens nucleus [23], while those for
vertical saccades lie in the rostral interstitial nucleus in the midbrain reticular
formation (MRF) near the oculomotor nucleus [24, 25]. As the functional architecture of the circuit subserving vertical saccades in the MRF follows the same
principles as the one for horizontal saccades in the PPRF, we will restrict our
description to the latter (for review on the vertical system, see [26]).
The PPRF projects ipsilaterally to the abducens nucleus [27–30], to the
prepositus hypoglossi nucleus (NPH) [27, 28, 30, 31], to the median vestibular
nucleus (MVN) [32] and to the posterior vermis [33]. The PPRF receives input
from the SC, the posterior vermis via the fastigial nuclei and the FEF. In the
PPRF, two types of burst neurons can be distinguished with respect to their
action: the excitatory burst neurons (EBNs, or short-lead burst neurons) and the
inhibitory burst neurons (IBNs) [34–36] (fig. 2).
The Excitatory and Inhibitory Burst Neurons
The EBNs of the PPRF are responsible for the activation of the agonist
MNs of the abducens nucleus which activate the ipsilateral lateral rectus muscle, and via internuclear neurons in the abducens nucleus neurons (INs) they are
also responsible for the activation of the agonist MNs in the oculomotor nucleus
controlling the contralateral medial rectus muscle [37, 38]. The EBNs are
Neural Control of Saccadic Eye Movements
55
Left
Right
SC-BN
LLBNs
SC-FN
Tr
TN
EBN
EBN
La
OPN
IBN
IBN
VI
IN
MN
VI
IN
MN
III
Lateral rectus
Medial rectus
Medial rectus Lateral rectus
Midline
Fig. 2. Brainstem circuitry involved in the execution of leftward saccades, involving a
contraction of the left lateral rectus and the right medial rectus, while the left medial rectus
and the right lateral rectus are relaxed (antagonist muscles). VI ⫽ Abducens nucleus; III ⫽
oculomotor nucleus; La ⫽ latch neurons; Tr ⫽ trigger neurons. Excitatory connections are
indicated by filled lines. The inhibitory connections are indicated by dashed lines.
completely silent during intersaccadic periods. On the other hand, these neurons
exhibit sharp and vigorous bursts of action potentials during the saccade that
starts around 5–15 ms before the ipsilateral saccade [23, 39]. The number of
action potentials fired during the saccade increases with saccade amplitude as
well as with instantaneous eye velocity [39].
The second type of burst neuron is represented by the IBNs. These neurons
inhibit the MN and IN of the contralateral abducens nucleus [35, 40]. The IBNs
are involved in the process of relaxation of the antagonist muscles. As the EBNs,
the IBNs are silent during the intersaccadic periods and their saccade-related
Catz/Thier
56
burst precedes the saccade onset by around 5–15 ms [41]. The duration of
the burst is proportional to the duration of the horizontal component of the
movement [26].
The Omnipause Neurons
The PPRF contains another distinct population of neurons, critical for the
timing of saccades, the OPNs. OPNs discharge tonically during fixation at rates
of more than 100 spikes per second and pause for saccades in all directions
[42]. The pause starts a few milliseconds before the onset of the burst of
EBNs/IBNs and ends at saccade offset. As EBNs and IBNs are subject to potent
inhibition from the OPNs, the OPNs contribute to stabilizing fixation. The
pause in OPN firing during the saccade, needed in order to allow the saccade to
develop, is most probably due to changes in several types of signals, impinging
on OPNs. First, it could be due to the cessation of the sustained activity of fixation neurons (SC-FNs) located in the rostral pole of the SC, exciting OPNs
monosynaptically [43]. Second, the inhibition of the OPNs during the saccade
could also be a consequence of the excitation of the long-lead burst neurons
(LLBNs) in the rostral PPRF, influenced by the saccade-related burst neurons
located in the SC, outside the fixation zone (SC-BN). These LLBNs, then,
excite the EBNs, which inhibit the OPNs via inhibitory latch neurons. A third
way to inhibit the OPNs is the excitation of inhibitory neurons located directly
between SC-BN and the OPNs [44]. Fourth, inhibition of the OPNs during saccades could originate from indirect inhibitory projections from the caudal fastigial nucleus (cFN), output nucleus of the oculomotor cerebellum [45].
The Tonic Neurons
The EBNs discussed before provide a signal related to eye velocity needed
in order to move the eyes against velocity-dependent viscous forces to the target. However, in order to stabilize the eyes in the new position acquired by the
saccade, a signal related to eye position, counteracting position-dependent elastic forces, trying to move the eyes back towards straight-ahead, is needed. This
signal is provided by tonic neurons (TNs). Horizontal TNs are located in the
PPRF, intermingled with horizontal EBNs, and like EBNs they make excitatory
connections with MNs. Vertical TNs are found in the MRF next to vertical
EBNs. The discharge of TNs is linearly related to eye position. Robinson [54]
suggested that the eye position-related signal of TNs could be the result of a
mathematical integration of the eye velocity-related signal provided by EBNs.
A copy of the eye velocity signal would be sent to a ‘neural integrator’ (NI) in
order to generate a tonic command coding for the eye position. This command
would allow the MNs to offer the constant position-dependent firing rate
needed in order to stabilize the eyes at an eccentric position. Lesion experiments
Neural Control of Saccadic Eye Movements
57
E*
冮dt
Step
[⫽TN]
⫺
Ed
⫹
e
Pulse generator
[⫽EBN]
.
E‘
MN
Plant
Fig. 3. The Robinson internal feedback model for saccades. Ed ⫽ Eye-desired displacement; E* ⫽ actual eye displacement.
suggest that two structures, the MVN, located caudally to the PPRF, and the
NPH, reciprocally connected to the PPRF, MVN, vestibular cerebellum (flocculus) and oculomotor cerebellar vermis (lobuli VI and VII ) are involved in the
integration of the velocity command as they lead to an inability to maintain the
eyes in an eccentric position: after any centrifugal saccades the eyes turn systematically back to a stable position at straight-ahead [46–48]. It has been proposed that the integration by the NI could be based on local recurrent
excitation, i.e. neurons will excite their neighbors, which in turn will feed them
back with excitation [49, 50]. The NPH, located caudal of the abducens
nucleus, which also contains a high number of TNs coding the position of the
eye, is probably part of this excitatory feedback network [51–53]. The activity
of TNs increases with the ipsilateral deviation of the gaze. The types of neurons
found in the PPRF have distinct roles in an influential model of the control of
saccadic eye movements, put forward by Robinson [54], whose key features
pervade any later models up to the present day. Probably the major feature is the
idea of internal feedback as a way to deal with the unacceptably long latencies
of visual feedback signals (fig. 3).
An ongoing targeting saccade should be stopped once the object image has
reached the fovea. However, the long latency of visual signals, having an order
of magnitude of 50 ms and more, precludes the possibility to use information
from the fovea to stop the saccade at the right point in time. The Robinson
model (fig. 3) assumes short-latency internal or ‘local’ feedback as an alternative to visual feedback. According to the local feedback concept, the eyes are
driven by a signal that is the difference between desired eye position and an
estimate of current eye position, the latter provided by the eye position-related
TNs. This ‘motor error’ activates the saccadic burst neurons, the EBNs, that
generate a pulse of activity proportional to the size of the motor error. The EBN
pulse and the TN position step signals are integrated by the ocular MNs and
Catz/Thier
58
Extrastriate
visual cortex
FEF
LIP
IO
Basal ganglia
DPN
Cerebellum
NRTP
Retina
SC
Burst generator
Ocular MNs
Fig. 4. Simplified diagram of the major cortical and subcortical areas involved in the
planning, preparation and execution of saccadic eye movements.
give rise to their characteristic burst-tonic discharge which is responsible for the
movement (discharge burst ⫽ ‘pulse’) and the subsequent stabilization of the
eyes in new orbital position (tonic discharge ⫽ position ‘step’). During the
movement, the ‘efference copy’ of the movement, represented by the TNs,
grows and consequently, the motor error is gradually reduced to zero, which is
why the movement will ultimately come to a stop.
The role of the OPNs in this model is basically to speed up the transition
from fixation to movement and back again and, moreover, to stabilize the
respective states. This is a direct consequence of the reciprocal inhibitory connections between OPNs and EBNs. The decision to start a saccade will activate
EBNs directly and in addition indirectly by reducing inhibition from OPNs,
Neural Control of Saccadic Eye Movements
59
whose activity will be reduced by the decision to start a saccade as well as by
the growing activity of the EBNs. Conversely, during fixation, the inhibition
from OPNs will tend to suppress spurious activation of EBNs and thereby unintended saccades (fig. 4).
The Superior Colliculus
The brainstem burst generators in the PPRF and the MRF receive input
from a number of brain structures such as the SC, the FEFs and the oculomotor
cerebellum. The input from the SC, homologue of the optic tectum in amphibians and fishes, is probably the most important and, moreover, the best understood source of input. The SC is a multilayered structure whose intermediate
layer plays a critical role in the control of visual fixation and saccadic eye
movements, serving as the key structure underlying the spatiotemporal transformation for saccades. Neurons in the intermediate layer of the SC show convergence of visual, auditory, and somatosensory informations, integrated to guided
saccades but also other types of orientation behavior [55–59]. The role of the
intermediate layer of the SC in the guidance of saccades has first been established by electrical microstimulation [60], which evokes saccades into the contralateral hemifield with amplitudes and directions fully determined by the
location of the microelectrode in the SC (fig. 5). Large saccades are elicited by
microstimulation of the caudal SC, whereas small saccades are evoked by
microstimulation of its more rostral part. Moving the stimulation microelectrode gradually within the intermediate layer leads to gradual changes in the
metrics of evoked saccades, demonstrating that the intermediate layer of the SC
contains a topographic map of saccade endpoints. The location of the endpoint
of evoked saccades coincides with the location of the circumscribed movement
fields of saccade-related burst neurons, found at the respective location in the
intermediate layer. Moreover, the map of saccade endpoints in the intermediate
layer is congruent with the retinotopic map in the overlying, purely visual
superficial layer of the SC. Three other types of neurons characterize the intermediate layer of the SC. In addition to the burst neurons (SC-BNs), which are
purely saccade-related, lacking any visual responses, the intermediate layer also
houses purely visual as well as mixed visuomotor neurons. One variety of the
latter, the so-called build-up cells play a decisive role in current models of the
role of the SC in the generation of saccades. Unlike the visual and the burst
cells, they are characterized by open response fields that lead to their activation
by any saccade in their preferred direction, independent of amplitude. The rostral pole of the SC, adjoining to the small saccade representation, is special as it
contains neurons (SC-FNs) that are active during fixation, rather than being
Catz/Thier
60
Left
15º
Right
5º
Caudal
20
10
10º
0
20 spike/s
–10
SC-BN
5º
30
20
2.5º
10
5
Rostral
Fixation
region
SC-FN
20 spike/s
0 250
a
b
Time from saccade
onset (ms)
Fig. 5. The superior collicular map for saccades. a The rostral-caudal (thin lines) axis
represents the saccade horizontal component, while the vertical component is represented by
the mediolateral axis (thick lines). b Discharge of a SC-BN and discharge of a SC-FN during
a 15⬚ saccade.
activated by saccades. Conversely, these fixation neurons are silent during saccades. While the fixation zone maintains an excitatory projection to the brainstem omnipause region, the burst neurons project to the brainstem burst
generators via LLBNs in the midbrain. The decision to carry out a saccade of a
given amplitude and direction will activate the neurons at the corresponding
location in the SC map, while at the same time inhibiting the SC fixation zone
(fig. 5b). Excitatory drive will be passed on from this location to the EBNs by
way of the LLBNs. At the same time, activity from this initial location in the SC
spreads to buildup neurons in neighboring locations representing smaller
amplitudes which will sustain the excitation of the brainstem burst generator.
The drive of the EBNs will come to an end, once the spread of activity on the
collicular map has reached the fixation zone, on the one hand, stopping EBNs
directly, and on the other hand, activating OPNs. In sum, the spatiotemporal
transformation for saccades is a direct consequence of the functional architecture of the SC and its connections with the brainstem (fig. 5).
The scheme sketched out before is a simplification of more elaborated
models on the role of the SC in the generation of saccades [61, 62]. Although
based on an abundance of anatomical and physiological observation, they still
contain a number of speculative and highly controversial elements. Alternative
views on the role of the SC in saccades that have recently been proposed suggest a direct involvement in the feedback control of saccades [63, 64] or the
elaboration of the ‘error signal’ needed in order to adjust the oculomotor plant
Neural Control of Saccadic Eye Movements
61
[65–67]. Bergeron et al. [67] proposed, in extension of the original assumption
of Robinson [60], that the SC encodes the distance to the target rather than saccade amplitude. Distance to target is given by comparing target position on the
retina with current gaze position, yielding the gaze shift needed (gaze position
error) to fovealize the target. The important difference with respect to the original Robinson model is that the variable controlled is gaze, the sum of eye and
head position, rather than just eye position and, secondly, that the SC is inside
the feedback loop calculating the motor error.
The Basal Ganglia
The interest in the role of the basal ganglia in the control of saccadic eye
movements emerged after saccade-related neurons had been demonstrated in
various parts of the basal ganglia [68, 69] and, moreover, a direct projection
from the substantia nigra pars reticulata (SNr) to the SC had been established
[70]. This inhibitory projection is in turn under the control of an inhibitory projection coming from the caudate nucleus (CN). One of the main functions of the
basal ganglia in the control of saccades seems to be the avoidance of unwanted
saccades. This is demonstrated by the emergence of spurious saccades, if the
tonic inhibitory input is blocked experimentally (fig. 6) [71]. For instance, in
order to suppress too early saccades in a memory-guided saccade task the SNr
continuously inhibits the SC-BN in the intermediate layer of the SC [71, 72]. If
the context allows the execution of the saccade, the CN via its negative action
on the SNr will disinhibit the SC-BN [73], allowing the SC-BN to fire and start
a saccade (fig. 6).
The Oculomotor Role of the Pontine Nuclei and the
Nucleus Reticularis Tegmenti Pontis
Both cortical structures we dispose of, cerebral cortex and cerebellar cortex are involved in the control of saccades. The major pathway linking the two
cortices, including those areas involved in saccades, is the cerebropontocerebellar projection with the pontine nuclei (PN) in the basilar brainstem serving as
intermediate station. In addition to input from saccade-related areas of the cerebral cortex such as area LIP and the FEF, the PN also receive visual and eye
movement-related input from the SC. Accordingly, the PN may be regarded as a
central integration unit in a major pathway subserving saccades. In this section,
we will describe the role of the PN in saccades and in addition discuss the role
of a neighboring major precerebellar nucleus, the nucleus reticularis tegmenti
Catz/Thier
62
CN
CN
⫺
⫺
SNr
SNr
Bicuculine
⫺
⫺
a
SC
SC
Brainstem burst
generator
Brainstem burst
generator
b
10º
100 ms
c
Fig. 6. a Scheme of the inhibitory projection from the basal ganglia to the SC. b The
injection of the GABA antagonist (bicuculine) into the SC suppresses the inhibition and
thereby induces spurious saccades shown in (c). c Saccadic jerks during fixation of a central
target after injection of bicuculine into the left SC while the monkey waits for the signal to
make a saccade to a memorized spatial location. The vertical line marks the end of the presence of the fixation target. Upper traces show horizontal and lower traces vertical eye position. From Hikosaka and Wurtz [71], with permission.
Neural Control of Saccadic Eye Movements
63
pontis (NRTP), a structure lying adjacent to the medial parts of the PN, but still
much less dependent on input from cerebral cortex than the PN.
The Pontine Nuclei
The dorsolateral PN (DLPN) and neighboring parts of the PN receive
ample input from a number of cerebrocortical and subcortical structures known
to be involved in saccadic eye movements such as the FEF, parietal areas LIP
and MP, or the SC. Hence, the anatomy strongly suggests that the PN might be
involved in information processing for saccades as well, rather than being confined to the slow visually guided eye movements emphasized by the early electrophysiological and lesion work on the PN [74, 75]. Actually, as it turns out,
saccade-related single units can be encountered almost as frequently as single
units activated by smooth pursuit eye movements if the dorsal parts of the PN
are explored without any bias for the one or the other type of oculomotor behavior. In two rhesus monkeys trained to perform smooth pursuit eye movements as
well as visually and memory-guided saccades, out of 281 neurons isolated from
the dorsal PN (DPN), 138 were responsive in oculomotor tasks. Forty-five were
exclusively activated in saccade paradigms, 68 exclusively by smooth pursuit,
and 25 neurons showed responses in both [76]. The various types of oculomotor
neurons could be encountered in the lateral as well as medial parts of the DPN
without any distinctive differences in their relative frequencies, further putting
into perspective the notion of the DLPN as the only oculomotor part of the PN.
Saccade-related neurons in the DPN were found intermingled with those discharging in conjunction with smooth pursuit eye movements. Most saccaderelated neurons had a preferred saccade direction. However, with respect to
other features, they were quite heterogeneous, exhibiting a wide variety of
response patterns when tested in a memory-guided saccade task. Whereas some
discharged only at the time of the eye movement, others displayed additional
visual responses or activity in the ‘memory’ period. Even the features of
saccade-related bursts differed substantially between neurons, as among others
reflected by the wide distribution of burst onset latencies, varying between substantial lead and lag relative to eye movement onset. The sources of afferents
impinging on the DPN involve probably all cerebrocortical representations of
saccadic eye movements, areas which house neurons with very different types
of saccade-related responses. The heterogeneity of saccade-related responses in
the DPN is therefore most probably a reflection of the diversity of the cerebrocortical input. While about 90% of the afferents impinging on the DPN are of
cerebrocortical origin [77], there is additional input from a number of subcortical sources, including the SC [78]. Hence, in principal saccade-related signals
in the DPN might also reflect saccade-related input from the SC, rather than
information originating from the saccade-related areas of the cerebral cortex.
Catz/Thier
64
While some of the saccade-related neurons encountered in the DPN may indeed
have been driven by input from the SC, it seems unlikely to be true for the
majority of these neurons. This is suggested by the fact that the projection from
the SC is not only small, compared with the one originating from cerebral cortex, but, moreover, largely restricted to the rostral DLPN proper [78]. However,
saccade-related neurons were found in extended parts of the DPN, most probably also in locations far away from the putative target zones of the SC projection,
and, moreover, without any clear differences in the properties of saccade-related
responses in different parts of the DPN.
Neurons showing combined sensitivities to saccades and to smooth pursuit, surprisingly frequent in the DPN, do not seem to have a cerebrocortical
counterpart. This might suggest that they are constructed by convergence of
more specialized oculomotor streams originating from different parts of the
cerebral cortex. The functional role of these ‘combination’ neurons is unclear.
One might speculate that they play a specific role in the generation of catch-up
saccades, executed in an attempt to bring the eye back on target in case of insufficient smooth pursuit eye movements. However, such a role would probably
require coinciding preferred directions for saccades and smooth pursuit, a coincidence these ‘combination’ neurons typically lack.
Unlike the effects on smooth pursuit eye movements, small experimental
lesions of the monkey DLPN do not affect saccades made to stationary visual
targets. However, saccades made to targets moving away from the starting position of the eyes become hypometric for target movement toward the side of the
lesion [74]. Larger lesions of the human basilar pons, sparing the brainstem
tegmentum, may cause hypometria also of saccades made toward stationary targets without changing saccade velocity and its dependence on saccade amplitude [Bunjes and Thier, unpubl. obs.].
The Nucleus Reticularis Tegmenti Pontis
The dominating type of saccade-related neurons in the NRTP produces
bursts of spikes before and during a saccadic eye movement directed toward circumscribed movement fields. Unlike neurons in the nearby PPRF, the discharge
intensity or duration does not reflect the saccade metrics. Some of these
neurons exhibit additional visual sensitivity to spots of light turned on within
the movement field. These neurons are functionally intermediate between the
saccade-only neurons mentioned before and neurons with purely visual
responses found in the same area. The features of these three types of neurons
are reminiscent of the neurons in the SC, from which some of the input of the
NRTP is derived. However, unlike movement fields of saccade neurons in the
SC, those in the NRTP have a 3-D organization, reflecting eye torsion as well as
the vertical and the horizontal excursions of the eye [79]. Moreover, unlike
Neural Control of Saccadic Eye Movements
65
microstimulation of the SC, which moves the eyes vertically and horizontally
but not torsionally [80], stimulation of the cNRTP induces torsional deviations
of the eyes. Finally, lesions of the NRTP seem to impair the ability to reset torsional errors. Taken together, these observations strongly support the idea that
the NRTP is a key element in a circuit downstream of the SC stabilizing
Listing’s plane against torsional errors of the saccadic system.
The Oculomotor Cerebellum
Several regions of the cerebellum house Purkinje cells that discharge in
relation to saccadic eye movements. The region first identified and probably
best understood is located in the posterior vermis, comprising vermal lobuli VI
and VII and occasionally also referred to as the oculomotor vermis or Noda’s
vermis, the latter name chosen to honor the late Hiroharu Noda, whose work
has contributed considerably to our current view of this part of the cerebellum.
A contribution of the posterior vermis and neighboring parts of the cerebellum
to saccades was first suggested by experiments in which surgical lesions of this
part of the cerebellum were carried out. For instance, Aschoff and Cohen [81]
observed fewer saccades to the impaired hemifield after unilateral lesions of the
cerebellar vermis, and Ritchie [82] described dysmetric saccades to visual targets following lesions of the posterior vermis. Dysmetric saccades have also
been reported in the clinical literature as the consequences of cerebellar pathology involving the human vermis due to disease [83]. Ron and Robinson [84]
showed that electric stimulation through electrodes placed in the posterior
vermis and neighboring paravermis with currents of up to 1 mA was able to
evoke saccadic eye movements. While this early work suggested a quite
extended saccade representation in the posterior cerebellum, Noda and coworkers, by resorting to electric microstimulation, could show that the saccade
representation was actually much smaller than hitherto assumed [85–88]. When
stimulation currents were kept below 10 ␮A, saccades could only be evoked
from lobuli VIc and VIIA of the posterior vermis, but not from the adjoining
regions of the vermis and paravermis. Moreover, Noda and Fujikado [89] could
show that the stimulation effects were a consequence of activating Purkinje cell
axons and could rule out that the antidromic activation of vermal afferents,
originating from brainstem centers for saccades, contributed to the evoked saccades. The oculomotor vermis projects to the saccade representation in the cFN,
which in turn projects to the brainstem centers for saccades [88, 90]. The cFN
contains numerous saccade-related neurons. The properties of the saccaderelated bursts depend on the direction of the saccade being controversive or
ipsiversive [91–94]. Furthermore, the unilateral inactivation of the cFN induces
Catz/Thier
66
saccadic dysmetria, ipsiversive hypermetria and controversive hypometria [95].
The induced dysmetria is accompanied by abnormalities in saccade kinematics
[96].
It is therefore very likely that the effects of activating Purkinje cells artificially by electric stimulation are mediated by this pathway. Electric microstimulation has clearly been very helpful in identifying the saccade-related parts of
the posterior vermis and the pathway originating from there. On the other hand,
its contribution to the characterization of the functional role of cerebellar cortex
in the control of saccades has been limited.
Our own recent work on the posterior vermis [97] suggests that posterior
vermal Purkinje cells provide a signal used to adapt the duration of the pulse
offered by the brainstem pulse generator, a hypothesis which is based on the
analysis of the properties of saccade-related neurons in the posterior vermis.
When tested in the memory-saccade paradigm, in which center-out saccades are made in darkness towards the remembered location of a cue, turned
off a couple of 100 ms before the saccade is carried out, most saccade-related
Purkinje cells exhibit pure saccade bursts. They only rarely show visual responses
or activity in the period of time; the monkey is waiting for the go-signal to start
the saccade. Moreover, these saccade-related responses are usually direction
selective. Saccade duration and amplitude are closely linked. Saccade duration
increases linearly with amplitude for up to 40⬚, allowing one to change saccade
duration by simply asking monkeys to make saccades of different amplitudes.
When saccades of different amplitudes are carried out in the preferred direction
of a given cell, the amplitude dependency of the saccade-related bursts is highly
idiosyncratic. Whereas some cells may show a monotonous increase in the
number of spikes fired with increasing saccade amplitude, others show preferred amplitudes or no dependency on amplitude at all within a range of amplitudes up to 40⬚. In other words, one would most probably fail if one tried to
determine the duration or amplitude of a saccade made by the monkey by monitoring the discharge pattern of individual cells. Unlike individual cells, though,
larger groups of these saccade-related Purkinje cells provide a precise signature
of saccade duration and amplitude. This is suggested by the conspicuous relationship between saccade duration and the duration of the population burst, the
instantaneous discharge rate of a larger (n ⱖ 50) group of saccade-related
Purkinje cells, obtained by considering the timing of each spike fired by each
cell in the sample. Figure 7 shows a plot of the simple spike (SS) population
burst, based on 94 Purkinje cells from the posterior vermis as function of time
around a saccadic eye movement. The population burst is plotted for three different saccade durations (fig. 7a). It starts, independent of saccade duration a
couple of 10 ms before saccade onset and peaks exactly at the time the saccade
starts, again independent of saccade duration. It is the decline of the population
Neural Control of Saccadic Eye Movements
67
Saccade
onset
100
50
60
c
Sac
Rate (1/s)
80
Rate (1/s)
30 ms
49 ms
65 ms
100
60
ade
40
atio
dur
20
0
20
40 60
80
a
b
⫺50
0
50
Time (ms)
c
Time (ms)
s)
Saccade
end
b
n (m
⫺40 ⫺20
a
40
⫺100
⫺50
0
50
Time (ms)
d
Time (ms)
60
50
40
30
c
100
Fig. 7. Cerebellar Purkinje cells population response. a Population burst profiles for
3 saccade durations of 30, 49 and 65 ms. b Dependence of population burst on saccade
duration. The x-axis plots the time relative to saccade onset at 0 ms, the y-axis saccade
duration, and the z-axis the mean instantaneous discharge rate of the population of 94
Purkinje cells. c Regression plots relating different parameters characterizing the saccade
timing and the burst time to each other. See the text for explanation. a, c Taken from Thier et
al. [97], with permission.
burst, which depends on saccade duration: it is longer the longer the saccade
lasts. This clear dependency of the time the population burst ends on the time
the saccade ends is not restricted to the three saccade durations presented in figure 7a but characterizes the full range of saccade durations tested (from less
than 30 ms to almost 80 ms).
This is shown in figure 7b, which depicts a pseudo 3-D plot of the population burst as a function of saccade duration. In order to relate the time course
Catz/Thier
68
of the population burst more precisely to the time course of the saccade, we
measured the times of onset (a), peak (b) and offset (c) of the population burst
relative to saccade onset of each saccade duration as well as the population
burst duration (d), given by c – a. We determined population onset and offset
times as the times when the population burst reached 4 times the baseline firing
rate when building up and when declining. Figure 7c plots time t as a function
of a, b, c, and d, respectively. In the case of a, b and d, t corresponds to saccade
duration, in the case of c to the time of saccade termination. The plots are fitted
by linear regressions. Both c and d increased linearly (c: p ⫽ 0.00004, d:
p ⬍ 0.01) with the time of saccade termination and saccade duration, respectively, whereas neither a nor b depended significantly (p ⬎ 0.05) on saccade
duration. The end of the population burst (c) as predicted by the regression, corresponds very closely to the end of the saccades, whereas the population burst
duration (d) underestimates saccade duration by 24%. This fact and the significantly higher coefficient of correlation for c compared with d indicate that the
population burst reflects the time of saccade termination. Individual cells fire
their bursts at different times relative to the saccade, some reaching their maximum quite early, even before saccade onset, while others fire much later. None
of the individual Purkinje cells reflect the termination of the saccade as accurately as the population response [97].
Based on the number of Purkinje cells in rhesus monkeys [98] and the
number of deep cerebellar nuclei neurons [99], it can be estimated that on the
order of 20–30 Purkinje cells converge on individual cells in the deep cerebellar
nuclei. This means that a cell in the caudal part of the fastigial nucleus, the target of the posterior vermis, is probably influenced by a compound signal, not
too different from the population burst as described before. In other words, the
population burst is not a mathematical artifact but most probably a direct functional consequence of the properties of the cerebellonuclear projection. In view
of the GABAergic nature of this projection, the population burst will deliver a
strong hyperpolarizing signal to the recipient nuclear neuron, probably turning
it off while the saccade is carried out. In vitro studies have shown that nuclear
neurons fire strong rebound bursts upon cessation of hyperpolarization, as a
consequence of hyperpolarization-activated mixed cation and calcium channels
[100]. If such rebound bursts were also generated under in vivo conditions, we
would expect to see saccade-related bursts close to the end of a saccade.
Actually, many saccade-related nuclear neurons show such late saccade-related
bursts [92, 94, 101], a signal, which if sent to the brainstem machinery for saccades, might help to stop an ongoing saccade. Scudder et al. [102] have recently
shown that the timing of these late bursts can be changed by adapting saccade
amplitude. For instance, if manipulations are carried out leading to longer-lasting, larger amplitude saccades, these bursts occur even later. If we assume that
Neural Control of Saccadic Eye Movements
69
the timing of these later bursts fired by nuclear neurons is determined by the
end of the vermal population burst, the conclusion obviously is that the manipulation leading to longer and larger saccades has increased the duration of the
vermal simple spike (SS) population bursts. In other words, changes in the
duration of the population bursts might underlie saccadic plasticity or adaptation, in which the relationship between a given retinal vector, defining the location of the target and the saccade vector is changed, if appropriate [103]. While
we do not know yet how the vermal population burst duration is changed by
saccadic adaptation, we do know that the vermis is indispensable for saccadic
adaptation. Lesioning vermal lobule VI and VII leads to an irreversible loss of
short-term saccadic plasticity [104]. Short-term saccadic plasticity is the function which allows us to generate thousands of precise saccades despite the fact
that the oculomotor periphery changes continuously due to fatigue. We hypothesize that this is possible because of careful adjusting of saccade duration,
realized by tuning the neuronal representation of saccade time offered by the
posterior vermal population signal.
In order to induce any changes of the population burst duration that may
be needed in order to accommodate changes of the oculomotor periphery, the
vermis should receive information on the state of the motor plant. Any inadequate consideration of the plant will lead to imprecise saccades, missing the
goal and thereby generating a ‘performance error’. It is commonly assumed
that such error signals underlie the changes observed during saccadic adaptation [for review, see 103]. It is close at hand to assume that the performance
error leads to adaptation by modulating the duration of the posterior vermal
population burst. Our recent observations on the climbing fiber input to the
saccade-related posterior vermis are in full accordance with this idea [105].
Climbing fibers originate from the inferior olive (IO) and are responsible for
the complex spikes (CS) fired by cerebellar Purkinje cells, which modulate the
efficacy of the second line of input, in the case of saccades, fed by the dorsal
PN and the NRTP. A careful analysis of the changes of CS patterns during saccadic learning shows that they would be appropriate to lead to the changes of
the SS population burst, needed in order to explain the changes in saccade
metrics due to learning. Note that in this scenario, the changes in the CS profile induced by learning do not reflect an error per se but adjustments, which
are prompted by an error. Given the strong input from the SC to the IO, the origin of the climbing fibers, one may speculate that it is the SC that extracts the
error in the first place.
Irrespective of the details and the remaining open questions, the work on
the posterior vermis is fully compatible with the notion that this part of the cerebellum contributes to the fine tuning needed in order to allow the brainstem
saccade generator to work at the precision we observe.
Catz/Thier
70
References
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
Ter Braak JWG: Untersuchungen über optokinetischen Nystagmus. Arch Neer Physiol 1936;21:
309–376.
Fischer B: Visually guided eye and hand movements in man. Brain Behav Evol 1989;33:109–112.
Amador N, Schlag-Rey M, Schlag J: Primate antisaccades. I. Behavioral characteristics.
J Neurophysiol 1998;80:1775–1786.
Zhang M, Barash S: Neuronal switching of sensorimotor transformations for antisaccades. Nature
2000;408:971–975.
Munoz DP, Everling S: Look away: the anti-saccade task and the voluntary control of eye movement. Nat Rev Neurosci 2004;5:218–228.
Boghen D, Troost BT, Daroff RB, Dell’Osso LF, Birkett JE: Velocity characteristics of normal
human saccades. Invest Ophthalmol 1974;13:619–623.
Fischer B, Ramsperger E: Human express saccades: extremely short reaction times of goal
directed eye movements. Exp Brain Res 1984;57:191–195.
Fischer B, Boch R, Ramsperger E: Express-saccades of the monkey: effect of daily training on
probability of occurrence and reaction time. Exp Brain Res 1984;55:232–242.
Thier P, Ilg UJ: The neural basis of smooth-pursuit eye movements. Curr Opin Neurobiol
2005;15:645–652.
Von Helmholtz H: Ueber die normalen Bewegungen des menschlichen Auges. Arch Ophthalmol
1863;9:153–214.
Tweed D, Vilis T: Geometric relations of eye position and velocity vectors during saccades. Vision
Res 1990;30:111–127.
Schall JD, Hanes DP: Neural basis of saccade target selection in frontal eye field during visual
search. Nature 1993;366:467–469.
Gaymard B, Ploner CJ, Rivaud S, Vermersch AI, Pierrot-Deseilligny C: Cortical control of saccades. Exp Brain Res 1998;123:159–163.
Tehovnik EJ, Sommer MA, Chou IH, Slocum WM, Schiller PH: Eye fields in the frontal lobes of
primates. Brain Res Rev 2000;32:413–448.
Peck CK: Visual responses of neurones in cat superior colliculus in relation to fixation of targets.
J Physiol 1989;414:301–315.
Munoz DP, Wurtz RH: Fixation cells in monkey superior colliculus. I. Characteristics of cell discharge. J Neurophysiol 1993;70:559–575.
Averbuch-Heller L, Kori AA, Rottach KG, Dell’Osso LF, Remler BF, Leigh RJ: Dysfunction of
pontine omnipause neurons causes impaired fixation: macrosaccadic oscillations with a unilateral
pontine lesion. Neuroophthalmology 1996;16:99–106.
Andersen RA, Bracewell RM, Barash S, Gnadt JW, Fogassi L: Eye position effects on visual, memory, and saccade-related activity in areas LIP and 7a of macaque. J Neurosci 1990;10:1176–1196.
Barash S, Bracewell RM, Fogassi L, Gnadt JW, Andersen RA: Saccade-related activity in the lateral intraparietal area. I. Temporal properties; comparison with area 7a. J Neurophysiol 1991;66:
1095–1108.
Barash S, Bracewell RM, Fogassi L, Gnadt JW, Andersen RA: Saccade-related activity in the lateral intraparietal area. II. Spatial properties. J Neurophysiol 1991;66:1109–1124.
Schall JD: On building a bridge between brain and behavior. Annu Rev Psychol 2004;55:23–50.
Fuchs AF, Kaneko CR, Scudder CA: Brainstem control of saccadic eye movements. Annu Rev
Neurosci 1985;8:307–337.
Luschei ES, Fuchs AF: Activity of brain stem neurons during eye movements of alert monkeys.
J Neurophysiol 1972;35:445–461.
Büttner U, Büttner-Ennever JA, Henn V: Vertical eye movement related unit activity in the rostral
mesencephalic reticular formation of the alert monkey. Brain Res 1977;130:239–252.
Büttner-Ennever JA, Büttner U: A cell group associated with vertical eye movements in the rostral
mesencephalic reticular formation of the monkey. Brain Res 1978;151:31–47.
Moschovakis AK, Scudder CA, Highstein SM: The microscopic anatomy and physiology of the
mammalian saccadic system. Prog Neurobiol 1996;50:133–254.
Neural Control of Saccadic Eye Movements
71
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
Büttner-Ennever JA, Henn V: An autoradiographic study of the pathways from the pontine reticular formation involved in horizontal eye movements. Brain Res 1976;108:155–164.
Graybiel AM: Direct and indirect preoculomotor pathways of the brainstem: an autoradiographic
study of the pontine reticular formation in the cat. J Comp Neurol 1977;175:37–78.
Grantyn A, Grantyn R, Gaunitz U, Robine KP: Sources of direct excitatory and inhibitory inputs
from the medial rhombencephalic tegmentum to lateral and medial rectus motoneurons in the cat.
Exp Brain Res 1980;39:49–61.
Sirkin DW, Feng AS: Autoradiographic study of descending pathways from the pontine reticular
formation and the mesencephalic trigeminal nucleus in the rat. J Comp Neurol 1987;256:483–493.
Hikosaka O, Igusa Y, Imai H: Inhibitory connections of nystagmus-related reticular burst neurons
with neurons in the abducens, prepositus hypoglossi and vestibular nuclei in the cat. Exp Brain
Res 1980;39:301–311.
Fukushima K, Ohno M, Takahashi K, Kato M: Location and vestibular responses of interstitial and
midbrain reticular neurons that project to the vestibular nuclei in the cat. Exp Brain Res 1982;45:
303–312.
Thielert CD, Thier P: Patterns of projections from the pontine nuclei and the nucleus reticularis
tegmenti pontis to the posterior vermis in the rhesus monkey: a study using retrograde tracers.
J Comp Neurol 1993;337:113–126.
Highstein SM, Maekawa K, Steinacker A, Cohen B: Synaptic input from the pontine reticular
nuclei to abducens motoneurons and internuclear neurons in the cat. Brain Res 1976;112: 162–167.
Hikosaka O, Igusa Y, Nakao S, Shimazu H: Direct inhibitory synaptic linkage of pontomedullary
reticular burst neurons with abducens motoneurons in the cat. Exp Brain Res 1978;33:337–352.
Igusa Y, Sasaki S, Shimazu H: Excitatory premotor burst neurons in the cat pontine reticular formation related to the quick phase of vestibular nystagmus. Brain Res 1980;182:451–456.
Highstein SM, Baker R: Excitatory termination of abducens internuclear neurons on medial rectus
motoneurons: relationship to syndrome of internuclear ophthalmoplegia. J Neurophysiol 1978;41:
1647–1661.
Steiger HJ, Büttner-Ennever JA: Oculomotor nucleus afferents in the monkey demonstrated with
horseradish peroxidase. Brain Res 1979;160:1–15.
Strassman A, Highstein SM, McCrea RA: Anatomy and physiology of saccadic burst neurons in
the alert squirrel monkey. I. Excitatory burst neurons. J Comp Neurol 1986;249:337–357.
Hikosaka O, Nakao S, Shimazu H: Postsynaptic inhibition underlying spike suppression of secondary vestibular neurons during quick phases of vestibular nystagmus. Neurosci Lett 1980;16:
21–26.
Strassman A, Highstein SM, McCrea RA: Anatomy and physiology of saccadic burst neurons in
the alert squirrel monkey. II. Inhibitory burst neurons. J Comp Neurol 1986;249:358–380.
Yoshida K, Iwamoto Y, Chimoto S, Shimazu H: Saccade-related inhibitory input to pontine omnipause neurons: an intracellular study in alert cats. J Neurophysiol 1999;82:1198–1208.
Büttner-Ennever JA, Horn AK, Henn V, Cohen B: Projections from the superior colliculus motor
map to omnipause neurons in monkey. J Comp Neurol 1999;413:55–67.
Yoshida K, Iwamoto Y, Chimoto S, Shimazu H: Disynaptic inhibition of omnipause neurons following electrical stimulation of the superior colliculus in alert cats. J Neurophysiol 2001;85:
2639–2642.
Langer TP, Kaneko CR: Brainstem afferents to the omnipause region in the cat: a horseradish peroxidase study. J Comp Neurol 1984;230:444–458.
Cannon SC, Robinson DA: Loss of the neural integrator of the oculomotor system from brain stem
lesions in monkey. J Neurophysiol 1987;57:1383–1409.
Cheron G, Godaux E: Disabling of the oculomotor neural integrator by kainic acid injections in
the prepositus-vestibular complex of the cat. J Physiol 1987;394:267–290.
Kaneko CR, Fuchs AF: Saccadic eye movement deficits following ibotenic acid lesions of the
nuclei raphe interpositus and prepositus hypoglossi in monkey. Acta Otolaryngol Suppl 1991;481:
213–215.
Robinson DA: Integrating with neurons. Annu Rev Neurosci 1989;12:33–45.
Koulakov AA, Raghavachari S, Kepecs A, Lisman JE: Model for a robust neural integrator. Nat
Neurosci 2002;5:775–782.
Catz/Thier
72
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
McFarland JL, Fuchs AF: Discharge patterns in nucleus prepositus hypoglossi and adjacent medial
vestibular nucleus during horizontal eye movement in behaving macaques. J Neurophysiol 1992;68:
319–332.
Scudder CA, Fuchs AF: Physiological and behavioral identification of vestibular nucleus neurons
mediating the horizontal vestibuloocular reflex in trained rhesus monkeys. J Neurophysiol 1992;68:
244–264.
Cullen KE, Chen-Huang C, McCrea RA: Firing behavior of brain stem neurons during voluntary
cancellation of the horizontal vestibuloocular reflex. II. Eye movement related neurons.
J Neurophysiol 1993;70:844–856.
Robinson DA: Oculomotor control signals; in Lennerstrandand G, Bach-y-Rita P (eds): Basic
Mechanisms of Ocular Motility and Their Clinical Implications. Oxford, Pergamon Press, 1975,
pp 337–374.
Groh JM, Sparks DL: Saccades to somatosensory targets. I. Behavioral characteristics.
J Neurophysiol 1996;75:412–427.
Groh JM, Sparks DL: Saccades to somatosensory targets. II. Motor convergence in primate superior colliculus. J Neurophysiol 1996;75:428–438.
Groh JM, Sparks DL: Saccades to somatosensory targets. III. Eye-position-dependent somatosensory activity in primate superior colliculus. J Neurophysiol 1996;75:439–453.
Werner W, Dannenberg S, Hoffmann KP: Arm-movement-related neurons in the primate superior
colliculus and underlying reticular formation: comparison of neuronal activity with EMGs of muscles of the shoulder, arm and trunk during reaching. Exp Brain Res 1997;115:191–205.
Bell AH, Meredith MA, van Opstal AJ, Munoz DP: Crossmodal integration in the primate superior
colliculus underlying the preparation and initiation of saccadic eye movements. J Neurophysiol
2005;93:3659–3673.
Robinson DA: Eye movements evoked by collicular stimulation in the alert monkey. Vision Res
1972;12:1795–1808.
Girard B, Berthoz A: From brainstem to cortex: computational models of saccade generation circuitry. Prog Neurobiol 2005;77:215–251.
Goossens HH, van Opstal AJ: Dynamic ensemble coding of saccades in the monkey superior colliculus. J Neurophysiol 2006;95:2326–2341.
Soetedjo R, Kaneko CR, Fuchs AF: Evidence that the superior colliculus participates in the feedback control of saccadic eye movements. J Neurophysiol 2002;87:679–695.
Choi WY, Guitton D: Responses of collicular fixation neurons to gaze shift perturbations in headunrestrained monkey reveal gaze feedback control. Neuron 2006;50:491–505.
Krauzlis RJ, Basso MA, Wurtz RH: Shared motor error for multiple eye movements. Science
1997;276:1693–1695.
Bergeron A, Guitton D: In multiple-step gaze shifts: omnipause (OPNs) and collicular fixation
neurons encode gaze position error; OPNs gate saccades. J Neurophysiol 2002;88:1726–1742.
Bergeron A, Matsuo S, Guitton D: Superior colliculus encodes distance to target, not saccade
amplitude, in multi-step gaze shifts. Nat Neurosci 2003;6:404–413.
Hikosaka O, Wurtz RH: The basal ganglia. Rev Oculomot Res 1989;3:257–281.
Hikosaka O, Sakamoto M, Usui S: Functional properties of monkey caudate neurons. I. Activities
related to saccadic eye movements. J Neurophysiol 1989;61:780–798.
Hikosaka O, Takikawa Y, Kawagoe R: Role of the basal ganglia in the control of purposive saccadic eye movements. Physiol Rev 2000;80:953–978.
Hikosaka O, Wurtz RH: Modification of saccadic eye movements by GABA-related substances. II.
Effects of muscimol in monkey substantia nigra pars reticulata. J Neurophysiol 1985;53:292–308.
Hikosaka O, Wurtz RH: Visual and oculomotor functions of monkey substantia nigra pars reticulata. IV. Relation of substantia nigra to superior colliculus. J Neurophysiol 1983;49:1285–1301.
Wurtz RH, Hikosaka O: Role of the basal ganglia in the initiation of saccadic eye movements.
Prog Brain Res 1986;64:175–190.
May JG, Keller EL, Suzuki DA: Smooth-pursuit eye movement deficits with chemical lesions in
the dorsolateral pontine nucleus of the monkey. J Neurophysiol 1988;59:952–977.
Gaymard B, Pierrot-Deseilligny C, Rivaud S, Velut S: Smooth pursuit eye movement deficits after
pontine nuclei lesions in humans. J Neurol Neurosurg Psychiatry 1993;56:799–807.
Neural Control of Saccadic Eye Movements
73
76 Dicke PW, Barash S, Ilg UJ, Thier P: Single-neuron evidence for a contribution of the dorsal pontine nuclei to both types of target-directed eye movements, saccades and smooth-pursuit. Eur J
Neurosci 2004;19:609–624.
77 Brodal P, Bjaalie JG: Organization of the pontine nuclei. Neurosci Res 1992;13:83–118.
78 Harting JK: Descending pathways from the superior colliculus: an autoradiographic analysis in
the rhesus monkey (Macaca mulatta). J Comp Neurol 1977;173:583–612.
79 Van Opstal J, Hepp K, Suzuki Y, Henn V: Role of monkey nucleus reticularis tegmenti pontis in
the stabilization of Listing’s plane. J Neurosci 1996;16:7284–7296.
80 van Opstal AJ, Hepp K, Hess BJ, Straumann D, Henn V: Two- rather than three-dimensional representation of saccades in monkey superior colliculus. Science 1991;252:1313–1315.
81 Aschoff JC, Cohen B: Changes in saccadic eye movements produced by cerebellar cortical
lesions. Exp Neurol 1971;32:123–133.
82 Ritchie L: Effects of cerebellar lesions on saccadic eye movements. J Neurophysiol 1976;39:
1246–1256.
83 Botzel K, Rottach K, Buttner U: Normal and pathological saccadic dysmetria. Brain 1993;116(pt 2):
337–353.
84 Ron S, Robinson DA: Eye movements evoked by cerebellar stimulation in the alert monkey.
J Neurophysiol 1973;36:1004–1022.
85 Yamada J, Noda H: Afferent and efferent connections of the oculomotor cerebellar vermis in the
macaque monkey. J Comp Neurol 1987;265:224–241.
86 Noda H, Fujikado T: Involvement of Purkinje cells in evoking saccadic eye movements by microstimulation of the posterior cerebellar vermis of monkeys. J Neurophysiol 1987;57:1247–1261.
87 Fujikado T, Noda H: Saccadic eye movements evoked by microstimulation of lobule VII of the
cerebellar vermis of macaque monkeys. J Physiol 1987;394:573–594.
88 Noda H, Sugita S, Ikeda Y: Afferent and efferent connections of the oculomotor region of the fastigial nucleus in the macaque monkey. J Comp Neurol 1990;302:330–348.
89 Noda H, Fujikado T: Topography of the oculomotor area of the cerebellar vermis in macaques as
determined by microstimulation. J Neurophysiol 1987;58:359–378.
90 Yamada T, Suzuki DA, Yee RD: Smooth pursuitlike eye movements evoked by microstimulation in
macaque nucleus reticularis tegmenti pontis. J Neurophysiol 1996;76:3313–3324.
91 Ohtsuka K, Noda H: Saccadic burst neurons in the oculomotor region of the fastigial nucleus of
macaque monkeys. J Neurophysiol 1991;65:1422–1434.
92 Fuchs AF, Robinson FR, Straube A: Role of the caudal fastigial nucleus in saccade generation.
I. Neuronal discharge pattern. J Neurophysiol 1993;70:1723–1740.
93 Kleine JF, Guan Y, Buttner U: Discharge properties of saccade-related neurons in the primate fastigial oculomotor region. Ann N Y Acad Sci 2003;1004:252–261.
94 Kleine JF, Guan Y, Buttner U: Saccade-related neurons in the primate fastigial nucleus: what do
they encode? J Neurophysiol 2003;90:3137–3154.
95 Robinson FR, Straube A, Fuchs AF: Role of the caudal fastigial nucleus in saccade generation.
II. Effects of muscimol inactivation. J Neurophysiol 1993;70:1741–1758.
96 Goffart L, Chen LL, Sparks DL: Deficits in saccades and fixation during muscimol inactivation of
the caudal fastigial nucleus in the rhesus monkey. J Neurophysiol 2004;92:3351–3367.
97 Thier P, Dicke PW, Haas R, Barash S: Encoding of movement time by populations of cerebellar
Purkinje cells. Nature 2000;405:72–76.
98 Lange W: Cell number and cell density in the cerebellar cortex of man and some other mammals.
Cell Tissue Res 1975;157:115–124.
99 Gould BB, Rakic P: The total number, time or origin and kinetics of proliferation of neurons comprising the deep cerebellar nuclei in the rhesus monkey. Exp Brain Res 1981;44:195–206.
100 Czubayko U, Sultan F, Thier P, Schwarz C: Two types of neurons in the rat cerebellar nuclei as distinguished by membrane potentials and intracellular fillings. J Neurophysiol 2001;85:2017–2029.
101 Ohtsuka K, Noda H: Direction-selective saccadic-burst neurons in the fastigial oculomotor region
of the macaque. Exp Brain Res 1990;81:659–662.
102 Scudder CA, Batourina EY, Tunder GS: Comparison of two methods of producing adaptation of
saccade size and implications for the site of plasticity. J Neurophysiol 1998;79:704–715.
Catz/Thier
74
103 Hopp JJ, Fuchs AF: The characteristics and neuronal substrate of saccadic eye movement plasticity. Prog Neurobiol 2004;72:27–53.
104 Barash S, Melikyan A, Sivakov A, Zhang M, Glickstein M, Thier P: Saccadic dysmetria and adaptation after lesions of the cerebellar cortex. J Neurosci 1999;19:10931–10939.
105 Catz N, Dicke PW, Thier P: Cerebellar complex spike firing is suitable to induce as well as to stabilize motor learning. Curr Biol 2005;15:2179–2189.
Prof. Dr. P. Thier
Department of Cognitive Neurology, Hertie Institute for Clinical Brain Research
Hoppe-Seyler Strasse 3
DE–72076 Tübingen (Germany)
Tel. ⫹49 7071 2983057, Fax ⫹49 7071 295326, E-Mail [email protected]
Neural Control of Saccadic Eye Movements
75
Straube A, Büttner U (eds): Neuro-Ophthalmology.
Dev Ophthalmol. Basel, Karger, 2007, vol 40, pp 76–89
Smooth Pursuit Eye Movements and
Optokinetic Nystagmus
Ulrich Büttner, Olympia Kremmyda
Department of Neurology, Ludwig-Maximilians University, Munich, Germany
Abstract
Smooth pursuit eye movements are used to track small moving visual objects and
depend on an intact fovea. Optokinetic nystagmus is the oculomotor response to large moving visual fields. In addition, the ocular following response is considered, which reflects
short latency, involuntary eye movements to large moving visual fields. This chapter will
consider the general characteristics and the anatomical and physiological basis of these eye
movements. It will conclude with disorders, particularly those seen in clinical investigations.
Copyright © 2007 S. Karger AG, Basel
General Characteristics
Smooth Pursuit Eye Movements
The performance of smooth pursuit eye movements (SPEM) is a voluntary
task and depends on motivation and attention. SPEM are only found in species
with a fovea and are used to maintain a clear image of small moving visual
objects on the retina. The latency for the initiation of SPEM is 100–150 ms [1],
which is generally shorter than for a saccade. During initiation (eye acceleration) SPEM depend mainly on visual signals, and during maintained pursuit on
a ‘velocity memory’ signal [2].
In contrast to saccades, SPEM are usually considered as ‘slow’ eye movements, although velocities above 100⬚/s can be reached [man: 3; monkey: 4].
Cats, with a coarse area centralis can track larger stimuli only up to 20⬚/s [5]. In
man, there is a clear age dependence of SPEM [6]. They are already present in
4-week-old infants and reach a gain close to 1 at 3 months [7]. As a rule, maximal velocity decreases every year by 1⬚/s starting at the age of 20 [3]. There
seems to be no further decline above the age of 75 [8].
Under normal circumstances, tracking of small moving visual objects is
done by eye and head movements. Head movements induce the vestibulo-ocular
reflex (VOR), which drives the eyes in the direction opposite to the eye movements. During visual tracking the VOR has to be suppressed, and it is assumed
that the central nervous system actually generates a smooth pursuit signal to
cancel the VOR [9]. Thus, a SPEM deficit is generally accompanied by
impaired VOR suppression.
Usually SPEM are tested with sinusoidal stimuli which only refer to steady
state conditions. They are different from the initial 20–40 ms, when SPEM are
independent from stimulus parameters. To account for the different motor programs on a neuronal level for SPEM generation, often the step-ramp (Rashbass)
paradigm is used. So far, only few clinical studies addressed the question of
partial dysfunction in SPEM generation [10].
Both SPEM and saccades are voluntary eye movements. Traditionally they
have been considered as two distinct systems. However, it is becoming increasingly evident that both types of eye movements share similar anatomical networks
at the cortical and subcortical level. These networks are presumably used for
selection processes involving attention, perception, memory and expectation [11].
Optokinetic Response
Large moving visual fields (with the head stationary) lead to slow compensatory eye movements. These eye movements are driven by the optokinetic
system. During continuous motion of the visual surround, fast resetting eye
movements occur, which are basically saccades. The combination of slow compensatory and fast resetting eye movements is called optokinetic nystagmus
(OKN), the direction being labeled after the fast phase.
Two components can be distinguished in the generation of the slow compensatory phase [12]. One is called the ‘direct’ component, because it occurs
directly after the onset of the optokinetic stimulus and is considered to reflect
the ocular following response (OFR) [13]. It can best be demonstrated by the
rapid increase in slow-phase eye velocity after the sudden presentation of a
constant optokinetic stimulus. In contrast, the second component is called the
‘indirect’ component, because it leads to a more gradual increase in slow-phase
eye velocity during continuous stimulation. The best demonstration of the ‘indirect’ component alone is optokinetic after-nystagmus (OKAN) – the nystagmus
that continues in the dark after the light has been turned off [12]. The ‘indirect’
or ‘velocity storage’ component can be related to concomitant activity changes
in the vestibular nuclei [14–16].
There is also some evidence that the ‘direct’ component is more involved
in translational optical flow in contrast to rotational optical flow for the ‘indirect’ component [17].
Smooth Pursuit and Optokinetic Nystagmus
77
In birds and lateral-eyed animals (rat, rabbit) the optokinetic response
consists almost entirely of the ‘indirect’ component. In the monkey, both
components are well developed, and maximal OKN velocities can reach more
than 180⬚/s [12, 18]. In contrast, in humans the ‘indirect’ component is
often weak (as indicated by OKAN), variable, and sometimes virtually missing [3, 19].
Maximal OKN velocities in the horizontal plane seldom exceed 120⬚/s in
humans and can be mainly related to the ‘direct’ component. Clinically, values
above 60⬚/s are considered normal [3]. There seems to be some age-related
decline in OKN responses for subjects aged ⬎75 years [8]. At constant stimulus
velocities below 60⬚/s, the gain (eye/stimulus velocity) is about 0.8 [20].
Responses can still be obtained at sinusoidal stimulation above 1 Hz [21]. OKN
is also used to determine residual visual capacities in patients with severe motor
and intellectual disabilities [22].
Vertical OKN has been less intensively investigated. In general, vertical
OKN is slower than horizontal OKN and upward stimulation is more effective
than downward stimulation [23]. At the bedside, normal function can be
assumed as long as up and down OKN can be elicited. In the upright body position, vertical OKAN is often missing or only present after upward optokinetic
stimulation [23]. With a rotating visual field, also torsional OKN with a low
gain (⬍0.2) can be elicited [24, 25].
Ocular Following Response
The immediate involuntary response to a large moving visual field is
called OFR. OFR in humans can have latencies as short as 60–70 ms, which are
shorter than those for SPEM. The size of the visual stimulus and the involuntary
character are further features to distinguish these eye movements. The OFR is
functionally linked to the translational VOR in contrast to OKN being related to
the rotational VOR [26]. Experiments in humans with moving square waves and
stimuli, in which the fundamental frequency of the square wave pattern was
removed, revealed that the eyes always move in the direction of the strongest
Fourier component, which is in the latter case the third harmonic. Under these
conditions the eyes can move in the opposite direction (due to the third harmonic) of the movement of the general stimulus pattern [27]. Longer interstimulus intervals can reverse the direction of the OFR [27]. These findings support
the hypothesis that visual motion detection for OFR is sensed by low-level
(energy-based) rather than feature-based (high-level) mechanisms [28]. The
middle temporal visual area (MT) and medial superior temporal visual area
(MST) appear to be early cortical stages involved in motion responses [29] and
in the initiation of OFR [30].
Büttner/Kremmyda
78
Frontal cortex
FEF, SEF
Posterior cortex
MT, MST
NRTP
PN
Cerebellum
Vermis
Floccular region
VPFL (FL)
FOR
MVN, Y group
Motoneurons
Fig. 1. Major SPEM-related structures and their connections. The cortical structures
(FEF, SEF, MT, MST) project via pontine structures (NRTP, PN) to the cerebellum [vermis,
VPFL (FL)]. From here, activity travels via deep cerebellar nuclei (FOR) and the vestibular
nuclei (MVN, Y group) to the oculomotor neurons in the brainstem. The anatomical pathway
from the FOR to the motoneurons is not well established (dashed line). There is some evidence
that the frontal cortex projects mainly via NRTP to the vermis and the posterior cortex mainly
via PN to the FL
Anatomy and Physiology
Smooth Pursuit Eye Movements
SPEM are the result of a complex visuo-oculomotor transformation
process, which involves many structures at the cortical as well as the cerebellar
and brainstem level [31, 32] (fig. 1). Frontal as well parietotemporal areas are
involved in smooth pursuit generation. The main areas posterior to the central
sulcus are the occipital cortex, the MT, the MST and the parietal cortex. With
lesions in the occipital cortex SPEM are abolished in the contralateral hemifield, when step-ramp stimuli are used [33]. However, with sinusoidal stimuli
SPEM remain intact due to the use of predictive SPEM properties and the sparing of the macular projection.
Area 17 (occipital cortex) projects ipsilaterally to the MT (also called V5).
Neurons here have large receptive fields and encode the speed and the direction
of moving visual stimuli [34]. In the monkey, small lesions in the extrafoveal
part of the MT cause a deficit in SPEM initiation [35]. Based on functional
MRI, the MT in humans is located posterior to the superior temporal sulcus at
the parieto-temporo-occipital junction (Brodmann areas 19, 37 and 39) [36].
Smooth Pursuit and Optokinetic Nystagmus
79
The MST is adjacent to the MT, from where it receives an input. Also neurons
in the MST have large receptive fields and are well suited for the analysis of
optic flow [37]. In contrast to the MT, MST neurons can still be active without
retinal motion being present [38]. Experimental lesions of the MST produce a
SPEM deficit to the ipsilateral side in both visual hemifields [39]. The MST
appears to be largely involved in SPEM maintenance, whereas the MT is more
involved in SPEM initiation [32]. In man, the homologues of the MT and MST
are also adjacent to each other at the occipitotemporoparietal junction.
Over the last years, it became increasingly clear that also the frontal eye
fields (FEFs) and the supplementary eye field (SEF) in the frontal cortex are
involved in SPEM generation. Both structures, FEF and SEF, have been known
for their involvement in saccade generation. The SPEM-area of the FEF is
anatomically distinct of the saccade area [40]. Lesions in monkeys [41] and
humans [42] cause a severe ipsidirectional deficit particularly in predictive
aspects of SPEM. Interestingly, optokinetic responses can be preserved [43].
Also the SEF appears to be involved in predictive aspects of SPEM [44]. It has
been suggested that SEF is particularly involved in the planning of SPEM [32].
Evidence starts to emerge that also the basal ganglia [45] and the thalamus
are involved in SPEM control. Anatomically, it has been shown that both the
saccade and the SPEM-related division of the FEF project to separate areas in
the caudate nucleus [46]. Also, the saccade and the SPEM-related division of
FEF receive different thalamic inputs [47]. Recent single unit studies indicate
that the thalamus regulates and monitors SPEM by providing a corollary discharge to the cortex [48].
There is some evidence that FEF projects mainly to the nucleus reticularis
tegmenti pontis (NRTP) [49] and MT/MST more strongly to the dorsolateral
pontine nuclei (DLPN) [50] (fig. 1). The DLPN projects only to the cerebellum.
Here afferents terminate in lobulus VI and VII of the vermis (oculomotor vermis; OV) [51] and the paraflocculus [49]. Neuronal activity in DLPN would
preferentially allow a role in maintaining steady-state SPEM [49]. Discrete
chemical lesions in DLPN in monkeys produce mainly an ipsilateral SPEM
deficit [52]. NRTP projects to the OV [51] and to a lesser degree to the
paraflocculus [53]. Neurons here encode primarily eye acceleration, which
would indicate a larger role of NRTP in smooth pursuit initiation [49].
In the cerebellar cortex, the floccular region (FL) and OV are most intensively investigated in relation to SPEM. In monkeys, lesions in both the FL [54]
and OV [55] lead to SPEM deficits. OV lesions in monkeys lead to a smooth
pursuit gain reduction particularly during the first 100 ms (in the open-loop
period). Deficits are also seen in humans after OV lesions [56]. The OV projects
to the caudal part of the fastigial nucleus (fastigial oculomotor region; FOR)
(fig. 1), where lesions also cause a SPEM deficit (to the contralateral side) [57].
Büttner/Kremmyda
80
The FL projects directly to the vestibular nuclei, from where SPEM signals
can reach the oculomotor nuclei. It is not quite clear yet, how the SPEM signals
from FOR reach the oculomotor nuclei.
There is some evidence for two parallel pathways from the cortex for
SPEM. The parietotemporal structures (MT, MST) project preferentially to the
pontine nuclei, which in turn send afferents to the FL. In contrast, the FEF
mainly sends signals via NRTP to the OV and FOR (fig. 1). The functional differences for these two routes at all levels still have to be determined.
Optokinetic Nystagmus
As outlined above, here only the ‘indirect’ or ‘velocity storage’ component
of OKN will be considered. Although the ‘velocity storage’ component can be
transmitted solely via brainstem pathways, it is important to remember, that
these pathways are under cortical control. Bilateral occipital lesions lead to a
loss of optokinetic responses in both humans [58] and monkeys [59].
Fibers from the retina terminate in the brainstem in the nuclei of the accessory optic tract (AOT) and the nucleus of the optic tract (NOT), only the latter
being part of the pretectal nuclear complex [60]. Both AOT [61] and NOT [50]
receive cortical inputs. Being located in the mesencephalon, they project to
more caudal brainstem areas like the pontine nuclei, NRTP, the inferior olive,
nucleus prepositus hypoglossi and the vestibular nuclei. Neurons in AOT and
NOT have large receptive fields and respond best to large textured stimuli moving in specific directions [62].
It is well known that vestibular nuclei neurons not only respond to vestibular stimulation in the dark but also to large moving visual stimuli that cause
OKN [15, 14]. During OKAN, vestibular nuclei activity and slow-phase eye
velocity change in parallel.
The cerebellum does not appear to play a major role in mediating the
‘indirect’ component of OKN [63]. Cerebellectomy in cat does not greatly
affect optokinetic responses. The nodulus and uvula appear to have an
inhibitory effect. In the monkey, ablation maximizes the ‘indirect’ component
[64]. This lack of inhibition is considered as the cause for periodic alternating
nystagmus.
Ocular Following Response
Single unit recordings and chemical lesion studies indicate that the OFR is
mediated by a pathway including the MST, DLPN and the ventral paraflocculus
(VPFL), i.e. pathways involved in SPEM. Detailed analysis of the neural activity
suggests that the MST locally encodes the dynamic properties of the visual
stimulus, whereas the VPFL provides the motor command for OFR [65].
Smooth Pursuit and Optokinetic Nystagmus
81
Disorders
Smooth Pursuit Eye Movements
Cortex
Both frontal and parietal lesions in patients lead to SPEM deficits [66].
Lesions of the MT region cause a deficit [67] similar to that seen in monkeys
[68]. Moving stimuli within the contralateral visual field defect cannot be adequately tracked independent of the movement direction, whereas saccades to
the defective area remain intact. In contrast, lesions of the neighboring MST
lead to a directional (ipsiversive) deficit independent of the retinal location.
Also lesions of the FEF lead to an ipsiversive SPEM deficit [69]. The MT, MST,
FEF and SEF project via the internal capsula to the pons. Accordingly, an
ipsiversive deficit is also seen after lesions in the internal capsula [70].
Pontine Structures
Lesions of the pontine nuclei lead to a predominantly ipsiversive SPEM
deficit [71, 72]. However, even bilateral lesions of the pontine nuclei do not
abolish SPEM. This might reflect that also the NRTP is involved in SPEM generation. Smooth pursuit deficits in ‘progressive supranuclear palsy’ [73] and
spinocerebellar ataxia types 1, 2 and 3 [74] have also been related to lesions of
the pontine structures.
Cerebellum
In the cerebellar cortex, lesions of the OV and the FL lead to SPEM
deficits. Patients with cerebellar ataxia and bilateral vestibulopathy show a
reduced SPEM gain [75]. A total loss of SPEM is only seen when both structures are lesioned (total cerebellectomy, monkey). In the OV, SPEM- as well as
saccade-related neurons are found. Lesions always lead to related deficits [76]
(table 1). A bilateral lesion of the OV leads to hypometric saccades and SPEM
with a reduced gain. This is also seen in patients [77, 78]. Effects of unilateral
lesions have not yet been described in patients.
The Purkinje cells of the OV project to the FOR and have an inhibitory
effect. Consequently, a bilateral lesion of the FOR leads to hypermetric saccades.
This should be combined with an increased SPEM gain (gain ⬎1). In this case,
back up instead of catch up saccades should occur during SPEM. However, this
pattern is only rarely seen [79] (fig. 2). Still, a patient with a severe hypermetria
due to a bilateral FOR lesion showed highly normal values with a SPEM gain
close to 1 [80]. Experimental (monkey) unilateral lesions lead to a SPEM gain
reduction and hypometric saccades to the contralateral side and normal SPEM
and hypermetric saccades to the ipsilateral side [57] (table 1).
Büttner/Kremmyda
82
Table 1. The effect of cerebellar midline lesions and lateral medullary infarction on
SPEM and saccades
Smooth pursuit
unilateral
ipsi-
Saccades
bilateral
unilateral
ipsi-
contra-
⇓
hypo-
hyper-
hypo-
normal
hyper-
hypo-
hyper-
contra-
OV
(lobulus VI, VII)
bilateral
FOR
normal
⇓
Rostral cerebellum
(cereb. outflow)
⇓
⇓
hypo-
hyper-
Lateral medulla
(Wallenberg)
normal
⇓
hyper-
hypo-
In general, a reduced SPEM gain is combined with hypometric saccades. This is not the
case for lesions in the rostral cerebellum since not only FOR efferents but also pathways to
and from the FL are affected.
T
RT
10º
H (NORM)
LT
H (MUSC)
*
*
*
*
*
Fig. 2. Effect of transient inactivation by local muscimol injection in the right FOR on
SPEM. T ⫽ Target position; H (NORM) ⫽ horizontal eye position before muscimol injection; H (MUSC) ⫽ horizontal eye position after muscimol injection; RT ⫽ right; LT ⫽ left.
During rightward movements, the SPEM gain is ⬎1 and back-up saccades (marked by asterisks) occur. During leftward movements, the smaller gain is corrected by catch-up saccades;
from Fuchs et al. [79].
Smooth Pursuit and Optokinetic Nystagmus
83
Efferent pathways from the FOR cross immediately to the other side before
they enter the brainstem. Accordingly, patients with a lesion to the rostral cerebellum show saccadic contrapulsion [81], i.e. the reverse pattern of a unilateral
FOR lesion. It is usually found with lesions in the territory of the superior cerebellar artery. In this case, saccades to the contralateral side are hypermetric and
hypometric to the ipsilateral side. However, SPEM show a low gain in both
directions [82] occasionally more pronounced to the ipsilateral side [83]. The
reason probably is that lesions of the rostral cerebellum do not only affect the
FOR pathways but also the pathways to and from the FL.
Lesions of the FL lead to a partial SPEM deficit, more pronounced to the
ipsilateral side. In contrast to OV and FOR lesions, the SPEM deficit is usually
combined with gaze-evoked nystagmus due to a gaze holding deficit [84].
Medulla
The most common ischemic lesion of the brainstem is the lateral medulla
infarction (Wallenberg’s syndrome); in patients, it always (100%) leads to oculomotor deficits [85]. This includes a SPEM deficit to the contralateral side
[86]. As pointed out above for OV and FOR lesions, also this deficit corresponds with hypometric saccades to the contralateral side (table 1). It is postulated that this deficit is caused by interruption of olivocerebellar pathways after
their crossing in the medulla [87, 88] (fig. 3).
Optokinetic Nystagmus
For patients, there are no good methods available to test the ‘indirect’ component of OKN in isolation. One possible method would be to test their OKAN.
However, even in normals OKAN can be missing [19]. On the bedside, usually
a handheld optokinetic cylinder is rotated for several seconds in one direction.
This however only activates the ‘direct’ (smooth pursuit-related) component,
since the time is not sufficient to provide a substantial contribution of the ‘indirect’ component [16]. When optokinetic stimuli are used, a side difference of up
to 20⬚/s for the maximal velocity is still considered normal [89]. Pathological
side differences are more obvious with the use of smaller stimuli [90]. For the
monkey, it could be shown that mesencephalic lesions in the pretectum lead to
a reduction in the ‘indirect’ component to the ipsilateral side. Also the OKAN
in this direction is missing or reduced [91]. There is also some evidence that in
addition pretectal lesions can affect the ‘direct’ component [92]. Clinical
reports on this topic are still missing.
Büttner/Kremmyda
84
Vermis
FN
?
VN
PPRF
Floccular region
Climbing fiber
IO
Fig. 3. Schematic drawing of the climbing fiber pathway from the medulla (lower part)
to the cerebellar cortex (vermis). It originates in the inferior olive (IO) and is interrupted by
lateral medullary infarction (shaded area). The lesions causes disinhibition of Purkinje
cell simple spike resting activity in the vermis, and as a consequence increased inhibition
in the FN. The resulting SPEM and saccade deficits are shown in table 1; from Helmchen
et al. [88].
References
1
2
3
4
Robinson DA: The mechanics of human smooth pursuit eye movements. J Physiol 1965;180:
569–591.
Morris EJ, Lisberger SG: Different responses to small visual errors during initiation and maintenance of smooth-pursuit eye movements in monkeys. J Neurophysiol 1987;58:1351–1369.
Simons B, Büttner U: The influence of age on optokinetic nystagmus. Eur Arch Psychiatry Neurol
Sci 1985;234:369–373.
Lisberger SG, Miles FA, Optican LM, Eighmy BB: Optokinetic response in monkey: underlying
mechanisms and their sensitivity to long-term adaptive changes in vestibuloocular reflex.
J Neurophysiol 1981;45:869–890.
Smooth Pursuit and Optokinetic Nystagmus
85
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
Robinson DA: The use of control systems analysis in the neurophysiology of eye movements. Ann
Rev Neurosci 1981;4:463–503.
Morrow MJ, Sharpe JA: Smooth pursuit initiation in young and elderly subjects. Vision Res
1993;33:203–310.
Phillips JO, Finocchio DV, Ong L, Fuchs AF: Smooth pursuit in 1- to 4-month-old infants. Vision
Res 1997;37:3009–3020.
Kerber KA, Ishiyama GP, Baloh RW: A longitudinal study of oculomotor function in normal older
people. Neurobiol Aging 2006;27:1346–1353.
Leigh RJ, Zee DS: The Neurology of Eye Movements. Oxford University Press, New York, 2006.
Thurston SE, Leigh RJ, Crawford T, Thompson A, Kennard C: Two distinct deficits of visual tracking caused by unilateral lesions of cerebral cortex in humans. Ann Neurol 1988;23:266–273.
Krauzlis RJ: The control of voluntary eye movements: new perspectives. Neuroscientist 2005;11:
124–137.
Cohen B, Matsuo V, Raphan T: Quantitative analysis of the velocity characteristics of optokinetic
nystagmus and optokinetic after-nystagmus, J Physiol 1977;270:321–344.
Miles FA: The neural processing of 3-D visual information: evidence from eye movements. Eur J
Neurosci 1998;10:811–822.
Waespe W, Henn V: Neuronal activity in the vestibular nuclei of the alert monkey during vestibular and optokinetic stimulation. Exp Brain Res 1977;27:523–538.
Waespe W, Henn V: Vestibular nuclei activity during optokinetic after-nystagmus (OKAN) in the
alert monkey. Exp Brain Res 1977;30:323–330.
Boyle R, Büttner U, Markert G: Vestibular nuclei activity and eye movements in the alert monkey
during sinusoidal optokinetic stimulation. Exp Brain Res 1985;57:362–369.
Miles FA: The sensing of rotational and translational optic flow by the primate optokinetic system;
in Miles FA, Wallman J (eds): Visual Motion and Its Role in the Stabilization of Gaze. Amsterdam,
London, New York, Tokyo, Elsevier, 1993, pp 393–403.
Büttner U, Meienberg O, Schimmelpfennig B: The effect of central retinal lesions on optokinetic
nystagmus in the monkey. Exp Brain Res 1983;52:248–256.
Waespe W, Henn V: Conflicting visual-vestibular stimulation and vestibular nucleus activity in
alert monkeys. Exp Brain Res 1978;33:203–211.
van-den-Berg AV, Collewijn H: Directional asymmetries of human optokinetic nystagmus. Exp
Brain Res 1988;70:597–604.
Barnes GR: Visual-vestibular interaction in the control of head and eye movement: the role of
visual feedback and predictive mechanisms. Prog Neurobiol 1993;41:435–472.
Sakai S, Hirayama K, Iwasaki S, Yamadori A, Sato N, Ito A, Kato M, Sudo M, Tsuburaya K:
Contrast sensitivity of patients with severe motor and intellectual disabilities and cerebral visual
impairment. J Child Neurol 2002;17:731–737.
Murasugi CM, Howard IP: Updown asymmetry in human vertical optokinetic nystagmus and
afternystagmus: contributions of the central and periphral retinae. Exp Brain Res 1988;77:183–192.
Collewijn H, Van-der-Steen J, Ferman L, Jansen TC: Human ocular counterroll: assessment of static and dynamic properties from electromagnetic scleral coil recordings. Exp Brain Res
1985;59:185–196.
Van-Rijn LJ, Van-der-Steen J, Collewijn H: Visually induced cycloversion and cyclovergence.
Vision Res 1992;32:1875–1883.
Adeyemo B, Angelaki DE: Similar kinematic properties for ocular following and smooth pursuit
eye movements. J Neurophysiol 2005;93:1710–1717.
Chen KJ, Sheliga BM, Fitzgibbon EJ, Miles FA: Initial ocular following in humans depends critically on the Fourier components of the motion stimulus. Ann N Y Acad Sci 2005;1039:260–271.
Sheliga BM, Chen KJ, Fitzgibbon EJ, Miles FA: Initial ocular following in humans: a response to
first-order motion energy. Vision Res 2005;45:3307–3321.
Maunsell JH, Nealey TA, DePriest DD: Magnocellular and parvocellular contributrions to
responses in the middle temporal visual area (MT) of the macaque monkey. J Neurosci
1990;10:3323–3334.
Takemura A, Inoue Y, Kawano K: Visually driven eye movements elicited at ultra-short latency are
severely impaired by MST lesions. Ann NY Acad Sci 2002;956:456–459.
Büttner/Kremmyda
86
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
Thier P, Ilg UP: The neural basis of smooth-pursuit eye movements. Curr Opin Neurobiol
2005;15:1–8.
Krauzlis RJ: Recasting the smooth pursuit eye movement system. J Neurophysiol 2004;91:
591–603.
Segraves MA, Goldberg JM, Deng SY, Bruce CJ, Ungerleider LG, Mishkin M: The role of striate
cortex in the guidance of eye movements in the monkey. J Neurosci 1987;7:3040–3058.
Maunsell JHR, Van Essen DC: Functional properties of neurons in middle temporal visual area of
the macaque monkey. I. Selectivity for stimulus direction, speed, and orientation. J Neurophysiol
1983;49:1127–1147.
Newsome WT, Wurtz RH, Dürsteler MR, Mikami A: Deficits in visual motion processing following ibotenic acid lesions of the middle temporal visual area of the macaque monkey. J Neurosci
1985;5:825–840.
Watson JD, Myers R, Frackowiak RS, Hajnal JV, Woods RP, Mazziotta JC, Shipp S, Zeki S: Area
V5 of the human brain: evidence from a combined study using positron emission tomography and
magnetic resonance imaging. Cereb Cortex 2004;3:79–94.
Duffy CJ, Wurtz RH: Planar directional contributions to optic flow responses in MST neurons. J
Neurophysiol 1997;77:782–796.
Ilg UJ, Thier P: Visual tracking neurons in primate area MST are activated by smooth-pursuit eye
movements of an ‘imaginary’ target. J Neurophysiol 2003;90:1489–1502.
Dürsteler MR, Wurtz RH: Pursuit and optokinetic deficits following chemical lesion of cortical
areas MT and MST. J Neurophysiol 1988;60:940–965.
Tanaka M, Lisberger SG: Role of acurate frontal cortex of monkeys in smooth pursuit eye movements. I. Basic response properties to retinal image motion and position. J Neurophysiol
2002;87:2684–2699.
Shi D, Friedman HR, Bruce CJ: Deficits in smooth-pursuit eye movements after muscimol inactivation within the primate’s frontal eye field. J Neurophysiol 1998;80:458–464.
Morrow MJ, Sharpe JA: Deficits of smooth-pursuit eye movement after unilateral frontal lobe
lesions. Ann Neurol 1995;37:443–451.
Keating EG, Pierre A, Chopra S: Ablation of the pursuit area in the frontal cortex of the primate
degrades foveal but not optokinetic smooth eye movements. J Neurophysiol 1996;76:637–641.
Heinen SJ, Liu M: Single-neurons activity in the dorsomedial frontal cortex during smooth-pursuit
eye movements to predictable target motion, Vis Neurosci 1997;14:853–865.
Basso MA, Pokorny JJ, Liu P: Activity of substantia nigra pars reticulata neurons during smooth
pursuit eye movements in monkeys. Eur J Neurosci 2005;22:448–464.
Cui DM, Yan YJ, Lynch JC: Pursuit subregion of the frontal eye field projects to the caudate
nucleus in monkeys. J Neurophysiol 2003;89:2678–2684.
Tian J-R, Lynch JC: Subcortical input to the smooth and saccadic eye movement subregions of the
frontal eye field in Cebus monkey. J Neurosci 1997;17:9233–9247.
Tanaka M: Involvement of the central thalamus in the control of smooth pursuit eye movements.
J Neurosci 2005;25:5866–5876.
Ono S, Das VE, Economides JR, Mustari MJ: Modeling of smooth pursuit-related neuronal
responses in the DLPN and NRTP of the Rhesus Macaque. J Neurophysiol 2005;93:108–116.
Distler C, Mustari MJ, Hoffmann KP: Cortical projections to the nucleus of the optic tract and dorsal terminal nucleus and to the dorsolateral pontine nucleus in macaques: a dual retrograde tracing
study. J Comp Neurol 2002;444:144–158.
Thielert CD, Thier P: Patterns of projections from the pontine nuclei and the nucleus reticularis
tegmenti pontis to the posterior vermis in the rhesus monkey – a study using retrograde tracers.
J Comp Neurol 1993;337:113–126.
May JG, Keller EL, Suzuki DA: Smooth-pursuit eye movement deficits with chemical lesions in
the dorsolateral pontine nucleus of the monkey. J Neurophysiol 1988;59:952–977.
Glickstein M, Gerrits N, Kralj-Hans I, Mercier B, Stein J, Voogd J: Visual pontocerebellar projections in the macaque. J Comp Neurol 1994;349:51–72.
Zee DS, Yamazaki A, Butler PH, Gücer G: Effects of ablation of flocculus and paraflocculus on
eye movements in primates. J Neurophysiol 1981;46:878–899.
Smooth Pursuit and Optokinetic Nystagmus
87
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
Takagi M, Zee DS, Tamargo RJ: Effects of lesions of the oculomotor cerebellar vermis on eye
movements in primate: smooth pursuit. J Neurophysiol 2000;83:2047–2062.
Vahedi K, Rivaud S, Amarenco P, Pierrot-Deseilligny C: Horizontal eye movement disorders after
posterior vermis infarctions. J Neurol Neurosurg Psychiatry 1995;58:91–94.
Robinson FR, Straube A, Fuchs AF: Participation of caudal fastigial nucleus in smooth pursuit eye
movements. II. Effects of muscimol inactivation. J Neurophysiol 1997;78:848–859.
Verhagen W, Huygens P, Mulleners W: Lack of optokinetic nystagmus and visual motion perception in acquired cortical blindness. Neuro-ophthalmol 1997;17:211–216.
Zee DS, Tusa RJ, Herdman SJ, Butler PH, Gücer G: Effects of occipital lobectomy upon eye movements in primate. J Neurophysiol 1987;58:883–907.
Simpson JI, Giolli RA, Blanks RHI: The pretectal nuclear complex and the accessory optic system. Rev Oculomot Res 1988;2:335–364.
Blanks RHI, Giolli RA, van der Wandt JJL: Neuronal circuitry and neurotransmitters in the pretectal and accessory optic systems; in Beitz AJ, Anderson JH (eds): Neurochemistry of the
Vestibular System. Boca Raton, FL, CRC Press, 2000, pp 303–328.
Ilg UJ, Hoffmann KP: Responses of neurons of the nucleus of the optic tract and the dorsal terminal nucleus of the accessory optic tract in the awake monkey. Eur J Neurosci 1996;8:92–105.
Waespe W, Henn V: Gaze stabilization in the primate. The interaction of the vestibulo-ocular reflex,
optokinetic nystagmus, and smooth pursuit. Rev Physiol Biochem Pharmacol 1987;106:37–125.
Waespe W, Cohen B, Raphan T: Dynamic modification of the vestibulo-ocular reflex by the nodulus and uvula. Science 1985;228:199–202.
Takemura A, Kawano K: Sensory-to-motor processing of the ocular-following response. Neurosci
Res 2002;43:201–206.
Heide W, Kurzidim K, Kömpf D: Deficits of smooth pursuit eye movements after frontal and parietal lesions. Brain 1996;119:1951–1969.
Leigh RJ: The cortical control of ocular pursuit movements. Rev Neurol (Paris) 1989;145:605–612.
Newsome WT, Wurtz RH: Probing visual cortical function with discrete chemical lesions. Trends
Neurosci 1988;11:393–399.
Rivaud S, Müri RM, Gaymard B, Vermersch AI, Pierrot-Deseilligny C: Eye movement disorders
after frontal eye field lesions in humans. Exp Brain Res 1994;102:110–120.
Brigell M, Babikian V, Goodwin JA: Hypometric saccades and low-gain pursuit resulting from a
thalamic hemorrhage. Ann Neurol 1984;15:374–378.
Gaymard B, Pierrot-Deseilligny C, Rivaud S, Velut S: Smooth pursuit eye movement deficits after
pontine nuclei lesions in humans. J Neurol Neurosurg Psychiatry 1993;56:799–807.
Thier P, Bachor A, Faiss J, Dichgans J, Koenig E: Selective impairment of smooth-pursuit eye
movements due to an ischemic lesion of the basal pons. Ann Neurol 1991;29:443–448.
Malessa S, Gaymard B, Rivaud S, Cerevera P, Hirsch E, Verny M, Duyckaerts C, Agid Y, .PierrotDeseilligny C: Role of pontine nuclei damage in smooth pursuit impairment of progressive
supranuclear palsy: a clinical-pathologic study. Neurology 1994;44:716–721.
Rüb U, Bürk K, Schöls L, Brunt ER, de Vos RAI, Orozco Diaz G, Gierga K, Ghebremedhin E, Schultz
C, Del Turco D, Mittelbronn M, Auburger G, Deller T, Braak H: Damage to the reticulotegmental
nucleus of the pons in spinocerebellar ataxia type 1,2 and 3. Neurology 2004;63:1258–1263.
Migliaccio AA, Halmagyi GM, McGarvie LA, Cremer PD: Cerebellar ataxia with bilateral vestibulopathy: description of a syndrome and its characteristic clinical sign. Brain 2004;127:280–293.
Büttner U, Straube A: The effect of cerebellar midline lesions on eye movements. Neuro-ophthalmol 1995;15:75–82.
Pierrot-Deseilligny C, .Amarenco P, Roullet E, Marteau R: Vermal infarct with pursuit eye movement disorders. J Neurol Neurosurg Psychiatry 1990;53:519–521.
Thier P, Herbst H, Thielert C-D, Erickson RG: A cortico-ponto-cerebellar pathway for smoothpursuit eye movements; in Delgado-Garcia JM, Godaux E, Vidal P-P (eds): Information
Processing Underlying Gaze Control. Oxford, Pergamon, 1994, pp 237–249.
Fuchs AF, Robinson FR, Straube A: Preliminary observations on the role of the caudal fastigial
nucleus in the generation of smooth-pursuit eye movements; in Fuchs AF, Brandt T, Büttner U, Zee
D (eds): Contemporary Ocular Motor and Vestibular Research: A Tribute to David A. Robinson.
Stuttgart, Georg Thieme Verlag, 1994, pp 165–170.
Büttner/Kremmyda
88
80
81
82
83
84
85
86
87
88
89
90
91
92
Büttner U, Straube A, Spuler A: Saccadic dysmetria and ‘intact’ smooth pursuit eye movements
after bilateral deep cerebellar nuclei lesions. J Neurol Neurosurg Psychiatry 1994;57:832–834.
Ranalli PJ, Sharpe JA: Contrapulsion of saccades and ipsilateral ataxia: a unilateral disorder of the
rostral cerebellum. Ann Neurol 1986;20:311–316.
Uno A, Mukuno K, Sekiya H, Ishikawa S, Suzuki S, Hata T: Lateropulsion in Wallenberg’s syndrome and contrapulsion in the proximal type of the superior cerebellar artery syndrome. Neuroophthalmol 1989;9:75–80.
Straube A, Büttner U: Pathophysiology of saccadic contrapulsion in unilateral rostral cerebellar
lesions. Neuro-ophthalmol 1994;1:3–7.
Büttner U, Grundei T: Gaze-evoked nystagmus and smooth pursuit deficits: their relationship
studied in 52 patients. J Neurol 1995;242:384–389.
Norrving B, Cronqvist S: Lateral medullary infarction: prognosis in an unselected series.
Neurology 1991;41:244–248.
Kommerell G, Hoyt WF: Lateropulsion of saccadic eye movements. Arch Neurol 1973;28:
313–318.
Waespe W, Wichmann W: Oculomotor disturbances during visual-vestibular interaction in
Wallenberg’s lateral medullary syndrome. Brain 1990;113:821–846.
Helmchen C, Straube A, Büttner U: Saccadic lateropulsion in Wallenberg’s syndrome may be
caused by a functional lesion of the fastigial nucleus. J Neurol 1994;241:421–426.
Jung R, Kornhuber HH: Results of electronystagmography in man: the value of optokinetic,
vestibular and spontaneous nystagmus for neurological diagnosis and research; in Bender MB
(ed): The Oculomotor System. New York, Harper & Row, 1964, pp 428–488.
Dichgans J, Kolb B, Wolpert E: Provokation optokinetischer Seitendifferenzen durch
Einschränkung der Reizfeldbreite und ihre Bedeutung für die Klinik. Arch Psychiatr Nervenkr
1974;219:117–131.
Schiff D, Cohen B, Büttner-Ennever J, Matsuo V: Effects of lesions of the nucleus of the optic tract
on optokinetic nystagmus and after-nystagmus in the monkey. Exp Brain Res 1990;79:225–239.
Mustari MJ, Fuchs AF, Kaneko CRS, Robinson FR, Kaneko CR: Anatomical connections of the
primate pretectal nucleus of the optic tract. J Comp Neurol 1994;349:111–128.
Prof. Dr. U. Büttner
Department of Neurology
Klinikum Grosshadern, Marchioninistrasse 15
DE–81377 Munich (Germany)
Tel. ⫹49 89 7095 2560, Fax ⫹49 89 7095 5561, E-Mail [email protected]
Smooth Pursuit and Optokinetic Nystagmus
89
Straube A, Büttner U (eds): Neuro-Ophthalmology.
Dev Ophthalmol. Basel, Karger, 2007, vol 40, pp 90–109
Disconjugate Eye Movements
Dominik Straumann
Neurology Department, Zurich University Hospital, Zurich, Switzerland
Abstract
To foveate targets in different depths, the movements of the two eyes must be disconjugate. Fine measurements of eye rotations about the three principal axes have demonstrated
that disconjugate eye movements may appear not only in the horizontal, but also in the vertical and torsional directions. In the presence of visual targets, disconjugate eye movements
are driven by the vergence system, but they may also appear during vestibular stimulation.
Disconjugate eye movements are highly adaptable by visual disparities, but under normal
condition the effects of adaptation only persist when one eye is covered. Finally, disorders of
the brainstem and cerebellum may lead to abnormal disconjugate eye movements that are
often specific for the topography of the lesion. This chapter reviews the literature on the
phenomenology of disconjugate eye movements over the last 15 years.
Copyright © 2007 S. Karger AG, Basel
The goal of normal disconjugate eye movements is to direct the corresponding retinal points of the two eyes to a visual object that is nearer or farther
than the previous object. Such vergence movements can also be smooth when
the object of interest moves slowly in depth. Both disparity and accommodation-vergence synkinesis can drive vergence movements. Recently, it has also
been shown that perceived depth alone elicits vergence eye movements [1].
Geometrically, binocular movements are disconjugate, if amplitude and/or
direction are unequal for both eyes. Considering the full kinematics of eye rotations, the term ‘direction’ includes ocular rotation about the line of sight, which
is an important degree of freedom to ensure extrafoveal retinal correspondence.
If one takes into account the rigid geometric specifications for 3-D – i.e. horizontal, vertical, and torsional – binocular rotations, it is not surprising that normal eye movements are generally disconjugate when subjects view near targets.
As we shall see, even eye movements for foveation of targets at infinity exhibit
some disconjugacy due to neural and mechanical factors.
This paper reviews the literature on the phenomenology, including
pathophenomenology, of disconjugate eye movements over the last 15 years.
Horizontal Vergence Movements
Under natural viewing conditions, horizontal vergence movements are
usually dysmetric, i.e. moving gaze from a near to a far target leads to excessive convergence, and moving gaze from a far to a near target to insufficient
convergence [2]. The degree of this physiological vergence weakness can
be reduced by increased attention [3] and instruction [4], but vergence is
always less precise than version [5]. In subjects with strong monocular preference, vergence movements are typically associated with small horizontal
saccades [6].
Upon symmetric step stimulation with horizontal disparity, convergence is
usually faster than divergence [7]. While the dynamics of convergence movements is independent of target location, divergence movements become faster
the closer the initial target is to the eyes [8]. When visual feedback is eliminated
during vergence, the position trajectories are step-like, not smooth. This openloop response consists of a pulse-like or transient component and a step-like or
sustained component [9, 10]. While both components are adaptable, only the
pulse-like component influences the dynamics of the adapted vergence
response [11]. Experiments eliciting vergence movements by velocity steps of
horizontal disparities suggest that the vergence open-loop response may originate from monocular visual pathways [12].
Disparity-driven convergence eye movements frequently show large asymmetries, which vary from trial to trial and are usually compensated in the later
phase of the convergence movement [13]. While this later phase probably uses
visual feedback, the initial phase seems to be preprogrammed [14]. The occasional appearance of two closely spaced high-velocity vergence movements in
response to disparity supports the notion that the initial vergence component is
evoked by an internal, not visual, feedback mechanism that is switched on and
off, analogous to the saccadic system [15, 16].
Small or large dichoptic displays that are counterphasically oscillated in
the horizontal direction elicit dynamic convergence/divergence [17]. Brief horizontal (or vertical) disparity steps of 2⬚ or less evoke short-latency vergence
movements, which are enhanced when the stimulus is presented shortly after a
saccade [18–20]. Similar vergence movements with short latencies are also
driven by radial flow [21]. When vergence movements with or without accompanying saccades are elicited with a gap period before target onset, vergence
latency decreases significantly [22].
Disconjugate Eye Movements
91
Vertical Vergence Movements
A vertical prism placed in front of one eye induces divergent eye movements in the vertical direction. Training with vertical prisms can increase the
vertical fusional amplitude, predominantly by enhancing the motor, not the sensory component [23]. The motor capability to fuse vertical disparities increases
with convergence. This increase is due to the motor component, while the sensory component for far and near viewing is practically the same [24]. Similarly,
skew deviation associated with static counterroll (intorting eye hypertropic)
increases with convergence [25].
Vertical fusion is accompanied by conjugate torsion toward the higher eye
[26], a pattern that qualitatively resembles the one seen in patients with dissociated vertical deviation [27]. Whether the binocular torsion associated with
vertical fusion is mediated by the superior oblique muscles (SO) [26] or is of
central origin [28] remains to be answered. 3-D eye movement trajectories
during vertical fusion suggest that patients with congenital trochlear nerve
palsy use predominantly the vertical recti, while patients with acquired
trochlear nerve palsy show various patterns of vertical and oblique eye muscle
activations [29].
Dichoptic counterphasic oscillation of displays in the vertical direction
elicits vertical vergence [30]. These movements show increased gain and
reduced phase lag with larger stimulus diameter, which contrasts horizontal dichoptic display oscillation, in which display diameter is less important
[31].
Cyclovergence
Spontaneous fluctuation of torsional eye position is generally conjugate,
i.e. cyclovergence is considerably more stable than cycloversion [32]. Opposite
cyclorotation of the images presented to the two eyes evokes static cyclovergence, which adds to the eye position-dependent cyclovergence [33]. The latter
results from the outward rotations of Listing’s planes during convergence (see
below).
Dynamic cyclovergence can be elicited by fusible visual patterns projected
to each eye separately and oscillated out of phase in the frontal plane [34, 35].
The gain of dynamic cyclovergence is highest for low frequencies and low
amplitudes and therefore is appropriate to correct for drifts in binocular stereoscopic alignment, which are both slow and small [35]. Occlusion of the central
area does not influence the gain of cyclovergence, although the gain of
cycloversion decreases [36].
Straumann
92
␣
␣/4
␣/4
Fig. 1. Top view of binocular Listing’s planes during far (left) and near (right) viewing.
Each Listing’s plane rotates temporally by a quarter of the vergence angle (␣).
Listing’s Law during Convergence
For the following considerations, eye positions need to be described threedimensionally with a horizontal, vertical, and torsional component. Since rotations are noncommutative, the most convenient conventions, such as rotation
vectors or quaternion vectors, express every eye position as a single axis rotation from a reference position. Accordingly, vergence is then defined as the
rotation that transforms the left eye position into the right eye position [37].
Rotation or quaternion vectors hold a specific 3-D orientation in the head.
Listing’s law states that, in the absence of dynamic vestibular stimulation, these
3-D vectors all lie in one plane, so-called Listing’s plane. In the absence of convergence, the Listing’s planes of the two eyes are relatively parallel and oriented
approximately frontal. With convergence the planes rotate outward [38–41], i.e.
they ‘swing out like saloon doors’ [42]. In other words, the primary positions of
the two eyes diverge during convergence [43]. Among the cited studies, the angle
of the outward rotation of the Listing’s planes varies considerably and amounts
roughly to about 1/4 (range: 0.16–0.43) of the convergence angle (fig. 1).
An explanation of why the Listing’s planes rotate outward during convergence has to consider both visual and motor variables [44]. Tweed [45] proposed a most compelling hypothesis that is based on an optimal compromise
between visual and motor variables: The visual variable is the maximal alignment of images in the visual plane on the two retinas irrespective of gaze direction; the motor variable is to keep rotation about the line of sight as close as
possible to the zero vergence primary position. Since the amount of cyclovergence
varies with gaze elevation when the Listing’s planes are rotated outward, stereograms that critically depend on the relative torsional orientation of the two
retinas are only visible at a specific gaze elevation [46]. Hence, ocular motor
control plays an important role in depth vision.
Disconjugate Eye Movements
93
MR images demonstrate that rectus pulleys in converging eyes are slightly
extorted [47]. The outward rotation of Listing’s plane, however, cannot be
explained by this change of the rectus pulleys and therefore must be due to variations of oblique muscle innervations. The convergence-induced outward rotation of Listing’s planes does not depend on whether convergence is induced by
a stereogram, a horizontal prism, or an accommodative stimulus [48–50]. The
orientation of Listing’s planes can, however, be modified by phoria adaptation
(see below).
Vergence movements with the eyes at various elevations lead to different
torsional components that can be explained by the vergence-modulated orientation of Listing’s plane [41]. Accordingly, during pure vergence movements with
gaze elevated or depressed, the eyes rotate about an axis which is orthogonal to
the gaze direction [51]. This is different from the orientation of rotation axes
during saccades, which tilt in the direction of gaze by only half the gaze angle
[52]. During asymmetric vergence movements, e.g. when foveating a target
moving along the line of sight of one eye, monocular torsion is less stable than
cyclovergence and varies between convergence and divergence [53, 54]. Pitch
head impulses while the eyes are converging on a near target in front of one eye
lead to torsional movement components in both the adducting and the straight
ahead viewing eye [55]. This effect corresponds to a modification of ocular
rotation axes due to the convergence-induced outward rotation of Listing’s
planes.
The Listing’s planes in patients with acquired trochlear nerve palsy are not
symmetric; the plane of the affected eye is rotated outward, as if this eye were
converging [56]. In congenital trochlear nerve palsy, the orientation of Listing’s
plane of the affected eye is normal; thus, congenital trochlear nerve palsy is not
due to changed function of a single extraocular eye muscle [56]. In patients
with acquired or congenital trochlear nerve palsy, Listing’s plane of the affected
eye does not rotate temporally upon convergence. This finding suggests an
important role of the SO in modifying the orientation of Listing’s plane as a
function of vergence [57]. In patients with acute trochlear nerve palsy, Listing’s
law is violated by the affected eye during downward saccades; this eye shows
dynamic extorsion as a result of the missing agonistic action of the SO [58]. In
patients with central abducens nerve palsy, Listing’s law is violated by both
eyes, while in patients with peripheral abducens nerve palsy, Listing’s law is
violated by the paretic eye and in the acute state only [59].
Compared to healthy subjects, patients with intermittent horizontal strabismus exhibit a similar, but more variable relation between vergence angle and
angle between the Listing’s planes [60]. In patients with intermittent exotropia,
vertical gaze-dependent cyclovergence is increased, possibly because additional
convergence is required to cancel the exodeviation between the two eyes [61].
Straumann
94
Symmetric
Asymmetric
Fig. 2. Top view of both eyes during symmetric and asymmetric convergence movements. The visual target moves from far to near (arrow).
In a stereoblind patient with strabismus, the Listing’s planes of the two eyes
were normal in shape, i.e. relatively planar, but changed their orientation
depending on which eye was fixating [62]. This effect was most probably due to
accommodation-induced vergence.
Asymmetric Vergence Movements and Hering’s Law
Hering’s law of equal innervation implies that equal version and vergence
commands are sent to both eyes and that the binocular motor output represents
the sum of the two signals. The analysis of asymmetric vergence movements
(fig. 2) can give some indication whether Hering’s law holds [63, 64] or
whether the two eyes are independently controlled, as advocated by Helmholtz
[65, 66]. As we will see, there are arguments for both theories.
During static convergence on a target in front of one eye, i.e. asymmetric
convergence, only the inferior oblique muscle contracts in this eye, as demonstrated with MRI; contraction of the same muscle, apart from contractile
changes in the lateral and medial rectus muscles, is also seen in the fellow eye,
which is directed inward [47]. During rapid gaze shifts along the line of sight of
one eye, which calls for asymmetric vergence, the horizontal peak accelerations
of the two eyes are similar, despite different position trajectories [67]. This finding suggests equal saccadic pulses for each eye, according to Hering’s law,
together with an additional vergence signal. After human subjects were trained
to have a vertical vergence component during symmetric horizontal vergence,
the vertical vergence component could also be demonstrated during smooth
pursuit of targets in depth both along the line of sight of one eye [68]. Thus
symmetric smooth pursuit seems to be combined with vergence to produce
Disconjugate Eye Movements
95
asymmetric slow eye movements, which speaks against monocular control of
these movements.
Some subjects are able to initiate smooth asymmetrical ‘saccade-free’ convergence movements when changing gaze from a far to a near target [69]. Thus,
during binocular viewing, the ocular motor system is able to generate eye
movements that do not adhere to Hering’s law of equal innervation. Similarly,
the initial monocular smooth pursuit response to a target that moves in depth
solely depends on target motion and is independent of the response of the other
eye [70].
The firing rate of abducens motoneurons for a given eye position is higher
with than without convergence, but, paradoxically, lateral rectus force (and similarly medial rectus force) is not increased [70a]. This finding still awaits an
explanation. A reanalysis of single neuron recordings during eye movements
that included vergence revealed that neural signals in abducens motoneurons,
abducens interneurons, and medial rectus motoneurons encode the position of
both eyes, not just one eye [71]. On the other hand, premotor neurons in the
paramedian pontine reticular formation encode saccadic velocity signals for
only one eye, not both [72]. These findings speak against a neural implementation of Hering’s law.
Saccade-Associated Vergence Movements
Peak vergence velocity increases when vergence is combined with a saccade, an effect that is more pronounced in divergence than convergence [73].
Vice versa, when saccades occur with vergence movements, the peak velocity
of the saccades is reduced, more prominently so with convergence than divergence [74]. These findings suggest a nonlinear interaction between conjugate
and disconjugate premotor systems; the omnipause neurons probably represent
the crucial neural structure for gating saccade-related horizontal vergence [75].
This would also explain why saccadic oscillations occur, when saccades end
during ongoing vergence [76–78]. Note that even horizontal and vertical saccades between far targets are associated with small transient vergence components, but these are probably related to mechanical differences between
adducting and abducting muscles [75, 79]. Horizontal saccades also produce
small torsional transients out of Listing’s plane, which are not equal in amplitude; hence, the eyes cycloverge somewhat shortly after the beginning of each
saccade [80].
Saccades in patients with one deeply amblyopic eye are nonconjugate, i.e.
Hering’s law seems to rely on intact binocular vision [81]. Subjects with anisometropic spectacles show saccades with different amplitudes in both eyes and
Straumann
96
asymmetric postsaccadic drift [82]. When saccades are made between targets at
different distances, a presaccadic vergence movement along the isovergent line
of the initial target appears [83]. This observation speaks for separate version
and vergence channels contributing to fast eye displacements. A similarly
strong coupling between version and vergence is found during incorrect saccades evoked by two targets appearing simultaneously in 3-D space [84].
Conversely, when targets are placed at closer distances from the eyes, no presaccadic convergence and only a small presaccadic divergence is observed, and
postsaccadic vergence is usually asymmetric [85]. The latter finding speaks
against a balanced interaction between the vergence and version systems during
the saccade, and therefore against a Hering-type implementation of such movements. Such saccades are dominated by one eye, so that a least one of the two
eyes is on target in time.
Binocular vertical displacements between near targets in front of one eye
require different vertical amplitudes of each eye to maintain binocular alignment. In downward movements, a major portion of the required disconjugacy
takes place during the saccades, while in upward movements the intrasaccadic
portion amounts to about half [86]. Dynamic dissociations between saccadic
and vergence movements can also be observed during vertical saccades
between targets in the midsagittal plane at different depth [87].
Binocular Adaptation
Phoria Adaptation
Normal binocular fixation of a near target in a tertiary position requires a
vertical vergence component, when eye positions are expressed in a head-fixed
coordinate system. This component appears to be independent of whether subjects are viewing monocularly or binocularly [88]. Eight hours of monocular
occlusion leads to excyclophoria and hyper- or hypophoria [89]. If an eye is
covered and passively rotated away from the position of the fellow eye with a
scleral suction lens during a few minutes, ocular misalignment persists up to
10 min or until binocular viewing is permitted [90].
When short-term phoria adaptation is performed with a vertical disparity
at a single location, phoria becomes uniform for all gaze directions. Upon two
vertical disparities at opposite gaze directions and with opposite sign, adapted
phoria shows a gradient along the line between the two stimuli [91, 92]. Phoria
adaptation to opposite vertical disparities is also effective along the depth axis
[93] or to multiple vertical disparities at different near and far locations [94].
Human subjects are also able to adapt vertical phoria to different prism-induced
vertical disparities that vary with head position [95] or with head and gaze
Disconjugate Eye Movements
97
position [96]. When monkeys are trained to synchronize vergence eye movements in synchrony with vestibularly evoked eye movements upon pitch oscillations, these oscillations evoked vergence eye movements even in the dark [97, 98].
Adaptation to discrete increments of refraction along a horizontal prism is
also possible, but adapted vergence changes only gradually when crossing the
prism edges [99]. After 30–150 s of cyclovergence evoked by incyclo- or excyclodisparity, the eyes do not tort back to their previous torsional positions, even
in the presence of a visual stimulus [100]. Most likely, this torsional hysteresis
is the result of fast phoria adaptation.
Phoria adaptation with a vertical prism over one eye is often impaired in
patients with cerebellar disease. Thus the cerebellum seems to be decisively
involved in phoria adaptation [101].
Adaptation of Listing’s Plane
Three days of vertical disparity with prisms induces, besides vertical phoria, reorientations of Listing’s planes; Listing’s plane of the higher eye is rotated
up and Listing’s plane of the lower eye rotated down [102]. Phoria adaptation to
different cyclodisparities along the vertical axis also modifies the orientation of
Listing’s planes [103].
Binocular Saccade Adaptation
Intrasaccadic displacement of a visual target leads to rapid binocular saccade adaptation. If the displacement is only presented to one eye, while the target is unchanged for the other eye, short-term adjustments are again conjugate,
which suggests that there is no mechanism for fast disconjugate saccade adaptation [104]. Dichoptically presented random-dot patterns with local disparities
representing a 3-D object lead to immediate position-dependent saccadic disconjugacies that persist during subsequent monocular viewing [105]. Similar
immediate disconjugacies of saccades can be observed when disparities are
introduced by dichoptical images that differ in size [106].
Subjects with anisometropic spectacles show saccades with different
amplitudes and postsaccadic drifts between both eyes, even during monocular
viewing [82, 107]. Already an image size inequality of 2% leads to disconjugate
horizontal and vertical saccades, which persist after a short training period
when tested in the absence of normal binocular visual targets [108]. Placing an
afocal magnifier in front of one eye leads to disconjugate memory-guided saccades, which outlasts the removing of the magnifier after the training period,
when subjects are viewing monocularly [109, 110]. Dichoptically presented
patterns that are displaced at the end of each vertical saccade induce amplitude
disconjugacy, but only little disconjugate postsaccadic drift [111]. Apparently,
this effect does not require foveal fusion since microstrabismic patients adapt as
Straumann
98
well [112]. When vertical saccades are disconjugately adapted, smooth pursuit
movements remain conjugate and vice versa [113]. Thus, the two classes of eye
movements have separate mechanisms for binocular adaptation.
In patients with trochlear nerve palsy, saccades become more conjugate
after strabismus surgery, an effect that is more pronounced in patients with congenital than in patients with acquired trochlear nerve palsy [114]. In rhesus monkeys with one surgically weakened extraocular muscle, the paretic eye shows
postsaccadic drift with the normal eye viewing. Deafferenting the paretic eye
leaves postsaccadic drift unchanged; thus, proprioception from the paretic eye
does not play a role in the adaptation of postsaccadic drift [115]. Proprioceptive
deafferentation alone impairs ocular alignment and saccade conjugacy [116].
Disconjugate Eye Movements Evoked by Vestibular Stimulation
Vergence eye movements are elicited by linear motion in the dark with or
without visual targets [117]. The gain of the translational vestibulo-ocular
reflex (VOR) during heave ( ⫽ up-down) and sway ( ⫽ left-right) whole-body
oscillation increases with increasing convergence [118, 119]. During surge
( ⫽ fore-aft) oscillation, the gain of the translational VOR increases with both
increasing gaze eccentricity and increasing convergence, which is qualitatively
accurate for foveal stabilization of both eyes [120–122]. Such vergence responses are enhanced by the presence of visual stimuli [123]. During visual fixation
upon isovergence targets along the horizontal meridian and concurrent rapid
oscillations in various directions in the horizontal plane, both eyes move in the
geometrically correct direction needed to stabilize the targets on the two foveae;
the gain of the version component (average velocity of both eyes divided target
velocity), however, amounts to only around 0.5, while the gain of the vergence
component (right eye velocity minus left eye velocity) ranges around unity
[124]. This finding might reflect the fact that for visual acuity it is more important to stabilize the relative orientation of the lines of sight than binocular position. Vergence also modifies the gain of the angular VOR for gaze stabilization.
For example, the gain of the VOR elicited on a horizontal turntable anticipates
the vergence angle by about 50 ms [125].
Ocular counterroll elicited by head or whole-body roll interferes with
stereopsis. This geometric incompatibility increases further with decreasing target distance. It is therefore advantageous that ocular counterroll decreases
strongly during convergence [126, 127]. In the presence of ocular counterroll,
binocular movements from a far to a near target show unequal torsion; the
required torsion for the undermost eye is larger than for the uppermost eye,
since convergence is associated with extorsion. Such torsional disconjugacy,
Disconjugate Eye Movements
99
however, cannot be demonstrated for divergent eye movements [128]. Static
head roll also leads to excyclovergent eye positions [129]. This phenomenon
can be explained by a static hysteresis that differs between the eyes contra- and
ipsilateral to head roll [130]. Probably, ocular torsional hysteresis is introduced
at the level of the otolith pathways because the direction-dependent torsional
position lag of the eyes was related to head roll position, not eye position.
Asymmetric binocular torsion evoked by hypo- or hypergravity may be a predictor for space sickness [131–133].
During position steps of head roll, the eyes show dynamic binocular counterrolling and skewing. While the gain of dynamic binocular torsion is larger in
upright than in supine position, dynamic skewing is unaffected by the additional otolith input that appears in upright position [134]. Constant rotation
about an off-vertical axis causes horizontal vergence movements [135]. During
oscillatory head roll, the ocular rotation axes of the two eyes are convergent
both in the dark and when fixating upon a far light dot; when subjects fix upon
a near light dot, the convergence of binocular rotation axes exceeds the convergence of binocular positions [136]. The Bielschowsky head-tilt sign in unilateral trochlear nerve palsy, i.e. increased vertical and torsional divergence with
the head tilted towards the affected eye, can be explained by inward tilt of the
rotation axis of the covered eye during head oscillation about the naso-occipital
axis [137]. This ‘convergence’ of ocular rotation axes is the result of decreased
force by the SO of the covered paretic eye or, according to Hering’s law,
increased force parallel to the paretic SO in the covered unaffected eye. The
gain of the VOR in an eye with trochlear nerve palsy is reduced in all directions,
but especially towards intorsion, depression and abduction, in accordance with
the 3-D pulling direction of the SO [138]. In patients with peripheral abducens
nerve palsy, the gain of the horizontal VOR in the affected eye is reduced in
both directions, when tested in the dark. In the light, horizontal gains normalize
in patients with mild or moderate palsy [139]. The gain of the torsional VOR is
reduced in both the healthy and the affected eye [140].
The orientation of ocular rotation axes as a function of eye position depends
on the gain of the torsional VOR; the lower the torsional gain, the more the axes
tilt with eccentric gaze position [141]. As the torsional gain decreases further
with increasing convergence, average 3-D eye positions scatter closely around
the temporally rotated Listing’s plane, which is advantageous for binocular retinal stabilization [142]. Head roll in patients with peripheral abducens nerve
palsy leads to a hyperdeviation of the ipsilateral eye, independent of which eye is
affected. In patients with central abducens palsy, the same eye (healthy or
affected) hyperdeviates when rolling the head to the left or the right side [143].
At low frequencies, the horizontal and vertical VOR can be cancelled by
visually fixing upon head-fixed targets. During head oscillations about the
Straumann
100
naso-occipital axis visual suppression of the elicited torsional VOR is incomplete, but the lines of sight of the two eyes remain on target [144]. If subjects
during head roll fix upon head-fixed eccentric horizontal targets at near distance,
the eyes also show vertical movement components, even if one eye is covered
[145]. These components are required to keep the lines of sight pointed to the
targets. Thus, the vergence system correctly modifies the eye movements that are
not visually cancelled to prevent horizontal and vertical retinal slip in either eye.
Disconjugate Eye Movements and Blinks
Initial eye movements during voluntary blinks are extorsional, downward,
and inward, consistent with an early pulse-like innervation of the inferior rectus
muscle [146]. Thus, during this early phase of blinking, the eyes converge and
excyclodiverge. Blinks modify the kinematics and dynamics saccade-vergence
and slow vergence eye movements [147, 148]. Besides mechanical factors of
the eye plant, the found changes might reflect the blink-induced decrease in
omnipause neuron activity.
Pathological Disconjugate Eye Movements
Normally, vergence eye movements in response to steps of a visual stimuli
become slower with age, which has to be taken into account when evaluating
patients with suspected vergence disorders [149].
Binocular positions in patients with cerebellar dysfunction are usually
esophoric or even esotropic. In addition, there is a hypertropia that varies as a
function of horizontal eye position, so-called alternating skew deviation with
the abducting eye higher. The patients show both conjugate and disconjugate
saccadic abnormalities that are also eye position dependent [150]. The mechanism of alternating skew deviation in patients with cerebellar disease could be
due to a lost correction of changed eye muscle pulling directions, which is
required when animals become frontal eyed. If, in addition, one assumes an
imbalance of graviceptive-ocular pathways responding to head pitch, alternating skew deviation can be explained by this mechanism [151].
Dissociated vertical divergence (DVD) includes the following ocular
motor phenomena [152]: Upon occlusion of either eye, a horizontal and
cyclovertical latent nystagmus develops. This is quickly followed by cycloversion/vertical vergence, with the fixing eye intorting and tending to move downward and the covered eye extorting and moving up. Simultaneously, upward
versions occur for the maintenance of fixation. This, in turn, leads to further
Disconjugate Eye Movements
101
upward movement of the covered eye and, at the same time, to a reduction of the
cyclovertical component of the latent nystagmus. Thus, a possible ‘purpose’ of
this cycloversion and vertical vergence is to damp the cyclovertical nystagmus
that occurs when one eye is covered [153]. Brodsky hypothesized that DVD is a
dorsal light reflex that occurs when binocular vision is impaired in infancy
[154]. Since patients with DVD only transiently perceive a tilt of the subjective
visual vertical when one eye is covered, it was speculated that the cancellation
of SVV tilt in these patients is the main function of DVD [155].
Binocular eye movements in patients with convergent-divergent pendular
nystagmus are conjugate in the vertical direction, but phase shifted by 180⬚ in
the horizontal and torsional directions [156]. The lesion is usually localized
within neural structures of the vergence system. If horizontal saccades or
smooth pursuit eye movements are pathologically coupled with convergence,
the abducting eye will appear paretic despite an intact abducens nerve. This socalled pseudo-abducens palsy is caused by lesions of convergence pathways
near the midbrain-diencephalic junction and is frequently associated with
upgaze palsy and convergence-retraction nystagmus [157]. Paramedian thalamic infarctions without involvement of the midbrain may lead to a selective
bilateral pseudo-abducens palsy [158]. Convergence-retraction nystagmus,
however, is due to a mesencephalic lesion [159] and represents a disorder of the
vergence system [160]. Pathologically disconjugate eye movements with the
vergence system intact, is typical of internuclear ophthalmoparesis [161]. Mild
internuclear ophthalmoparesis, in which the adducting eye is only slightly
slower than the abducting eye, is often missed by clinicians, as demonstrated by
infrared oculography [162].
Ocular bobbing, which rarely appears after infratentorial lesions, but otherwise has no localizing value, may be disconjugate [163]. Disconjugate vertical and torsional ocular movements, resembling seesaw nystagmus, have been
observed in a patient with locked-in syndrome after large infarction of the pons
[164]. Smaller lesions in the ventral pons involving the nucleus reticularis
tegmenti pontis lead to impairment of slow vergence movements to ramp targets [165]. On the other hand, fast vergence movements to step targets are
affected by lesions of upper pontine nuclei [166].
References
1
2
3
Sheliga BM, Miles FA: Perception can influence the vergence responses associated with openloop gaze shifts in 3D. J Vis 2003;3:654–676.
Cornell ED, MacDougall HG, Predebon J, Curthoys IS: Errors of binocular fixation are common
in normal subjects during natural conditions. Optom Vis Sci 2003;80:764–771.
Francis EL, Jiang BC, Owens DA, Tyrrell RA: Accommodation and vergence require effort-tosee. Optom Vis Sci 2003;80:467–473.
Straumann
102
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
Stevenson SB, Lott LA, Yang J: The influence of subject instruction on horizontal and vertical vergence tracking. Vision Res 1997;37:2891–2898.
Semmlow JL, Yuan W, Alvarez TL: Evidence for separate control of slow version and vergence eye
movements: support for Hering’s Law. Vision Res 1998;38:1145–1152.
van Leeuwen AF, Collewijn H, Erkelens CJ: Dynamics of horizontal vergence movements: interaction with horizontal and vertical saccades and relation with monocular preferences. Vision Res
1998;38:3943–3954.
Hung GK, Zhu H, Ciuffreda KJ: Convergence and divergence exhibit different response characteristics to symmetric stimuli. Vision Res 1997;37:1197–1205.
Alvarez TL, Semmlow JL, Pedrono C: Divergence eye movements are dependent on initial stimulus position. Vision Res 2005;45:1847–1855.
Semmlow JL, Hung GK, Horng JL, Ciuffreda K: Initial control component in disparity vergence
eye movements. Ophthalmic Physiol Opt 1993;13:48–55.
Semmlow JL, Hung GK, Horng JL, Ciuffreda KJ: Disparity vergence eye movements exhibit preprogrammed motor control. Vision Res 1994;34:1335–1343.
Semmlow JL, Yuan W: Adaptive modification of disparity vergence components: an independent
component analysis study. Invest Ophthalmol Vis Sci 2002;43:2189–2195.
Masson GS, Yang DS, Miles FA: Version and vergence eye movements in humans: open-loop
dynamics determined by monocular rather than binocular image speed. Vision Res 2002;42:
2853–2867.
Horng JL, Semmlow JL, Hung GK, Ciuffreda KJ: Dynamic asymmetries in disparity convergence
eye movements. Vision Res 1998;38:2761–2768.
Horng JL, Semmlow JL, Hung GK, Ciuffreda KJ: Initial component control in disparity vergence:
a model-based study. IEEE Trans Biomed Eng 1998;45:249–257.
Alvarez TL, Semmlow JL, Yuan W: Closely spaced, fast dynamic movements in disparity vergence. J Neurophysiol 1998;79:37–44.
Alvarez TL, Semmlow JL, Yuan W, Munoz P: Disparity vergence double responses processed by
internal error. Vision Res 2000;40:341–347.
Howard IP, Fang X, Allison RS, Zacher JE: Effects of stimulus size and eccentricity on horizontal
and vertical vergence. Exp Brain Res 2000;130:124–132.
Busettini C, Miles FA, Krauzlis RJ: Short-latency disparity vergence responses and their dependence on a prior saccadic eye movement. J Neurophysiol 1996;75:1392–1410.
Busettini C, FitzGibbon EJ, Miles FA: Short-latency disparity vergence in humans. J Neurophysiol
2001;85:1129–1152.
Masson GS, Busettini C, Miles FA: Vergence eye movements in response to binocular disparity
without depth perception. Nature 1997;389:283–286.
Busettini C, Masson GS, Miles FA: Radial optic flow induces vergence eye movements with ultrashort latencies. Nature 1997;390:512–515.
Coubard O, Daunys G, Kapoula Z: Gap effects on saccade and vergence latency. Exp Brain Res
2004;154:368–381.
Luu CD, Abel L: The plasticity of vertical motor and sensory fusion in normal subjects.
Strabismus 2003;11:109–118.
Hara N, Steffen H, Roberts DC, Zee DS: Effect of horizontal vergence on the motor and sensory
components of vertical fusion. Invest Ophthalmol Vis Sci 1998;39:2268–2276.
Betts GA, Curthoys U, Todd MJ: The effect of roll-tilt on ocular skew deviation. Acta Otolaryngol
Suppl 1995;520:304–306.
Enright JT: Unexpected role of the oblique muscles in the human vertical fusional reflex. J Physiol
1992;451:279–293.
Cheeseman EW Jr, Guyton DL: Vertical fusional vergence: the key to dissociated vertical deviation. Arch Ophthalmol 1999;117:1188–1191.
van Rijn LJ, Collewijn H: Eye torsion associated with disparity-induced vertical vergence in
humans. Vision Res 1994;34:2307–2316.
Mudgil AV, Walker M, Steffen H, Guyton DL, Zee DS: Motor mechanisms of vertical fusion in
individuals with superior oblique paresis. J AAPOS 2002;6:145–153.
Disconjugate Eye Movements
103
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
Howard IP, Allison RS, Zacher JE: The dynamics of vertical vergence. Exp Brain Res 1997;116:
153–159.
Howard IP, Fang X, Allison RS, Zacher JE: Effects of stimulus size and eccentricity on horizontal
and vertical vergence. Exp Brain Res 2000;130:124–132.
van Rijn LJ, Vandersteen J, Collewijn H: Instability of ocular torsion during fixation – cyclovergence is more stable than cycloversion. Vision Res 1994;34:1077–1087.
Hooge IT, van den Berg AV: Visually evoked cyclovergence and extended Listing’s law.
J Neurophysiol 2000;83:2757–2775.
van Rijn LJ, Vandersteen J, Collewijn H: Visually induced cycloversion and cyclovergence. Vision
Res 1992;32:1875–1883.
Howard IP, Zacher JE: Human cyclovergence as a function of stimulus frequency and amplitude.
Exp Brain Res 1991;85:445–450.
Howard IP, Sun L, Shen X: Cycloversion and cyclovergence: the effects of the area and position of
the visual display. Exp Brain Res 1994;100:509–514.
Minken AW, Gielen CC, van Gisbergen JA: An alternative three-dimensional interpretation of
Hering’s equal-innervation law for version and vergence eye movements. Vision Res 1995;35:
93–102.
Mok D, Ro A, Cadera W, Crawford JD, Vilis T: Rotation of Listing’s plane during vergence. Vision
Res 1992;32:2055–2064.
van Rijn LJ, van den Berg AV: Binocular eye orientation during fixations: Listing’s law extended
to include eye vergence. Vision Res 1993;33:691–708.
Somani RA, DeSouza JF, Tweed D, Vilis T: Visual test of Listing’s law during vergence. Vision Res
1998;38:911–923.
Minken AW, van Gisbergen JA: A three-dimensional analysis of vergence movements at various
levels of elevation. Exp Brain Res 1994;101:331–345.
Tweed D: Visual-motor optimization in binocular control. Vision Res 1997;37:1939–1951.
Bruno P, van den Berg AV: Relative orientation of primary positions of the two eyes. Vision Res
1997;37:935–947.
Hepp K: Theoretical explanations of Listing’s law and their implication for binocular vision.
Vision Res 1995;35:3237–3241.
Tweed D: Visual-motor optimization in binocular control. Vision Res 1997;37:1939–1951.
Schreiber K, Crawford JD, Fetter M, Tweed D: The motor side of depth vision. Nature 2001;410:
819–822.
Demer JL, Kono R, Wright W: Magnetic resonance imaging of human extraocular muscles in convergence. J Neurophysiol 2003;89:2072–2085.
Steffen H, Walker MF, Zee DS: Rotation of Listing’s plane with convergence: independence from
eye position. Invest Ophthalmol Vis Sci 2000;41:715–721.
Kapoula Z, Bernotas M, Haslwanter T: Listing’s plane rotation with convergence: role of disparity,
accommodation, and depth perception. Exp Brain Res 1999;126:175–186.
Mikhael S, Nicolle D, Vilis T: Rotation of Listing’s plane by horizontal, vertical and oblique
prism-induced vergence. Vision Res 1995;35:3243–3254.
Minken AW, van Gisbergen JA: Dynamical version-vergence interactions for a binocular implementation of Donders’ law. Vision Res 1996;36:853–867.
Tweed D, Vilis T: Geometric relations of eye position and velocity vectors during saccades. Vision
Res 1990;30:111–127.
Porrill J, Ivins JP, Frisby JP: The variation of torsion with vergence and elevation. Vision Res
1999;39:3934–3950.
Ivins JP, Porrill J, Frisby JP: Instability of torsion during smooth asymmetric vergence. Vision Res
1999;39:993–1009.
Migliaccio AA, Cremer PD, Aw ST, Halmagyi GM, Curthoys IS, Minor LB, Todd MJ: Vergencemediated changes in the axis of eye rotation during the human vestibulo-ocular reflex can occur
independent of eye position. Exp Brain Res 2003;151:238–248.
Straumann D, Steffen H, Landau K, Bergamin O, Mudgil AV, Walker MF, Guyton DL, Zee DS:
Primary position and Listing’s law is acquired and congenital trochlear nerve palsy. Invest
Ophthalmol Vis Sci 2003;44:4282–4292.
Straumann
104
57 Migliaccio AA, Cremer PD, Aw ST, Halmagyi GM: Vergence-mediated changes in Listing’s plane
do not occur in an eye with superior oblique palsy. Invest Ophthalmol Vis Sci 2004;45:3043–3047.
58 Wong AMF, Sharpe JA, Tweed D: Adaptive neural mechanism for Listing’s law revealed in
patients with fourth nerve palsy. Invest Ophthalmol Vis Sci 2002;43:1796–1803.
59 Wong AMF, Tweed D, Sharpe JA: Adaptive neural mechanism for Listing’s law revealed in
patients with sixth nerve palsy. Invest Ophthalmol Vis Sci 2002;43:112–119.
60 Somani RA, Hutnik C, DeSouza JF, Tweed D, Nicolle D, Vilis T: Using a synoptophore to test
Listing’s law during vergence in normal subjects and strabismic patients. Vision Res 1998;38:
3621–3631.
61 van den Berg AV, van Rijn LJ, de Faber JT: Excess cyclovergence in patients with intermittent
exotropia. Vision Res 1995;35:3265–3278.
62 Melis BJ, Cruysberg JR, van Gisbergen JA: Listing’s plane dependence on alternating fixation in
a strabismus patient. Vision Res 1997;37:1355–1366.
63 Moschovakis AK: Are laws that govern behavior embedded in the structure of the CNS? The case
of Hering’s law. Vision Res 1995;35:3207–3216.
64 Mays L: Has Hering been hooked? Nat Med 1998;4:889–890.
65 King WM, Zhou W: Neural basis of disjunctive eye movements. Ann N Y Acad Sci 2002;956:
273–283.
66 Dell’Osso LF: Evidence suggesting individual ocular motor control of each eye (muscle). J Vestib
Res 1994;4:335–345.
67 Ramat S, Das VE, Somers JT, Leigh RJ: Tests of two hypotheses to account for different-sized saccades during disjunctive gaze shifts. Exp Brain Res 1999;129:500–510.
68 Maxwell JS, Schor CM: Symmetrical horizontal vergence contributes to the asymmetrical pursuit
of targets in depth. Vision Res 2004;44:3015–3024.
69 Enright JT: Slow-velocity asymmetrical convergence: a decisive failure of ‘Hering’s law’. Vision
Res 1996;36:3667–3684.
70 King WM, Zhou W: Initiation of disjunctive smooth pursuit in monkeys: evidence that Hering’s law
of equal innervation is not obeyed by the smooth pursuit system. Vision Res 1995;35:3389–3400.
70a Miller JM, Bockisch CJ, Pavlovski DS: Missing lateral rectus force and absence of medial rectus
co-contraction in ocular convergence. J Neurophysiol 2002;8:2421–2433.
71 King WM, Zhou W, Tomlinson RD, McConville KM, Page WK, Paige GD, Maxwell JS: Eye position signals in the abducens and oculomotor nuclei of monkeys during ocular convergence.
J Vestib Res 1994;4:401–408.
72 Zhou W, King WM: Premotor commands encode monocular eye movements. Nature 1998;393:
692–695.
73 Maxwell JS, King WM: Dynamics and efficacy of saccade-facilitated vergence eye movements in
monkeys. J Neurophysiol 1992;68:1248–1260.
74 Collewijn H, Erkelens CJ, Steinman RM: Voluntary binocular gaze-shifts in the plane of regard:
dynamics of version and vergence. Vision Res 1995;35:3335–3358.
75 Zee DS, FitzGibbon EJ, Optican LM: Saccade-Vergence interactions in humans. J Neurophysiol
1992;68:1624–1641.
76 Ramat S, Somers JT, Das VE, Leigh RJ: Conjugate ocular oscillations during shifts of the direction and depth of visual fixation. Invest Ophthalmol Vis Sci 1999;40:1681–1686.
77 Bhidayasiri R, Somers JT, Kim JI, Ramat S, Nayak S, Bokil HS, Leigh RJ: Ocular oscillations
induced by shifts of the direction and depth of visual fixation. Ann Neurol 2001;49:24–28.
78 Ramat S, Leigh RJ, Zee DS, Optican LM: Ocular oscillations generated by coupling of brainstem
excitatory and inhibitory saccadic burst neurons. Exp Brain Res 2005;160:89–106.
79 Collewijn H, Erkelens CJ, Steinman RM: Trajectories of the human binocular fixation point during conjugate and non-conjugate gaze-shifts. Vision Res 1997;37:1049–1069.
80 Straumann D, Zee DS, Solomon D, Lasker AG, Roberts DC: Transient torsion during and after
saccades. Vision Res 1995;35:3321–3334.
81 Maxwell GF, Lemij HG, Collewijn H: Conjugacy of saccades in deep amblyopia. Invest
Ophthalmol Vis Sci 1995;36:2514–2522.
82 Lemij HG, Collewijn H: Long-term nonconjugate adaptation of human saccades to anisometropic
spectacles. Vision Res 1991;31:1939–1954.
Disconjugate Eye Movements
105
83 Collewijn H, Erkelens CJ, Steinman RM: Trajectories of the human binocular fixation point during conjugate and non-conjugate gaze-shifts. Vision Res 1997;37:1049–1069.
84 Chaturvedi V, van Gisbergen JA: Specificity of saccadic adaptation in three-dimensional space.
Vision Res 1997;37:1367–1382.
85 Enright JT: Monocularly programmed human saccades during vergence changes? J Physiol 1998;
512:235–250.
86 Ygge J, Zee DS: Control of vertical eye alignment in three-dimensional space. Vision Res
1995;35:3169–3181.
87 Kumar AN, Han Y, Dell’Osso LF, Durand DM, Leigh RJ: Directional asymmetry during combined
saccade-vergence movements. J Neurophysiol 2005;93:2797–2808.
88 Schor CM, Maxwell JS, Stevenson SB: Isovergence surfaces: the conjugacy of vertical eye
movements in tertiary positions of gaze. Ophthalmic Physiol Opt 1994;14:279–286.
89 Graf EW, Maxwell JS, Schor CM: Changes in cyclotorsion and vertical eye alignment during
prolonged monocular occlusion. Vision Res 2002;42:1185–1194.
90 Gauthier GM, Vercher JL, Zee DS: Changes in ocular alignment and pointing accuracy after
sustained passive rotation of one eye. Vision Res 1994;34:2613–2627.
91 Maxwell JS, Schor CM: Mechanisms of vertical phoria adaptation revealed by time-course and
2-dimensional spatiotopic maps. Vision Res 1994;34:241–251.
92 Schor CM, Gleason G, Maxwell J, Lunn R: Spatial aspects of vertical phoria adaptation. Vision
Res 1993;33:73–84.
93 Schor CM, McCandless JW: An adaptable association between vertical and horizontal vergence.
Vision Res 1995;35:3519–3527.
94 Schor CM, McCandless JW: Context-specific adaptation of vertical vergence to correlates of eye
position. Vision Res 1997;37:1929–1937.
95 Maxwell JS, Schor CM: Adaptation of vertical eye alignment in relation to head tilt. Vision Res
1996;36:1195–1205.
96 Maxwell JS, Schor CM: Head-position-dependent adaptation of nonconcomitant vertical skew.
Vision Res 1997;37:441–446.
97 Akao T, Kurkin S, Fukushima K: Latency of adaptive vergence eye movements induced by vergence-vestibular interaction training in monkeys. Exp Brain Res 2004;158:129–132.
98 Sato F, Akao T, Kurkin S, Fukushima J, Fukushima K: Adaptive changes in vergence eye movements induced by vergence-vestibular interaction training in monkeys. Exp Brain Res 2004;156:
164–173.
99 Oohira A, Zee DS: Disconjugate ocular motor adaptation in rhesus monkey. Vision Res 1992;32:
489–497.
100 Taylor MJ, Roberts DC, Zee DS: Effect of sustained cyclovergence on eye alignment: rapid
torsional phoria adaptation. Invest Ophthalmol Vis Sci 2000;41:1076–1083.
101 Kono R, Hasebe S, Ohtsuki H, Kashihara K, Shiro Y: Impaired vertical phoria adaptation in
patients with cerebellar dysfunction. Invest Ophthalmol Vis Sci 2002;43:673–678.
102 Steffen H, Walker M, Zee DS: Changes in Listing’s plane after sustained vertical fusion. Invest
Ophthalmol Vis Sci 2002;43:668–672.
103 Schor CM, Maxwell JS, Graf EW: Plasticity of convergence-dependent variations of cyclovergence with vertical gaze. Vision Res 2001;41:3353–3369.
104 Albano JE, Marrero JA: Binocular interactions in rapid saccadic adaptation. Vision Res 1995;35:
3439–3450.
105 Eggert T, Kapoula Z: Position dependency of rapidly induced saccade disconjugacy. Vision Res
1995;35:3493–3503.
106 Kapoula Z, Eggert T, Bucci MP: Immediate saccade amplitude disconjugacy induced by unequal
images. Vision Res 1995;35:3505–3518.
107 Oohira A, Zee DS, Guyton DL: Disconjugate adaptation to long-standing, large-amplitude, spectacle-corrected anisometropia. Invest Ophthalmol Vis Sci 1991;32:1693–1703.
108 Bucci MP, Gomes M, Paris S, Kapoula Z: Disconjugate oculomotor earning caused by feeble
image-size inequality: differences between secondary and tertiary positions. Vision Res 2001;41:
625–637.
Straumann
106
109 Paris S, Bucci MP, Kapoula Z: Disconjugate vertical memory-guided saccades to disparate targets.
Exp Brain Res 2000;135:267–274.
110 Donnet SP, Kapoula Z, Bucci MP, Daunys G: Vertical memory-based disconjugate learning for
downward saccades at a viewing distance of 70 cm: relation to horizontal vergence and to vertical
phoria. Exp Brain Res 2002;146:474–480.
111 Kapoula Z, Eggert T, Bucci MP: Disconjugate adaptation of the vertical oculomotor system.
Vision Res 1996;36:2735–2745.
112 Kapoula Z, Bucci MP, Eggert T, Zamfirescu F: Fast disconjugate adaptations of saccades in
microstrabismic subjects. Vision Res 1996;36:103–104.
113 Schor CM, Gleason J, Horner D: Selective nonconjugate binocular adaptation of vertical saccades
and pursuits. Vision Res 1990;30:1827–1844.
114 Lewis RF, Zee DS, Repka MX, Guyton DL, Miller NR: Regulation of static and dynamic ocular
alignment in patients with trochlear nerve pareses. Vision Res 1995;35:3255–3264.
115 Lewis RF, Zee DS, Goldstein HP, Guthrie BL: Proprioceptive and retinal afference modify postsaccadic ocular drift. J Neurophysiol 1999;82:551–563.
116 Lewis RF, Zee DS, Gaymard BM, Guthrie BL: Extraocular muscle proprioception functions in the
control of ocular alignment and eye movement conjugacy. J Neurophysiol 1994;72:1028–1031.
117 Paige GD, Tomko DL: Eye movement responses to linear head motion in the squirrel monkey. II.
Visual-vestibular interactions and kinematic considerations. J Neurophysiol 1991;65:1183–1196.
118 Schwarz U, Miles FA: Ocular responses to translation and their dependence on viewing distance.
I. Motion of the observer. J Neurophysiol 1991;66:851–864.
119 Paige GD, Tomko DL: Eye movement responses to linear head motion in the squirrel monkey. II.
Visual-vestibular interactions and kinematic considerations. J Neurophysiol 1991;65:1183–1196.
120 Paige GD, Tomko DL: Eye movement responses to linear head motion in the squirrel monkey. II.
Visual-vestibular interactions and kinematic considerations. J Neurophysiol 1991;65:1183–1196.
121 McHenry MQ, Angelaki DE: Primate translational vestibuloocular reflexes. II. Version and vergence responses to fore-aft motion. J Neurophysiol 2000;83:1648–1661.
122 Ramat S, Zee DS: Binocular coordination in fore/aft motion. Ann N Y Acad Sci 2005;1039:36–53.
123 Kodaka Y, Wada Y, Kawano K: Vergence responses to forward motion in monkeys: visual modulation at ultra-short latencies. Exp Brain Res 2003;148:541–544.
124 Angelaki DE, Hess BJM: Direction of heading and vestibular control of binocular eye movements.
Vision Res 2001;41:3215–3228.
125 Snyder LH, Lawrence DM, King WM: Changes in vestibulo-ocular reflex (VOR) anticipate
changes in vergence angle in monkey. Vision Res 1992;32:569–575.
126 Misslisch H, Tweed D, Hess BJ: Stereopsis outweighs gravity in the control of the eyes. J Neurosci
2001;21:RC126.
127 Ooi D, Cornell ED, Curthoys IS, Burgess AM, MacDougall HG: Convergence reduces ocular
counterroll (OCR) during static roll-tilt. Vision Res 2004;44:2825–2833.
128 Mandelli MJ, Misslisch H, Hess BJ: Static and dynamic properties of vergence-induced reduction
of ocular counter-roll in near vision. Eur J Neurosci 2005;21:549–555.
129 Pansell T, Ygge J, Schworm HD: Conjugacy of torsional eye movements in response to a head tilt
paradigm. Invest Ophthalmol Vis Sci 2003;44:2557–2564.
130 Palla A, Bockisch CJ, Bergamin O, Straumann D: Dissociated hysteresis of static ocular counterroll in humans. J Neurophysiol 2006;95:2222–2232.
131 Diamond SG, Markham CH: Ocular torsion as a test of the asymmetry hypothesis of space motion
sickness. Acta Astronaut 1992;27:11–17.
132 Markham CH, Diamond SG: Further evidence to support disconjugate eye torsion as a predictor
of space motion sickness. Aviat Space Environ Med 1992;63:118–121.
133 Diamond SG, Markham CH: Prediction of space motion sickness susceptibility by disconjugate
eye torsion in parabolic flight. Aviat Space Environ Med 1991;62:201–205.
134 Kori AA, Schmid-Priscoveanu A, Straumann D: Vertical divergence and counterroll eye movements
evoked by whole-body position steps about the roll axis of the head in humans. J Neurophysiol
2001;85:671–678.
Disconjugate Eye Movements
107
135 Dai M, Raphan T, Kozlovskaya I, Cohen B: Modulation of vergence by off-vertical yaw axis rotation in the monkey: normal characteristics and effects of space flight. Exp Brain Res 1996;111:
21–29.
136 Jauregui-Renaud K, Faldon ME, Gresty MA, Bronstein AM: Horizontal ocular vergence and the
three-dimensional response to whole-body roll motion. Exp Brain Res 2001;136:79–92.
137 Weber KP, Landau K, Palla A, Haslwanter T, Straumann D: Ocular rotation axes during dynamic
Bielschowsky head-tilt testing in unilateral trochlear nerve palsy. Invest Ophthalmol Vis Sci
2004;45:455–465.
138 Wong AMF, Sharpe JA, Tweed D: The vestibulo-ocular reflex in fourth nerve palsy: deficits and
adaptation. Vision Res 2002;42:2205–2218.
139 Wong AM, Tweed D, Sharpe JA: Adaptations and deficits in the vestibulo-ocular reflex after sixth
nerve palsy. Invest Ophthalmol Vis Sci 2002;43:99–111.
140 Wong AM, Tweed D, Sharpe JA: Adaptations and deficits in the vestibulo-ocular reflex after sixth
nerve palsy. Invest Ophthalmol Vis Sci 2002;43:99–111.
141 Misslisch H, Tweed D: Neural and mechanical factors in eye control. J Neurophysiol 2001;86:
1877–1883.
142 Misslisch H, Hess BJ: Combined influence of vergence and eye position on three-dimensional
vestibulo-ocular reflex in the monkey. J Neurophysiol 2002;88:2368–2376.
143 Wong AMF, Tweed D, Sharpe JA: Vertical misalignment in unilateral sixth nerve palsy.
Ophthalmology 2002;109:1315–1325.
144 Misslisch H, Tweed D, Fetter M, Dichgans J, Vilis T: Interaction of smooth pursuit and the vestibuloocular reflex in three dimensions. J Neurophysiol 1996;75:2520–2532.
145 Bergamin O, Straumann D: Three-dimensional binocular kinematics of torsional vestibular nystagmus during convergence on head-fixed targets in humans. J Neurophysiol 2001;86:113–122.
146 Bergamin O, Bizzarri S, Straumann D: Ocular torsion during voluntary blinks in humans. Invest
Ophthalmol Vis Sci 2002;43:3438–3443.
147 Rambold H, Sprenger A, Helmchen C: Effects of voluntary blinks on saccades, vergence eye
movements, and saccade-vergence interactions in humans. J Neurophysiol 2002;88:1220–1233.
148 Rambold H, Neumann G, Sprenger A, Helmchen C: Blink effect on slow vergence. Neuroreport
2002;13:2041–2044.
149 Rambold H, Neumann G, Sander T, Helmchen C: Age-related changes of vergence under natural
viewing conditions. Neurobiol Aging 2006;27:163–172.
150 Versino M, Hurko O, Zee DS: Disorders of binocular control of eye movements in patients with
cerebellar dysfunction. Brain 1996;119:1933–1950.
151 Zee DS: Considerations on the mechanisms of alternating skew deviation in patients with cerebellar lesions. J Vestib Res 1996;6:395–401.
152 Guyton DL: Dissociated vertical deviation: etiology, mechanism, and associated phenomena.
Costenbader Lecture. J AAPOS 2000;4:131–144.
153 Guyton DL, Cheeseman EW Jr, Ellis FJ, Straumann D, Zee DS: Dissociated vertical deviation: an
exaggerated normal eye movement used to damp cyclovertical latent nystagmus. Trans Am
Ophthalmol Soc 1998;96:389–424; discussion 424–429.
154 Brodsky MC: Dissociated vertical divergence: a righting reflex gone wrong. Arch Ophthalmol
1999;117:1216–1222.
155 Brodsky MC: Dissociated vertical divergence: perceptual correlates of the human dorsal light
reflex. Arch Ophthalmol 2002;120:1174–1178.
156 Averbuch-Heller L, Zivotofsky AZ, Remler BF, Das VE, Dell’Osso LF, Leigh RJ: Convergentdivergent pendular nystagmus: possible role of the vergence system. Neurology 1995;45:509–515.
157 Pullicino P, Lincoff N, Truax BT: Abnormal vergence with upper brainstem infarcts: pseudoabducens palsy. Neurology 2000;55:352–358.
158 Wiest G: Abnormal vergence with upper brainstem infarcts: pseudoabducens palsy. Neurology
2001;56:424–425.
159 Pullicino P, Lincoff N, Truax BT: Abnormal vergence with upper brainstem infarcts: pseudoabducens palsy. Neurology 2000;55:352–358.
160 Rambold H, Kömpf D, Helmchen C: Convergence retraction nystagmus: a disorder of vergence?
Ann Neurol 2001;50:677–681.
Straumann
108
161 Zee DS: Internuclear ophthalmoplegia: pathophysiology and diagnosis. Baillieres Clin Neurol
1992;1:455–470.
162 Frohman TC, Frohman EM, O’Suilleabhain P, Salter A, Dewey RB Jr, Hogan N, Galetta S, Lee
AG, Straumann D, Noseworthy J, Zee D, Corbett J, Corboy J, Rivera VM, Kramer PD: Accuracy of
clinical detection of INO in MS: corroboration with quantitative infrared oculography. Neurology
2003;61:848–850.
163 Gaymard B: Disconjugate ocular bobbing. Neurology 1993;43:2151.
164 Park SH, Na DL, Kim M: Disconjugate vertical ocular movement in a patient with locked-in syndrome. Br J Ophthalmol 2001;85:497–498.
165 Rambold H, Neumann G, Helmchen C: Vergence deficits in pontine lesions. Neurology 2004;62:
1850–1853.
166 Rambold H, Sander T, Neumann G, Helmchen C: Palsy of ‘fast’ and ‘slow’ vergence by pontine
lesions. Neurology 2005;64:338–340.
Dominik Straumann
Neurology Department
Zurich University Hospital
CH–8091 Zurich (Switzerland)
Tel. ⫹41 44 255 4407, Fax ⫹41 44 255 5564, E-Mail [email protected]
Disconjugate Eye Movements
109
Straube A, Büttner U (eds): Neuro-Ophthalmology.
Dev Ophthalmol. Basel, Karger, 2007, vol 40, pp 110–131
The Eyelid and Its Contribution to
Eye Movements
C. Helmchen, H. Rambold
Department of Neurology, University of Lübeck, Lübeck, Germany
Abstract
Lid and electromyographic recordings have contributed significantly to our understanding of clinical lid disorders. Tonic lid disorders (e.g. ptosis, blepharospasm, lid retraction, blepharocolysis) can be distinguished from dynamic lid disorders (lid lag) and from
specific deficits of eye-lid coordination (e.g. lid nystagmus). Electromyographic recordings
allow the identification of specific lid disorders that benefit from effective therapeutic interventions, e.g., botulinum toxin injections. Rapid lid closure (blink), which exerts substantial
neural influence on oculomotor systems without obscuring vision, can be used for the diagnosis of brainstem disease.
Copyright © 2007 S. Karger AG, Basel
Whereas clinicians often use peripheral eyelid disorders for a topologic
diagnosis, supranuclear eyelid disorders have received little attention. Over the
past 15 years, considerable progress has been made in our understanding of the
supranuclear control of eyelid function. Moreover, several lines of evidence
indicate a strong interaction between the neural control of eyelid and eye movements. Therefore, this chapter has three aims. First, the current knowledge of
the anatomic and physiologic basis of eyelid movements will be reviewed, with
particular emphasis on the supranuclear control of eyelid movements and eyelid coordination. Subsequently, the recent evidence for substantial interaction
between eyelid and eye movements will be given (e.g. saccades and smooth
pursuit eye movements) and the clinical implications. Finally, a variety of clinical eyelid disorders will be discussed.
Neural Control of the Eyelid
Although the position of the upper eyelid is actively controlled by several
muscles, eyelid closure (blink) is itself a passive movement of the eyelid. It
occurs when innervation of the levator palpebrae muscle (LPM) ceases [1]. In
addition to the LPM inhibition, connective tissue (canthal tendons, superior
transverse ligament) serves as an elastic force that is stretched during upgaze
and released during downgaze. Voluntary firm closure of the eyelid is supplied
by the orbicularis oculi (OO) muscles, which are innervated by the facial nerve
[2]. The OO muscle is, however, not active during lid movements that accompany vertical eye movements [2, 3]. Eyelid opening is largely controlled by the
strong LPM, which is innervated by the superior branch of the third cranial
(oculomotor) nerve. In contrast, the superior tarsal (Müller) muscle is supplied
by sympathetic efferents and regulates the width of the palpebral fissure. The
LPM contains singly (but not multiply) innervated fibers that enable tonic
activity [4]. Both fast-twitch and slow-twitch fibers of the LPM are rich in
mitochondria and help to resist fatigue. In addition, the frontal muscle helps to
retract the lid in maximal upgaze.
The motoneurons of the LPM lie in the central caudal nucleus (CCN) of
the oculomotor nucleus complex in the midbrain. This uniquely unpaired
nucleus is located midline between the caudal pole of the oculomotor nucleus
and the rostral pole of the trochlear nucleus [5]. Since motoneurons of both
LPMs intermingle within the CCN, any lesion of the CCN affects both eyelids.
Lid-Eye Coordination
Eyelid and vertical eye movements are tightly coupled to avoid visual disturbances on upward gaze and to protect the eye on downward gaze.
Accordingly, the neuronal activity of LP and superior rectus motoneurons [6]
and also the dynamic properties of lid and eye saccades are very similar in their
temporal profile, which is also reflected in electromyographic (EMG) recordings. The gain and phase shift of the eye and lid movement are similar during
sinusoidal smooth pursuit. In contrast, during saccades the lid starts about 5 ms
later than the eye but reaches the peak velocity at about the same time as the eye
[7]. Lid movements that accompany saccadic eye movements between the
straight ahead position and the lower visual field are larger than lid movements
that accompany saccadic eye movements between the straight ahead position
and the upper visual field [7]. Lid saccades are not as conjugate as saccades [8].
During fixation periods, lid position is quite unstable; the lids perform idiosyncratic eye movements that can amount to up to 5⬚ [7]. The tight coupling of lideye coordination may be changed by additional factors. The magnitude of
OO-EMG activity is reduced, when a saccade is made to a previously cued
The Eyelid and Its Contribution to Eye Movements
111
spatial location. Thus, the modulation of gaze-evoked OO-EMG activity does
not appear to depend on the presence of visual information per se, but results
from an extraretinal signal [9]. Moreover, the tonic lid position and the tonic
activity of the LPM depend on the state of alertness. The lid involuntarily lowers with increasing fatigue [10].
Levator motoneurons discharge at a steady rate. This increases linearly
with the elevating lid position. Upward lid saccades are caused by a burst of
activity in the LP motoneurons. Lid velocity increases with amplitude, saturating at about 450⬚/s [11]. LPM pause in firing during downward lid saccades,
which are entirely due to the elastic forces.
The eye and lid movement dissociate during a blink, and eye-lid coupling
is discontinued. In contrast to superior rectus motoneurons, LP motoneurons
cease firing [6]. Additional inhibition of the basal tonic LPM activity is
required. This inhibition is presumably received from the nucleus of the posterior commissure (nPC) [12]. Physiologically, the inhibition of LPM precedes
and outlasts the OO activation by about 10 ms [7]. Only during forced voluntary
eye closure does OO activity precede LPM inhibition [13].
Due to the tight coupling of eye-lid coordination, the supranuclear areas
for vertical eye movements are likely to also be involved, e.g. the interstitial
nucleus of Cajal (iC) and the rostral interstitial nucleus of the medial longitudinal fascicle (riMLF). A small region, the M group, has been identified to be
a supranuclear center of eye-lid coordination, at least for saccades. It is caudal
and medial from the riMLF in the cat [14], monkey, and human [15]; from
there, it projects to the superior rectus and the inferior oblique subnuclei. For
this reason, the M group is thought to control the eyelids and eyes bilaterally
[15], thus allowing close synchronicity of both eyelids. The CCN receives
input from the nPC, the riMLF, and the superior colliculus (SC). Accordingly,
disorders of eye-lid coordination in the absence of LPM or superior rectus
paresis are likely to be caused by lesions of the M group or the nPC (see
below).
The nPC is located bilaterally adjacent to the posterior commissure [16].
Experimental and clinical nPC lesions elicit vertical upward gaze palsy and lid
disorders [17]. Lid retraction is the most frequent sign [18–21]. Single vertical
saccade-related neurons have been identified in the nPC [22], but their relation
to lid movements has not yet been investigated. The nPC receives afferents from
the frontal eye field (FEF) and SC, and projects to the neural integrator for vertical and torsional eye movements (iC) [23, 24], the riMLF, SC, and the paramedian pontine reticular formation (PPRF) [16]. It has reciprocal connections
with the M group [25] and lesions involving the nPC [21] or the M group [26]
may impair supranuclear inhibition of the CCN, leading to lid retraction and
discoupling of eye-lid coordination.
Helmchen/Rambold
112
The saccade-related medium-lead burst neurons in the riMLF represent the
neural substrate for vertical saccades [27]. They receive input from the omnipause neurons (OPNs) in the pontine reticular formation (nucleus raphe interpositus), which control their activity [28], and the SC. The rostral SC in turn
exerts tonic excitation of the OPNs to suppress unwanted saccades, whereas the
caudal SC provides the motor command to the pontine saccade-related burst
neurons. The activity of SC neurons is reduced during blinks [29], but it
remains unknown whether their activity is related to lid movements. Lesion
experiments have not yet described lid disorders or deficits in lid-eye coordination [30]. The SC underlies the cortical control of the FEF, the parietal fields,
and the subcortical control of the basal ganglia, e.g. the caudate nucleus and the
substantia nigra (pars reticulata). Accordingly, disorders of eyelid movements
are found in (right-sided) cortical lesions involving the FEF [31–34] and
parkinsonian syndromes (see below).
The cortical control of voluntary blinking involving the OO muscles has
recently been identified by retrograde tracing experiments in the monkey [12].
Cortical afferents in OO motoneurons were obtained from multiple motor and
sensory areas, e.g. the motor cortex (M1), FEF, supplementary motor area, cingulate motor area, and lateral prefrontal areas. Functional imaging techniques
have demonstrated activation in the FEF, the supplementary eye field, the dorsolateral prefrontal cortex, and the posterior parietal eye field during voluntary
blinking [35, 36]. Cortical efferents might use anatomic projections to the pontine and mesencephalic brainstem [37–39], but the precise efferent pathways of
the cortical control of the supranuclear centers of lid and eye-lid coordination in
the brainstem remain largely unknown.
Physiology of the Interaction between Eyelid and Eye Movements
The quantitative recording of eyelid movements with the search coil system in a magnetic field [11, 40–42] allows a precise analysis of lid-eye coordination. Eyelid movements are classified as spontaneous, passive (following eye
saccades), reflectory (elicited by tone, air puff, visual signals), and acquired, for
example when they are learned during classic conditioning procedures [40].
Thus, apart from lid-eye coordination, the eyelid motor system has become an
excellent experimental tool for investigating learned motor behavior in experimental [43, 44] and clinical studies [43, 44]. Reflexive blink responses have a
slightly shorter duration (200 ms) than spontaneous or voluntary blinks [2, 45].
They have a latency of 9–16 ms in the cat [3, 46] and 12 ms in humans [47];
their amplitude is smaller, and they only cover the pupil by a smaller degree
than voluntary blinks. During voluntary blinks, only the pretarsal portion of the
The Eyelid and Its Contribution to Eye Movements
113
OO is involved [48]. Several blink-related aspects have to be considered in
experimental studies: (a) voluntary blinks are distinctly different from reflectory blinks [2, 3, 49], (b) blinks interfere to some degree with visual perception,
and (c) blinks elicit small amplitude eye movements. They will be discussed in
more detail.
Visual Consequences of Blinks
While blinks can interrupt vision for a considerable amount of time, one is
unaware of this type of blanking [49–54]. Visual sensitivity is reduced during
blinks [53]. This reduction in sensitivity was found to be closely related to the
duration of pupil occlusion during the blink [53]. Visual suppression during
blinks is incomplete compared to that of saccades [51, 52, 55]. Blinks applied
during saccades did not cause blanking of the target. Recent functional magnetic resonance imaging demonstrated a change in blink-related activity in the
visual cortex and in areas of parietal and prefrontal cortex [56, 57]. This indicates active top-down modulation of visual processing during blinking, suggesting a possible mechanism by which blinks go unnoticed.
Blink-Associated Eye Movements
Long-lasting eye closure causes an upward eye drift known as Bell’s
phenomenon [58, 59]; short eye closure with blinks induces distinctly different
eye movements in humans (fig. 1) [2, 42, 45, 47, 59, 60]. During a blink, there
is an early inward, downward, [45, 59, 61] and ex-torsional movement of the
eyes [62]. The amplitude and direction of these eye movements depend on the
initial eye position [45, 59]. During adduction and downward gaze, the amplitudes of the blink-associated eye movement components are minimal. The
horizontal amplitude increases during abduction, and the vertical amplitude
during upward gaze [45]. The horizontal, vertical, and torsional components of
the blink-associated eye movement start before lid movement onset [53, 60,
62], and the movement is completed before blink termination [47, 59]. Blinkassociated eye movements are slower than saccades; they do not obey the saccadic
main sequence [59] and Listing’s law [63]. Blink-associated eye movements are
caused by cocontraction of all eye muscles [1, 13, 62, 64]. Bergamin et al. [62]
showed in humans that during the early phase of eyelid closure of voluntary
blinks the eye moves in a 3-D direction that can best be explained by a pulselike activation of the inferior rectus muscle.
Blink-associated eye movements reflect an active process, i.e. they are not
caused by mechanical eye-lid interaction [59], and they are important for the
protection of the cornea [2, 40, 45]. Blink-associated eye movements are not
only found during fixation but are superimposed on all kinds of eye movements, e.g. smooth pursuit, saccades, and vergence eye movements [41, 65–68].
Helmchen/Rambold
114
Verg
200º/s
con
div
VeIH
200º/s
left
right
VeIV
200º/s
up
down
100 ms
0
close
1
Lid
open
Fig. 1. Effect of blinks on eye velocity
components at gaze straight ahead in a normal subject. Mean eye vergence velocity
(Verg), horizontal (VelH) and vertical
(VelV) version velocity, as well as relative
eyelid position (Lid) are averaged (5 blinks)
and aligned to blink onset. Note that the
blink duration exceeds the eye movement
duration; modified after Rambold et al.
[42], with permission.
Effect of Blinks on Eye Movements
Blinks affect eye movements in at least two ways: (1) by superimposing
blink-associated eye movements and (2) by modifying the neuronal premotor
activity in brainstem circuits, which change their dynamic properties. This second aspect will be discussed in more detail below.
Blinks and Saccades
Voluntary and reflexive blinks influence horizontal and vertical visually
guided saccades in monkeys and in humans [30, 42, 47, 69]. Blinks reduce horizontal saccade velocity, acceleration, deceleration, and increase saccade duration, but they do not change saccade amplitude (fig. 2) [42, 47]. The effect of
the blink on the saccade is time dependent. The maximum effect is observed
with blinks elicited about 150 ms before saccade onset [42, 69]. If blinks are
elicited later during the saccade, dynamic overshoots may occur [47]. Blinks
reduce saccade latency [69] when they are elicited shortly after but not before
[67] stimulus onset.
This influence of blinks can be explained by the blink-induced changes of
the neuronal oculomotor circuits in the brainstem [29, 30, 42, 47]. Medium-lead
burst neurons of the PPRF and the riMLF provide the premotor saccadic command to the extraocular motoneurons [70]. Several lines of evidence indicate
that OPNs in the nucleus raphe interpositus [71] control saccadic burst neurons
[72]. OPNs, which discharge spontaneously, cease firing during saccades [70,
The Eyelid and Its Contribution to Eye Movements
115
left
15
0
⫺15
⫺25
a
Velocity (degrees/s)
right
left
500
⫺15
300
100
⫺100
⫺300
down
⫺500
e
open
0
0
Lid
Lid
close
⫺25
500
up
⫺100
open
0
d
100
⫺500
b
15
down
300
⫺300
25
up
Position (degrees)
25
Velocity (degrees/s)
Position (degrees)
right
1
c
close
f
1
100 ms
Fig. 2. Eye movement traces for one normal subject are aligned with respect to saccade
begin. Horizontal (a–c) and vertical (d–f) saccades are displayed separately as eye position
(a, d), eye velocity (b, e), and lid position (c, f). Saccade duration is increased and peak
velocity decreased for both horizontal (a, b) and vertical (d, e) saccades in the blink condition (solid line), in contrast to the control condition (dotted line). The shift of the dotted lines
(f) indicates the accompanying lid movement with vertical eye movements; modified after
Rambold et al. [42], with permission.
73–75]. Ibotenic acid injections in the OPN region of the monkey decrease saccadic peak velocity and increase saccade duration without changing saccade
amplitude [76].
Blinks decrease OPN discharge even without eye movements [77–79]; the
discharge during saccades in medium-lead burst neurons of the PPRF [80] and
in saccade-related long-lead burst neurons in the intermediate layer of the SC is
decreased [29]. Accordingly, the inhibitory effect of blinks on the OPNs might
Helmchen/Rambold
116
10º
Vergence (degree)
a
b
Lid
open
phase 2
phase 2
close
phase 1
c
phase 1
d
200 ms
Fig. 3. The vergence eye movements are shown separately for the convergence (a, b)
and divergence (c, d) components of the vergence position (a, c) and the relative lid position
(b, d). Eye movements during the blink condition (black solid traces) are compared with
those during the no blink condition (dotted trace). All traces are aligned to vergence onset.
For better illustration, the onset of two phases of the vergence components is indicated by
vertical dotted lines. In phase 1, a convergence-divergence movement is found in the convergence (a) and in the divergence (c) paradigms. Note that vergence duration exceeds blink
duration; modified after Rambold et al. 2002 [42], with permission.
explain the outlined behavioral effects. Further evidence comes from a saccadic
brainstem model that incorporates rebound inhibition firing of the mediumlead burst neurons [81].
Blinks and Vergence Eye Movements
Vergence may be divided into two subsystems: a transient and a sustained
vergence system [82, 83]. The transient vergence system is elicited by large
retinal disparity errors, which cannot be fused on the retina; the sustained vergence is largely elicited by similar images, small disparity errors, or velocities
of less than 4⬚/s [83, 84]. Blinks affect both subsystems of vergence. Following
blink-associated eye movements, the subsequent transient vergence is increased
in duration and decreased in velocity when a voluntary blink is elicited (fig. 3).
The Eyelid and Its Contribution to Eye Movements
117
4º
Everg
(degrees)
Everg
(degrees)
conv
div
a
b
0
Lid
Lid
open
500 ms
close
1
c
d
div
5º/s
Vverg
(degrees/s)
con
100 ms
e
f
Fig. 4. Eye position traces are shown for vergence position (a, b) and lid position (c, d)
in one healthy subject. The two different vergence directions, convergence (a, c), and divergence (b, d) are shown separately. a–d Thick solid lines indicate the mean of the control condition (without blinks), while the dashed lines show recordings during the blink condition.
The long dashed line indicates the end of the blink. The gray inset (a, b) represents the part
shown below at higher resolution and as vergence velocity in e, f . e, f Thick solid lines indicate the vergence velocity in the control condition (dotted lines ⫾ 1 standard deviation), and
thin solid lines vergence velocity in the blink condition. The arrows mark the late peak vergence velocity. All traces are aligned to blink onset and shifted for better comparison; modified after Rambold et al. [68], with permission.
This effect is also time dependent; the earlier blinks start before the vergence
onset, the more their duration is increased and peak velocity decreased [42].
The blink effect on transient vergence movements may be related to
changes in the brainstem premotor circuit, including the OPNs [68], since
OPNs also control vergence burst neurons [85]. Accordingly, stimulation of the
OPN area slows vergence movements [85]. The peak of vergence velocity
depends on the stimulus direction when a reflexive blink is elicited during sustained vergence [68] (fig. 4). This velocity peak shows oscillations (1.7–3.3 Hz)
similar to vergence oscillations [25, 83]. These oscillations may be caused by
the inhibition of OPNs leading to a disinhibition of the vergence systems.
Blinks and Saccade-Vergence Interaction
To perform saccades in space, conjugate and vergence eye movements
are elicited together [86]. Blinks also exert a distinct influence on combined
Helmchen/Rambold
118
a
0
500 ms
10 deg/s
10 deg/s
100 deg/s
0
Delta velocity
100 deg/s
0
0
Leftward
0
Lid position
Lid position
Eye velocity
Rightward
0
b
100 ms
Fig. 5. Eye velocity responses of step-ramp smooth pursuit (target: thin, solid line) are
shown for the blink paradigm (gray lines) in rightward (1st trace) and leftward (2nd trace)
directions. The mean desaccaded control pursuit velocity (control paradigm; bold solid line)
is superimposed. Below each plot, the lid position is shown (3rd trace). Blink-associated eye
movements are marked by asterisks. The other fast peaks in eye velocity reflect saccades that
occur with some pause before or after the blink, but not during the blink. After the blinkassociated eye movements, there is a velocity decrease compared to control for both directions and subjects. b The pursuit velocity (mean: solid black line; individual data: thin gray
lines) in the blink and control paradigms are subtracted for rightward (1st trace) and leftward
(2nd trace) pursuit directions for the interval indicated by the dashed rectangle in a. All data
are aligned to maximal lid closure during the blink. Negative velocity indicates a decrease
compared to that of the control; modified after Rambold et al. [65], with permission.
saccade-vergence eye movements: both components are decreased in peak
velocity, acceleration, deceleration, and increased in duration [42]. This effect
might be related to the inhibitory effect of blinks on the OPNs [79, 80, 87].
Blinks and Smooth Pursuit Eye Movements
Introducing a blink just before target onset in a step-ramp smooth pursuit
paradigm causes a decrease in pursuit latency of about 10 ms. This effect is on the
average less than the gap effect of 35 ms in a gap paradigm (extinguishing the
visual stimulus before target onset) when using a comparable gap and blink duration [41]. Saccades are suppressed during the blink but not during the gap [65].
When a reflexive blink is introduced during ongoing smooth pursuit there
are blink-associated eye movements, which are followed by a decrease in pursuit velocity (fig. 5). This decrease is independent of the direction and the blink
The Eyelid and Its Contribution to Eye Movements
119
amplitude, i.e. regardless of whether it covers or does not cover the pupil.
Immediately before and during the blinks, correcting saccades are suppressed.
These effects are probably not related to blanking the visual target but rather to
changes of the activity of OPNs or to visual suppression [65]. The activity of
50% of the OPNs is decreased during ongoing smooth pursuit [88]. Electrical
stimulation of the OPN area during ongoing smooth pursuit decelerates smooth
pursuit eye movements [88].
Clinical Disorders of the Eyelid and Its Interaction with Saccades
Disorders of Blink Frequency
The spontaneous blink frequency shows a high interindividual variability
(10–30/min; on average, 24 blinks/min) [89]. The mean amplitude and peak
velocity of spontaneous blinks decrease with age. This is also true of voluntary
blinks, but to a less extent [90, 91]. Here, the narrowing of the palpebral fissure
width probably plays a role. Alternatively, the reduction in the blink main
sequence could reflect a reduction in OO motoneuron activity, which compensates for age-related increases in blink reflex excitability. In contrast, blink frequency and blink conjugacy do not change with age [90, 92]. Blink frequency is
strongly modulated by attentional mechanisms under normal and pathological
conditions, e.g., in schizophrenic patients [93]. In contrast to reflexive blinks,
voluntary blinks may crucially depend on internal vs. external commands, e.g.
in parkinsonian syndromes.
Special forms of increased blink frequency are lid nystagmus and eyelid
tremor. Lid nystagmus is usually associated with eye movements, is gaze
dependent, and modulated by vergence eye movements [94, 95]. It reflects a
slow downward drift of the lids with correcting upward jerks of the upper eyelid. Due to the tight lid-eye coupling, vertical nystagmus may be associated
with lid nystagmus. While it may be benign [96], it is usually associated with
lateral medullary infarction [97] or cerebellar or midbrain disease, e.g. lowgrade astrocytoma compressing the CCN [98]. Lid nystagmus may outlast vertical nystagmus [99]. Lid nystagmus may also occur without eye nystagmus due
to midbrain lesions [25, 98, 100]. Vestibular stimulation in midbrain-lesioned
monkeys causes an upward lid nystagmus, although upbeating nystagmus was
abolished [101]. Lid nystagmus with a horizontal nystagmus is found in lateral
medullary lesion (Wallenberg’s syndrome), which may be inhibited by convergence [97]. In contrast, eyelid nystagmus may also be elicited by convergence
in medullary and cerebellar lesions (Pick’s sign) [94, 102, 103].
Eyelid tremor is defined as regular eyelid twitches of 7 Hz and is usually
not gaze dependent. In contrast, blepharoclonus consists of repetitive eyelid
Helmchen/Rambold
120
jerks at a slower frequency (2–4 Hz) and may be induced by eye closure [104].
Eyelid tremor may be associated with parkinsonian syndromes [105], but also
paramedian thalamic lesions [106]. It is still not known whether the presumed
disinhibition of LPM and OO muscle activity is related to the thalamus, the
extension of the lesion into the midbrain, or disconnecting cortical areas
involved in voluntary lid control. Pathophysiologically, inappropriate contractions of LPM and OO with disturbed reciprocal inhibition have been proposed
[19].
In animal experiments, blink rates significantly and positively correlated
with the concentration of dopamine in the caudate nucleus, and the severity of
experimentally induced parkinsonism was inversely correlated with the blink
rate [107]. Accordingly, since spontaneous blink frequency probably reflects
central dopamine activity, it is characteristically decreased in parkinsonian syndromes (17 blinks per minute) [108], although it may vary in the ‘off’ and ‘on’
periods of patients with fluctuating Parkinson’s disease (PD) [109]. Blink rate
decreases as PD advances [110], but also de novo PD patients who have not
been exposed to dopaminergic therapy show decreased blink rates [108]. The
blink rate in patients with levodopa-induced dyskinesias has been shown to be
higher than that in optimally treated PD patients and normal individuals [111].
It is consistently found to be decreased in progressive supranuclear palsy (PSP)
[112], patients with PD [89], and those patients who receive dopaminergic medication [113], whereas it is not changed in Huntington’s disease and dystonia.
The strongest decrease is found in PSP patients (4 blinks per minute) [89]. In
addition, dopaminergic basal ganglia circuits play a role in the inhibition of
LPM during blinks and eye closure [19]. As a major adverse effect, decreased
blink rate in PD leads to ocular surface irritation (blepharitis), the most common ocular complaint of PD patients [108].
Apart from recording changes in blink rate, the blink reflex has been
established to be a reliable diagnostic tool for assessing the site of brainstem
lesions, in particular lesions in the dopaminergic circuit, which controls eyelid
blink. The blink reflex is known to be hyperexcitable in PD [92, 114–116].
Pathophysiologically, the loss of dopamine in the substantia nigra pars compacta
may lead to increased reflex blink excitability. Descending inhibitory pathways
from the basal ganglia modulate the excitability via tectoreticular projections.
Decreasing the basal ganglia inhibitory output to the SC and electrical stimulation of the SC reduce blink hyperexcitability and blink amplitude [114].
According to the latter model, the substantia nigra pars reticulata inhibits SC
neurons, which excite tonically active neurons of the raphe magnus nucleus. The
latter inhibits spinal trigeminal neurons involved in reflex blink circuits [115].
Thus, changes in reflex blink excitability and blink amplitude may help to detect
early or preclinical signs in PD. Since a reflex blink inhibits subsequent blinks,
The Eyelid and Its Contribution to Eye Movements
121
the magnitude of a blink reflects a balance between inhibitory and facilitatory
processes [117].
Disorders of Tonic Eyelid Position
The eyelid position is greatly influenced by cortical and brainstem mechanisms. Thus, ptosis may result from midbrain and cortical lesions. Midbrain
lesions involving the caudal third nerve nucleus (CCN) elicit complete bilateral
ptosis since the LPMs are deficient [118–123]. Nuclear third nerve lesions with
CCN involvement may elicit bilateral ptosis with contralateral superior rectus
paresis [124]. Isolated CCN lesions are rare but may preserve ocular motility
[125, 126]. In contrast to the complete ptosis in lesions of the LPM, sympathetic
lesions elicit a slight upper lid depression, e.g. in Horner’s syndrome, which may
be caused by carotid artery occlusion or dissection (peripheral) or lateral
medullary infarctions (central Horner’s syndrome) [120]. Unilateral ptosis may
result from fascicular or peripheral third nerve palsy [127] or large hemispheric
lesions, probably related to descending corticonuclear pathways of eyelid control
[120]. Weber’s syndrome and Claude’s syndrome reflect unilateral fascicular third
nerve lesion with contralateral hemiataxia or hemiparesis. Cortical bifrontal or
unilateral, predominantly right-hemispheric, lesions may elicit bilateral ptosis
[31, 32, 128, 129]. Controversial data exist as to which side is more strongly
affected: the contralateral [120] or ipsilateral eye [32]. Fourteen of 24 patients
with hemispheric strokes had predominantly ipsilateral ptosis, which is probably
related to an associated facial weakness superimposed on the asymmetry of the
palpebral fissures of bilateral partial ptosis [32]. Otherwise, the common concept
of a single motor nucleus innervating both levators would have to be challenged.
Two additional conditions with involuntary eyelid closure or the inability
to open the eyelids are blepharospasm and blepharocolysis. Pathological involuntary eyelid closure may result from a deficient excitation, a prolonged inhibition of the LPM (blepharocolysis), or involuntary excitation of the OO muscles,
e.g. focal dystonia (blepharospasm).
Blepharospasm is an excessive involuntary focal dystonic unilateral or
bilateral contraction of the OO muscles with LP muscle cocontraction. It is
characterized by frequent and prolonged blinks, clonic bursts, and prolonged
tonic OO contraction [130]. Clinically, the brows are lowered below the superior orbital rim (Charcot’s sign). Accordingly, EMG recordings of the LPM and
OO muscles simultaneously show impaired timing of the reciprocal inhibition,
which may lead clinically to dystonic blinks [48] and electrophysiologically
facilitate the R2 component of the blink reflex [131]. Cases of unilateral lid
spasm may occur in conjunction with unilateral or hemifacial spasm.
The most common cause of hemifacial spasm is irritation of the seventh
nerve roots by a dilated or tortuous vascular structure. Blepharospasm has also
Helmchen/Rambold
122
been reported to occur with thalamic [132, 133], subthalamic [132, 134], and
brainstem [135, 136] lesions, but it is often associated with PD or PSP [137].
Benign essential blepharospasm may be caused by an overexcitatory drive of
the basal ganglia. As initial treatment, artificial tear drops are recommended,
since ocular surface irritation (due to decreased blink rate) may also contribute
to increased OO tone [108]. Blepharospasm may also be secondary to Bell’s
palsy and may be relieved by passive eyelid lowering [138]. Otherwise, injections of botulinum toxin to weaken the affected muscles, in particular the pretarsal portion of the upper eyelid, are the appropriate treatment [139–141].
Blepharospasm may be restricted to dystonic contraction of only the pretarsal
portion of the OO without concomitant contraction of the OO (pretarsal LP
inhibition, pretarsal blepharospasm) [142]. In contrast to the typical blepharospasm, the eyes appear to be nearly closed, and there is a concomitant
contraction of the frontal muscles and elevation of the brows. Moreover, the
blink frequency is reduced. Patients usually suffer from PD or PSP. Tactile sensory stimulation (eyelash touching or glabellar tapping) may help to release the
dystonic position.
Blepharocolysis is a similar – possibly identical – condition characterized
by an excessive involuntary closure of the eyelids due to involuntary LPM
inhibition. The inappropriate, synonymous term ‘apraxia of eyelid opening,’
previously widely used, describes the inability of voluntary eyelid opening
[143] and of sustained lid elevation [139] caused by an involuntary LPM inhibition. In contrast to blepharospasm, blepharocolysis is due to an involuntary
overinhibition of the levator palpebrae superioris muscles with no evidence of
ongoing OO activity; it coexists with a coinhibition of these muscles [130], as
confirmed by simultaneous EMG recordings of the LP and OO muscles [139].
EMG recordings help to separate pretarsal blepharospasm from blepharocolysis and to make adequate therapeutic decisions. Since reflectory blinks remain
largely unaffected, it is likely to be a disorder of the supranuclear LP control.
However, the mechanism is only partly understood. Blepharocolysis is associated with PD, PSP, motor neuron disease, and putaminal [144] and subthalamic lesions [134]. Its prevalence is about 10% in patients with dystonia,
and about 2% in patients with parkinsonian syndromes (PD, 0.7%; PSP,
33.3%) [145].
Finally, under certain circumstances, the activity in the OO may only persist on voluntary eyelid opening but not when the eyes are open. This form of
pretarsal motor persistence [139] does not reveal any lid depression and is
therefore distinctly different from blepharocolysis. It also responds positively to
botulinum toxin.
Although lid retraction also reflects a tonic eyelid disorder, it leads to
impaired eyelid-eye coordination and will be discussed below.
The Eyelid and Its Contribution to Eye Movements
123
Disorders of Eyelid-Eye Coordination
Lid-eye coordination is preserved in most pathological eye movements.
For example, in vertical nystagmus the lid usually accompanies the eye movement [146]. Disorders of eyelid-eye coordination occur when lid saccades are
impaired but eye saccades preserved. Involuntary lid movement without accompanying vertical eye movement, e.g. in lid nystagmus, is less frequent. Lid nystagmus without vertical nystagmus may be elicited on horizontal gaze, e.g.
reported in a case of midbrain astrocytoma [98]. In midbrain lesions in the
monkey, vestibular stimulation caused an upward lid nystagmus, although the
upbeat nystagmus was abolished [101].
In accordance with the anatomical connections outlined above, lid nystagmus
may imply lesions of the M group, the nPC, or their reciprocal connections.
Lid lag and lid retraction are the most common disorders of impaired eyelid-eye coordination [147]. Whereas lid lag is a dynamic sign, which can be
observed on downgaze, lid retraction is a static phenomenon.
Lid retraction is diagnosed when the sclera is seen above the corneal limbus
during steady fixation. It indicates inappropriate LP muscle activity, presumably
related to neurogenic disinhibition of LP [19], but EMG evidence is still missing.
The basal tonic LPM activity is likely to be under the inhibitory control of the nPC
[12]. Deficient inhibition would result in lid retraction on gaze straight ahead or lid
lag with downgaze [147]. A clinicopathological retrospective correlation study
based on animal [18, 148] and human [149] case studies delineated the nPC as the
most likely lesion site for lid retraction [19]. This is consistent with very few eyelidand vertical saccade-related burst neurons that have been recorded in nPC [150].
Although lid lag and lid retraction may occur together [151], a feasible
pathomechanism has to account for lesions that cause only either lid lag or lid
retraction. A single case report showing a patient with slow vertical saccades
and lid lag but no lid retraction [152] suggests separate pathways for both clinical signs. This lesion spared the nPC but probably affected the M group. It
remains open whether dynamic and static lid-eye coordination is controlled by
separate pathways. Lid retraction is seen in ischemic midbrain lesions, e.g.
Parinaud’s syndrome, and extrapyramidal syndromes, e.g. PD and PSP [153,
154]. The prevalence of lid retraction/lid lag in PD patients is not exactly
known, but preliminary data indicate up to 37% of patients [147].
In incomplete vertical gaze palsy caused by midbrain lesions, the lid
appears to follow the eye, but it may also cause a lid saccade [19, 155]. In the
case of upward gaze palsy, the lids may retain the ability to elevate during
attempted vertical upgaze, i.e. so-called ‘pseudoretraction’. In turn, the lid may
lower during attempted downgaze in downgaze saccade palsy, leading to
‘pseudoptosis’ [19]. Eye-lid coordination in mesencephalic lesions has not yet
been systematically examined in detail.
Helmchen/Rambold
124
Clinical Application of Lid Movements
Blinks and the Initiation of Eye Movements
Under certain circumstances, blinks might slow eye movements down,
speed them up, or elicit specific eye movements. Patients with posterior fossa
lesions, for example, were found to have saccades of normal velocity, but only
if a blink was simultaneously elicited [156]. In patients with ocular flutter and
opsoclonus, eye movement oscillations are often elicited by blinks [157, 158].
Peli and McCormack [159] reported on a patient with uncorrected
antimetropia (one eye is myopic, the fellow eye hyperopic) who achieved motor
fusion by blinking. Although this patient could have used saccadic vergence and
slow fusional vergence, he usually relied on blink vergence. These observations
might also be explained by the inhibition of OPNs.
Blinks may also be used to initiate saccades in ocular motor apraxia [160].
Ocular motor apraxia is characterized by the loss of voluntary control of saccades but by preserved reflectory saccades of the optokinetic reflex and the
vestibulo-ocular reflex. Most of these clinical observations have been attributed
to the inhibition of OPNs, which facilitates the execution of saccades.
Blinks Unmasking Vestibular Imbalance
Blinks may exhibit blink-related torsional quick-phase-like eye movements in patients with acute or persisting vestibular tone imbalance, e.g. in
vestibular neuritis or a circumscribed brainstem infarction in the vestibular
nuclei [161]. These blinks were followed by slow drifts with a time constant of
1–2 s, suggesting an unmasking of a vestibular tone imbalance. It has therefore
been proposed that blinks might be another useful clinical test for identifying a
persistent vestibular failure once spontaneous nystagmus has resolved.
References
1
2
3
4
5
6
Evinger C, Shaw MD, Peck CK, Manning KA, Baker R: Blinking and associated eye movements
in humans, guinea pigs, and rabbits. J Neurophysiol 1984;52:323–339.
Evinger C, Manning KA, Sibony PA: Eyelid movements. Mechanisms and normal data. Invest
Ophthalmol Vis Sci 1991;32:387–400.
Gruart A, Blazquez P, Delgado-Garcia JM: Kinematics of spontaneous, reflex, and conditioned
eyelid movements in the alert cat. J Neurophysiol 1995;74:226–248.
Spencer RF, Porter JD: Structural organization of the extraocular muscles. Rev Oculomot Res
1988;2:33–79.
Porter JD, Burns LA, May PJ: Morphological substrate for eyelid movements: innervation and
structure of primate levator palpebrae superioris and orbicularis oculi muscles. J Comp Neurol
1989;287:64–81.
Fuchs AF, Becker W, Ling L, Langer TP, Kaneko CR: Discharge patterns of levator palpebrae
superioris motoneurons during vertical lid and eye movements in the monkey. J Neurophysiol
1992;68:233–243.
The Eyelid and Its Contribution to Eye Movements
125
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
Becker W, Fuchs AF: Lid-eye coordination during vertical gaze changes in man and monkey.
J Neurophysiol 1988;60:1227–1252.
Wouters RJ, van den Bosch WA, Stijnen T, Bubberman AC, Collewijn H, Lemij HG: Conjugacy of
eyelid movements in vertical eye saccades. Invest Ophthalmol Vis Sci 1995;36:2686–2694.
Williamson SS, Zivotofsky AZ, Basso MA: Modulation of gaze-evoked blinks depends primarily
on extraretinal factors. J Neurophysiol 2005;93:627–632.
Kennard D, Glaser G: An analysis of eyelid movements. J Nerv Ment Dis 1964;139:31–48.
Guitton D, Simard R, Codere F: Upper eyelid movements measured with a search coil during
blinks and vertical saccades. Invest Ophthalmol Vis Sci 1991;32:3298–3305.
Gong S, DeCuypere M, Zhao Y, LeDoux MS: Cerebral cortical control of orbicularis oculi
motoneurons. Brain Res 2005;1047:177–193.
Esteban A, Salinero E: Reciprocal reflex activity in ocular muscles: implications in spontaneous
blinking and Bell’s phenomenon. Eur Neurol 1979;18:157–165.
Chen B, May PJ: Premotor circuits controlling eyelid movements in conjunction with vertical saccades in the cat: I. the rostral interstitial nucleus of the medial longitudinal fasciculus. J Comp
Neurol 2002;450:183–202.
Horn AK, Büttner-Ennever JA, Gayde M, Messoudi A: Neuroanatomical identification of mesencephalic premotor neurons coordinating eyelid with upgaze in the monkey and man. J Comp
Neurol 2000;420:19–34.
Büttner-Ennever JA, Buttner U: Neuroanatomy of the oculomotor system. The reticular formation.
Rev Oculomot Res 1988;2:119–176.
Christoff N: A clinicopathologic study of vertical eye movements. Arch Neurol 1974;31:1–8.
Carpenter MB, Harbison JW, Peter P: Accessory oculomotor nuclei in the monkey: projections
and effects of discrete lesions. J Comp Neurol 1970;140:131–154.
Schmidtke K, Buttner-Ennever JA: Nervous control of eyelid function. A review of clinical, experimental and pathological data. Brain 1992;115(pt 1):227–247.
Pasik T, Pasik P: Experimental models of oculomotor dysfunction in the rhesus monkey. Adv
Neurol 1975;10:77–89.
Galetta SL, Gray LG, Raps EC, Schatz NJ: Pretectal eyelid retraction and lag. Ann Neurol
1993;33:554–557.
Moschovakis AK, Scudder CA, Highstein SM: Structure of the primate oculomotor burst generator. I. Medium-lead burst neurons with upward on-directions. J Neurophysiol 1991;65:203–217.
Crawford JD, Cadera W, Vilis T: Generation of torsional and vertical eye position signals by the
interstitial nucleus of Cajal. Science 1991;252:1551–1553.
Fukushima K: The interstitial nucleus of Cajal in the midbrain reticular formation and vertical eye
movement. Neurosci Res 1991;10:159–187.
Leigh RJ, Zee DS: The Neurology of Eye Movements, ed 3. New York, Oxford University Press,
1999.
Büttner-Ennever JA, Jenkins C, Armin-Parsa H, Horn AK, Elston JS: A neuroanatomical analysis
of lid-eye coordination in cases of ptosis and downgaze paralysis. Clin Neuropathol
1996;15:313–318.
Bhidayasiri R, Plant GT, Leigh RJ: A hypothetical scheme for the brainstem control of vertical
gaze. Neurology 2000;54:1985–1993.
Horn AK, Buttner-Ennever JA, Wahle P, Reichenberger I: Neurotransmitter profile of saccadic
omnipause neurons in nucleus raphe interpositus. J Neurosci 1994;14:2032–2046.
Goossens HH, Van Opstal AJ: Blink-perturbed saccades in monkey. II. Superior colliculus activity.
J Neurophysiol 2000;83:3430–3452.
Goossens HH, Van Opstal AJ: Blink-perturbed saccades in monkey. I. Behavioral analysis.
J Neurophysiol 2000;83:3411–3429.
Averbuch-Heller L, Stahl JS, Remler BF, Leigh RJ: Bilateral ptosis and upgaze palsy with right
hemispheric lesions. Ann Neurol 1996;40:465–468.
Averbuch-Heller L, Leigh RJ, Mermelstein V, Zagalsky L, Streifler JY: Ptosis in patients with
hemispheric strokes. Neurology 2002;58:620–624.
Afifi AK, Corbett JJ, Thompson HS, Wells KK: Seizure-induced miosis and ptosis: association
with temporal lobe magnetic resonance imaging abnormalities. J Child Neurol 1990;5:142–146.
Helmchen/Rambold
126
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
Benbadis SR, Kotagal P, Klem GH: Unilateral blinking: a lateralizing sign in partial seizures.
Neurology 1996;46:45–48.
Bodis-Wollner I, Bucher SF, Seelos KC: Cortical activation patterns during voluntary blinks and
voluntary saccades. Neurology 1999;53:1800–1805.
van Eimeren T, Boecker H, Konkiewitz EC, Schwaiger M, Conrad B, Ceballos-Baumann AO:
Right lateralized motor cortex activation during volitional blinking. Ann Neurol 2001;49:
813–816.
Leichnetz GR, Hardy SG, Carruth MK: Frontal projections to the region of the oculomotor complex in the rat: a retrograde and anterograde HRP study. J Comp Neurol 1987;263:387–399.
Leichnetz GR, Spencer RF, Smith DJ: Cortical projections to nuclei adjacent to the oculomotor
complex in the medial dien-mesencephalic tegmentum in the monkey. J Comp Neurol 1984;228:
359–387.
Leichnetz GR, Gonzalo-Ruiz A: Prearcuate cortex in the Cebus monkey has cortical and subcortical connections like the macaque frontal eye field and projects to fastigial-recipient oculomotorrelated brainstem nuclei. Brain Res Bull 1996;41:1–29.
Delgado-Garcia JM, Gruart A, Trigo JA: Physiology of the eyelid motor system. Ann N Y Acad
Sci 2003;1004:1–9.
Rambold H, El Baz I, Helmchen C: Differential effects of blinks on horizontal saccade and
smooth pursuit initiation in humans. Exp Brain Res 2004;156:314–324.
Rambold H, Sprenger A, Helmchen C: Effects of voluntary blinks on saccades, vergence
eye movements, and saccade-vergence interactions in humans. J Neurophysiol 2002;88:
1220–1233.
Gerwig M, Dimitrova A, Kolb FP, et al: Comparison of eyeblink conditioning in patients with
superior and posterior inferior cerebellar lesions. Brain 2003;126(pt 1):71–94.
Timmann D, Gerwig M, Frings M, Maschke M, Kolb FP: Eyeblink conditioning in patients with
hereditary ataxia: a one-year follow-up study. Exp Brain Res 2005;162:332–345.
Bour LJ, Aramideh M, de Visser BW: Neurophysiological aspects of eye and eyelid movements
during blinking in humans. J Neurophysiol 2000;83:166–176.
Gruart A, Schreurs BG, del Toro ED, Delgado-Garcia JM: Kinetic and frequency-domain properties of reflex and conditioned eyelid responses in the rabbit. J Neurophysiol 2000;83:836–852.
Rottach KG, Das VE, Wohlgemuth W, Zivotofsky AZ, Leigh RJ: Properties of horizontal saccades
accompanied by blinks. J Neurophysiol 1998;79:2895–2902.
Esteban A, Traba A, Prieto J: Eyelid movements in health and disease. The supranuclear impairment of the palpebral motility. Neurophysiol Clin 2004;34:3–15.
Manning KA, Riggs LA, Komenda JK: Reflex eyeblinks and visual suppression. PerceptPsychophys
1983;34:250–256.
Ridder WH, Tomlinson A: Spectral characteristics of blink suppression in normal observers.
Vision Res 1995;35:2569–2578.
Ridder WH, Tomlinson A: A comparison of saccadic and blink suppression in normal observers.
Vision Res 1997;37:3171–3179.
Stevenson SB, Volkmann FC, Kelly JP, Riggs LA: Dependence of visual suppression on the amplitudes of saccades and blinks. Vision Res 1986;26:1815–1824.
Volkmann FC, Riggs LA, Moore RK: Eyeblinks and visual suppression. Science 1980;207:
900–902.
Volkmann FC, Riggs LA, White KD, Moore RK: Contrast sensitivity during saccadic eye movements. Vision Res 1978;18:1193–1199.
Ridder WH, Tomlinson A: Suppression of contrast sensitivity during eyelid blinks. Vision Res
1993;33:1795–1802.
Bristow D, Haynes JD, Sylvester R, Frith CD, Rees G: Blinking suppresses the neural response to
unchanging retinal stimulation. Curr Biol 2005;15:1296–1300.
Bristow D, Frith C, Rees G: Two distinct neural effects of blinking on human visual processing.
Neuroimage 2005;27:136–145.
Wilkins RH, Brody IA: Bell’s palsy and Bell’s phenomenon. Arch Neurol 1969;21:661–662.
Collewijn H, van der Steen J, Steinman RM: Human eye movements associated with blinks and
prolonged eyelid closure. J Neurophysiol 1985;54:11–27.
The Eyelid and Its Contribution to Eye Movements
127
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
Riggs LA, Kelly JP, Manning KA, Moore RK: Blink-related eye movements. Invest Ophthalmol
Vis Sci 1987;28:334–342.
Rambold H, El Baz I, Helmchen C: Effect of blinks on saccades before smooth-pursuit eyemovement initiation. Ann NY Acad Sci 2005;1039:563–566.
Bergamin O, Bizzarri S, Straumann D: Ocular torsion during voluntary blinks in humans. Invest
Ophthalmol Vis Sci 2002;43:3438–3443.
Straumann D, Zee DS, Solomon D, Kramer PD: Validity of Listing’s law during fixations, saccades, smooth pursuit eye movements, and blinks. Exp Brain Res 1996;112:135–146.
Evinger C, Manning KA: Pattern of extraocular muscle activation during reflex blinking. Exp
Brain Res 1993;92:502–506.
Rambold H, El Baz I, Helmchen C: Blink effects on ongoing smooth pursuit eye movements in
humans. Exp Brain Res 2005;161:11–26.
Rambold H, El B, I, Helmchen C: Effect of Blinks on Saccades before Smooth-Pursuit EyeMovement Initiation. Ann NY Acad Sci 2005;1039:563–566.
Rambold H, El Baz I, Helmchen C: Differential effects of blinks on horizontal saccade and
smooth pursuit initiation in humans. Exp Brain Res 2004;156:314–324.
Rambold H, Neumann G, Sprenger A, Helmchen C: Blink effect on slow vergence. Neuroreport
2002;13:2041–2044.
Gandhi NJ, Bonadonna DK: Temporal interactions of air-puff-evoked blinks and saccadic eye
movements: insights into motor preparation. J Neurophysiol 2005;93:1718–1729.
Hepp K, Henn V, Vilis T, Cohen B. Brainstem regions related to saccade generation; in Wurtz RH,
Goldberg ME (eds): The Neurobiology of Saccadic Eye Movements. Amsterdam, Elsevier, 1989,
pp 105–212.
Büttner-Ennever J, Büttner U. The reticualr formation; in Büttner-Ennever J (ed): Neuroanatomy
of the Oculomotor System. Amsterdam, Elsevier, 1988.
Zee DS, Fitzgibbon EJ, Optican LM: Saccade-vergence interactions in humans. J Neurophysiol
1992;68:1624–1641.
Evinger C, Kaneko CR, Fuchs AF: Activity of omnipause neurons in alert cats during saccadic eye
movements and visual stimuli. J Neurophysiol 1982;47:827–844.
Keller EL: Control of saccadic eye movements by midline brainstem neurons; in Baker R, Berthoz
A (eds): Control of Gaze by Brainstem Neurons. Amsterdam, Elsevier, 1977.
Busettini C, Mays LE: Pontine omnipause activity during conjugate and disconjugate eye movements in macaques. J Neurophysiol 2003;90:3838–3853.
Kaneko CR: Effect of ibotenic acid lesions of the omnipause neurons on saccadic eye movements
in rhesus macaques. J Neurophysiol 1996;75:2229–2242.
Cohen B, Henn V: Unit activity in the pontine reticular formation associated with eye movements.
Brain Res 1972;46:403–410.
Fuchs AF, Ling L, Kaneko CRS, King W, Usher SD: The timing of the response of brainstem
omnipause neurons relative to saccadic eye movements in the rhesus monkey. 1991;17:462.
Mays LE, Morrisse EJ: Activity of omnipause neurons during blinks. Soc Neurosci 1993;19:1404.
Mays LE, Morrisse DW: Electrical stimulation of the pontine omnipause area inhibits eye blink.
J Am Optom Assoc 1995;66:419–422.
Miura K, Optican LM: Saccadic slowing after inactivation of omnipause neuron may be caused by
the membrane characteristics of brainstem burst neurons. 2002;716.8.
Rambold H, Sander T, Neumann G, Helmchen C: Palsy of ‘fast’ and ‘slow’ vergence by pontine
lesions. Neurology 2005;64:338–340.
Semmlow JL, Yuan W, Alvarez TL: Evidence for separate control of slow version and vergence eye
movements: support for Hering’s Law. Vision Res 1998;38:1145–1152.
Erkelens CJ: Adaptation of ocular vergence to stimulation with large disparities. Exp Brain Res
1987;66:507–516.
Mays LE, Gamlin PDR. A neuronal mechanism subserving saccade-vergence interactions; in
Findlay JM, Walker R, Kentridge RW (eds): Eye Movement Research: Mechanism, Processes,
Applications. Amsterdam, Elsevier, 1995, pp 215–223.
Kumar AN, Han Y, Dell’osso LF, Durand DM, Leigh RJ: Directional asymmetry during combined
saccade-vergence movements. J Neurophysiol 2005;93:2797–2808.
Helmchen/Rambold
128
87 Busettini C, Mays LE: Saccade-vergence interaction in macaques. II. Vergence eenhancement
as the product of a local feedback vergence motor error and a weighted saccadic burst.
J Neurophysiol 2005;in press.
88 Missal M, Keller EL: Common inhibitory mechanism for saccades and smooth-pursuit eye movements. J Neurophysiol 2002;88:1880–1892.
89 Karson CN, Burns RS, LeWitt PA, Foster NL, Newman RP: Blink rates and disorders of movement. Neurology 1984;34:677–678.
90 Sun WS, Baker RS, Chuke JC, et al: Age-related changes in human blinks. Passive and active
changes in eyelid kinematics. Invest Ophthalmol Vis Sci 1997;38:92–99.
91 Wouters RJ, van den Bosch WA, Mulder PG, Lemij HG: Upper eyelid motility in blepharoptosis
and in the aging eyelid. Invest Ophthalmol Vis Sci 2001;42:620–625.
92 Deuschl G, Goddemeier C: Spontaneous and reflex activity of facial muscles in dystonia,
Parkinson’s disease, and in normal subjects. J Neurol Neurosurg Psychiatry 1998;64:320–324.
93 Karson CN, Dykman RA, Paige SR: Blink rates in schizophrenia. Schizophr Bull 1990;16:
345–354.
94 Sanders MD, Hoyt WF, Daroff RB: Lid nystagmus evoked by ocular convergence: an ocular electromyographic study. J Neurol Neurosurg Psychiatry 1968;31:368–371.
95 Safran AB, Berney J, Safran E: Convergence-evoked eyelid nystagmus. Am J Ophthalmol
1982;93:48–51.
96 Ticho U: Synkinesis of upper lid elevation occurring in horizontal eye movements. Acta
Ophthalmol (Copenh) 1971;49:232–238.
97 Daroff RB, Hoyt WF, Sanders MD, Nelson LR: Gaze-evoked eyelid and ocular nystagmus inhibited by the near reflex: unusual ocular motor phenomena in a lateral medullary syndrome.
J Neurol Neurosurg Psychiatry 1968;31:362–367.
98 Brodsky MC, Boop FA: Lid nystagmus as a sign of intrinsic midbrain disease. J Neuroophthalmol
1995;15:236–240.
99 Rohmer F, Conraux C, Collard M: Convergence nystagmus and palpebral nystagmus. Rev
Otoneuroophtalmol 1972;44:89–94.
100 Brusa A, Massa S, Piccardo A, Stoehr R, Bronzini E: Palpebral nystagmus. Rev Neurol (Paris)
1984;140:288–292.
101 Pasik T, Pasik P, Bender MB: The pretectal syndrome in monkeys. II. Spontaneous and induced
nystagmus, and ‘lightning’ eye movements. Brain 1969;92:871–884.
102 Howard RS: A case of convergence evoked eyelid nystagmus. J Clin Neuroophthalmol 1986;6:
169–171.
103 Safran AB, Berney J: Synchronism of reverse ocular bobbing and blinking. Am J Ophthalmol
1983;95:401–402.
104 Jacome DE: Synkinetic blepharoclonus. J Neuroophthalmol 2000;20:276–284.
105 Slatt B, Loeffler JD, Hoyt WF: Ocular motor disturbances in Parkinson’s disease electromyographic observations. Can J Ophthalmol 1966;1:267–273.
106 Jungehulsing GJ, Ploner CJ: Eyelid tremor in a patient with a unilateral paramedian thalamic
lesion. J Neurol Neurosurg Psychiatry 2003;74:356–358.
107 Taylor JR, Elsworth JD, Lawrence MS, Sladek JR Jr, Roth RH, Redmond DE Jr: Spontaneous
blink rates correlate with dopamine levels in the caudate nucleus of MPTP-treated monkeys. Exp
Neurol 1999;158:214–220.
108 Biousse V, Skibell BC, Watts RL, Loupe DN, Drews-Botsch C, Newman NJ: Ophthalmologic features of Parkinson’s disease. Neurology 2004;62:177–180.
109 Kimber TE, Thompson PD: Increased blink rate in advanced Parkinson’s disease: a form of ‘off’period dystonia? Mov Disord 2000;15:982–985.
110 Karson CN, LeWitt PA, Calne DB, Wyatt RJ: Blink rates in parkinsonism. Ann Neurol 1982;12:
580–583.
111 Hallet M: Clinical physiology of dopa dyskinesia. Ann Neurol 2000;47:147–150.
112 Pfaffenbach DD, Layton DD Jr, Kearns TP: Ocular manifestations in progressive supranuclear
palsy. Am J Ophthalmol 1972;74:1179–1184.
113 Karson CN: Spontaneous eye-blink rates and dopaminergic systems. Brain 1983;106(pt 3):
643–653.
The Eyelid and Its Contribution to Eye Movements
129
114 Basso MA, Powers AS, Evinger C: An explanation for reflex blink hyperexcitability in Parkinson’s
disease. I. Superior colliculus. J Neurosci 1996;16:7308–7317.
115 Basso MA, Evinger C: An explanation for reflex blink hyperexcitability in Parkinson’s disease. II.
Nucleus raphe magnus. J Neurosci 1996;16:7318–7330.
116 Basso MA, Strecker RE, Evinger C: Midbrain 6-hydroxydopamine lesions modulate blink reflex
excitability. Exp Brain Res 1993;94:88–96.
117 Powers AS, Schicatano EJ, Basso MA, Evinger C: To blink or not to blink: inhibition and facilitation of reflex blinks. Exp Brain Res 1997;113:283–290.
118 Liu GT, Carrazana EJ, Charness ME: Unilateral oculomotor palsy and bilateral ptosis from paramedian midbrain infarction. Arch Neurol 1991;48:983–986.
119 Growdon JH, Winkler GF, Wray SH: Midbrain ptosis. A case with clinicopathologic correlation.
Arch Neurol 1974;30:179–181.
120 Caplan LR: Ptosis. J Neurol Neurosurg Psychiatry 1974;37:1–7.
121 Zackon DH, Sharpe JA: Midbrain paresis of horizontal gaze. Ann Neurol 1984;16:495–504.
122 Dehaene I, Dom R, Marchau M, Geens K: Locked-in syndrome with bilateral ptosis: combination
of bilateral horizontal pontine gaze paralysis and nuclear oculomotor nerve paralysis. J Neurol
1985;232:366–367.
123 Conway VH, Rozdilsky B, Schneider RJ, Sundaram M: Isolated bilateral complete ptosis. Can J
Ophthalmol 1983;18:37–40.
124 Bogousslavsky J, Regli F, Ghika J, Hungerbuhler JP: Internuclear ophthalmoplegia, prenuclear
paresis of contralateral superior rectus, and bilateral ptosis. J Neurol 1983;230:197–203.
125 Martin TJ, Corbett JJ, Babikian PV, Crawford SC, Currier RD: Bilateral ptosis due to mesencephalic lesions with relative preservation of ocular motility. J Neuroophthalmol 1996;16:
258–263.
126 Barton JJ, Kardon RH, Slagel D, Thompson HS: Bilateral central ptosis in acquired immunodeficiency syndrome. Can J Neurol Sci 1995;22:52–55.
127 Thomke F, Hopf HC: Acquired monocular elevation paresis. An asymmetric upgaze palsy. Brain
1992;115(pt 6):1901–1910.
128 Lepore FE: Bilateral cerebral ptosis. Neurology 1987;37:1043–1046.
129 Sibony P, Evinger C. Anatomy and physiology of normal and abnormal eyelid position and movements; in Miller N, Newman N (eds): Walsh and Hoyt’s Clinical Neuro-Ophthalmology, ed 5.
Baltimore, Williams & Wilkins, 1998, pp 1537–1540.
130 Esteban-Garcia A: Blepharospasm and blepharocolysis. Different sides of the same coin. Rev
Neurol 2005;40:298–302.
131 Berardelli A, Rothwell JC, Day BL, Marsden CD: Pathophysiology of blepharospasm and oromandibular dystonia. Brain 1985;108(pt 3):593–608.
132 Lee MS, Marsden CD: Movement disorders following lesions of the thalamus or subthalamic
region. Mov Disord 1994;9:493–507.
133 Miranda M, Millar A: Blepharospasm associated with bilateral infarcts confined to the thalamus:
case report. Mov Disord 1998;13:616–617.
134 Klostermann W, Vieregge P, Kompf D: Apraxia of eyelid opening after bilateral stereotaxic subthalamotomy. J Neuroophthalmol 1997;17:122–123.
135 Jankovic J, Patel SC: Blepharospasm associated with brainstem lesions. Neurology 1983;33:
1237–1240.
136 Aramideh M, Ongerboer de Visser BW, Holstege G, Majoie CB, Speelman JD: Blepharospasm in
association with a lower pontine lesion. Neurology 1996;46:476–478.
137 Hallett M, Daroff RB: Blepharospasm: report of a workshop. Neurology 1996;46:1213–1218.
138 Cattaneo L, Chierici E, Pavesi G: Bell’s palsy-induced blepharospasm relieved by passive eyelid
closure and responsive to apomorphine. Clin Neurophysiol 2005.
139 Aramideh M, Ongerboer de Visser BW, Brans JW, Koelman JH, Speelman JD: Pretarsal application of botulinum toxin for treatment of blepharospasm. J Neurol Neurosurg Psychiatry
1995;59:309–311.
140 Albanese A, Bentivoglio AR, Colosimo C, Galardi G, Maderna L, Tonali P: Pretarsal injections of
botulinum toxin improve blepharospasm in previously unresponsive patients. J Neurol Neurosurg
Psychiatry 1996;60:693–694.
Helmchen/Rambold
130
141 Kowal L: Pretarsal injections of botulinum toxin improve blephospasm in previously unresponsive
patients. J Neurol Neurosurg Psychiatry 1997;63:556.
142 Elston JS: A new variant of blepharospasm. J Neurol Neurosurg Psychiatry 1992;55:369–371.
143 Lepore FE, Duvoisin RC: ‘Apraxia’ of eyelid opening: an involuntary levator inhibition.
Neurology 1985;35:423–427.
144 Verghese J, Milling C, Rosenbaum DM: Ptosis, blepharospasm, and apraxia of eyelid opening secondary to putaminal hemorrhage. Neurology 1999;53:652.
145 Lamberti P, De Mari M, Zenzola A, Aniello MS, Defazio G: Frequency of apraxia of eyelid opening in the general population and in patients with extrapyramidal disorders. Neurol Sci 2002;23
(suppl 2):S81–S82.
146 Bjoerk L: Compulsive eye opening and associated phenomena. 1955;73 597–601.
147 Averbuch-Heller L: Neurology of the eyelids. Curr Opin Ophthalmol 1997;8:27–34.
148 Pasik P, Pasik T, Bender MB: The pretectal syndrome in monkeys. I. Disturbances of gaze and
body posture. Brain 1969;92:521–534.
149 Nashold BS Jr, Gills JP, Wilson WP: Ocular signs of brain stimulation in the human. Confin
Neurol 1967;29:169–174.
150 Scudder CA, Moschovakis AK, Karabelas AB, Highstein SM: Anatomy and physiology of saccadic long-lead burst neurons recorded in the alert squirrel monkey. I. Descending projections
from the mesencephalon. J Neurophysiol 1996;76:332–352.
151 Galetta SL, Gray LG, Raps EC, Grossman RI, Schatz NJ: Unilateral ptosis and contralateral eyelid retraction from a thalamic-midbrain infarction. Magnetic resonance imaging correlation. J Clin
Neuroophthalmol 1993;13:221–224.
152 Galetta SL, Raps EC, Liu GT, Saito NG, Kline LB: Eyelid lag without eyelid retraction in pretectal disease. J Neuroophthalmol 1996;16:96–98.
153 Grandas F, Esteban A: Eyelid motor abnormalities in progressive supranuclear palsy. J Neural
Transm Suppl 1994;42:33–41.
154 Friedman DI, Jankovic J, McCrary JA 3rd: Neuro-ophthalmic findings in progressive supranuclear
palsy. J Clin Neuroophthalmol 1992;12:104–109.
155 Pasik P, Pasik T, Bender MB: The pretectal syndrome in monkeys. I. Disturbances of gaze and
body posture. Brain 1969;92:521–534.
156 Zee DS, Chu FC, Leigh RJ, et al: Blink-saccade synkinesis. Neurology 1983;33:1233–1236.
157 Hain TC, Zee DS, Mordes M: Blink-induced saccadic oscillations. Ann Neurol 1986;19:299–301.
158 Herishanu Y, Abarbanel JM, Frisher S: Blink induced ocular flutter. Neuro-ophthalmol 1987;7:
175–177.
159 Peli E, McCormack G: Blink vergence in an antimetropic patient. Am J Optom Physiol Opt
1986;63:981–984.
160 Cogan DG: A type of congenital ocular motor apraxia presenting jerky head movements. Am J
Ophthalmol 1953;36:433–441.
161 Schneider E, Glasauer S, Dieterich M, Kalla R, Brandt T: Diagnosis of vestibular imbalance in the
blink of an eye. Neurology 2004;63:1209–1216.
Prof. Dr. Christoph Helmchen
Department of Neurology, University Hospitals Schleswig-Holstein, Campus Lübeck
Ratzeburger Allee 160
DE–23538 Lübeck (Germany)
Tel. ⫹49 451 500 2927, Fax ⫹49 451 500 2489
E-Mail [email protected]
The Eyelid and Its Contribution to Eye Movements
131
Straube A, Büttner U (eds): Neuro-Ophthalmology.
Dev Ophthalmol. Basel, Karger, 2007, vol 40, pp 132–157
Mechanics of the Orbita
Joseph L. Demer
Jules Stein Eye Institute, Departments of Ophthalmology and Neurology,
Neuroscience Bioengineering Interdepartmental Programs, David Geffen Medical
School at the University of California, Los Angeles, Calif., USA
Abstract
The oculomotor periphery was formerly regarded as a simple mechanism executing
complex behaviors explicitly specified by innervation. It is now recognized that several fundamental aspects of ocular motility are properties of the extraocular muscles (EOMs) and
their associated connective tissue pulleys. The Active Pulley Hypothesis proposes that rectus
and inferior oblique EOMs have connective tissue soft pulleys that are actively controlled by
the action of the EOMs’ orbital layers. Functional imaging and histology have suggested that
the rectus pulley array constitutes an inner mechanism, similar to a gimbal, that is rotated torsionally around the orbital axis by an outer mechanism driven by the oblique EOMs. This
arrangement may mechanically account for several commutative aspects of ocular motor
control, including Listing’s law, yet permits implementation of noncommutative motility as
during the vestibulo-ocular reflex. Recent human behavioral studies, as well neurophysiology in monkeys, are consistent with mechanical rather than central neural implementation of
Listing’s law. Pathology of the pulley system is associated with predictable patterns of strabismus that are surgically treatable when the pathologic anatomy is characterized by imaging. This mechanical determination may imply limited possibilities for neural adaptation to
some ocular motor pathologies, but indicates greater potential for surgical treatments.
Copyright © 2007 S. Karger AG, Basel
Ophthalmologists routinely interpret the ocular motility examination to
assess the status of cranial nerves and central ocular motor processing. While
normal motility is easily interpreted, the interpretation of abnormal motility can
be quite complex, since it is founded on an understanding of the anatomy of the
extraocular muscles (EOMs), the orbital connective tissues, and general principles of motor innervation that ordinarily coordinate binocular movements. Our
understanding of even fundamental gross EOM anatomy has been clarified by
imaging methods developed in the late 20th century. These insights have in turn
motivated investigations that have altered fundamental understanding of ocular
motility.
Classical Anatomy
There are six striated oculorotary EOMs, configured as antagonist pairs
[1, 2]. The medial (MR) and lateral rectus (LR) EOMs rotate the eye horizontally, with the MR accomplishing adduction and the LR accomplishing abduction. The superior (SR) and inferior rectus (IR) EOMs form a vertical
antagonist pair, with the SR supraducting and the IR infraducting the globe.
However, the vertical rectus EOMs have additional actions not strictly antagonistic. The superior (SO) and inferior oblique (IO) EOMs form an antagonist
pair implementing torsion around the line of sight. The SO intorts, while the
IO extorts. The oblique EOMs have additional actions that are not strictly
antagonistic.
EOM Layers
The oculorotary EOMs, but not the lid-elevating levator palpebrae superioris muscle, are bilaminar [3]. The global layer (GL), containing in humans a
maximum of approximately 10,000–15,000 fibers in the mid-length of the
EOM, is located adjacent to the globe in rectus EOMs and in the central core of
the oblique EOMs [4, 5]. In rectus EOMs and the SO, the GL anteriorly
becomes continuous with the terminal tendon that inserts on the sclera [6].
Each rectus orbital layer (OL) contains 40–60% of all the EOM’s fibers. The
OL terminates well posterior to the sclera, and at least some of its fibers insert
on connective tissue pulleys [6, 7]. The OL is located on the orbital surface of
rectus EOMs, sometimes C shaped, and constitutes the concentric peripheral
layer of the oblique EOMs.
Gross Structure of EOMs
Rectus EOMs originate in the orbital apex from the fibrous annulus of
Zinn. The SO muscle originates from the periorbita of the superonasal orbital
wall. The rectus EOMs course anteriorly through loose lobules of fat and connective tissues that form sheathes as the EOMs penetrate posterior Tenon’s fascia. Despite common clinical terminology to the contrary, there exists no
Mechanics of the Orbita
133
‘muscle cone’ of connective tissue forming bridges among the adjacent rectus
EOM bellies in the mid to deep orbit. The SO muscle remains tethered to the
periorbita via connective tissues as it courses anteriorly, thins to become continuous with its long, thin tendon. The concentric OL of the SO terminates posterior on a peripherally located sheath [5]. Both the SO sheath and tendon pass
through the trochlea, a cartilaginous rigid pulley attached to the superonasal
orbital wall. After reflection in the trochlea, the SO tendon passes inferior to the
SR, thins, and flattens as it spreads out to its broad scleral insertion posterolaterally on the globe [5]. The IO muscle originates much more anteriorly from the
periorbita of the inferonasal orbital rim adjacent to the anterior lacrimal crest,
continuing laterally to enter its connective tissue pulley inferior to the IR where
the IO penetrates Tenon’s fascia [8].
Notwithstanding the implications of many textbooks, a recent fundamental
insight is that rectus EOMs do not follow straight-line paths from their origins
to their scleral insertions. In eccentric gaze, rectus EOM paths are inflected
sharply at discrete points in the anterior orbit. Even in the 19th century, it was
supposed that inflections in EOM paths might be due to orbital connective tissues acting as pulleys, although the archaic concept of early anatomists was
largely concerned with bowing of rectus EOM paths away from the orbital center rather than prevention of muscle sideslip relative to the orbital wall [9, 10].
The modern concept of pulleys was first conceived by Joel M. Miller [11], and
any eponym applied to rectus pulleys should be his. The ‘pulleys of Miller’
change the anterior paths of rectus EOMs, and thus their pulling directions, in
an orderly way during duction. This is shown in the axial magnetic resonance
images (MRI) in figure 1, illustrating that the anterior path of the IR muscle
changes by half the change in the angle of duction. MRI has shown the same
behavior for all the rectus EOMs. The anterior path angle of a rectus EOM
changes by half the amount of duction [12].
Structure of Pulleys
Rectus EOM inflection points constitute the functional pulleys of Miller.
Anterior to these, rectus EOM paths follow the scleral insertions in eccentric
gazes. The pulleys thus act mechanically as rectus EOM origins. The EOM segment between the scleral insertion and pulley defines the direction of force
applied to the globe. Pulleys consist of discrete rings of dense collagen encircling the EOM, transitioning gradually into less substantial but broader collagenous sleeves. Anteriorly, these sleeves thin to form slings convex to the orbital
wall, and more posteriorly the sleeves thin to form slings convex toward the
orbital center. The anterior pulley slings have also been called the ‘intermuscular
Demer
134
43º Abduction
30º Adduction
ON
MR
LR
73º Gaze shift
47º
11º
IR
36º Inferior rectus
path change
WJ
Fig. 1. Axial MRI images of a right orbit taken at the level of the lens, fovea, and optic
nerve (top row), and simultaneously in an inferior plane along the IR muscle path (bottom
row), in abduction (left) and adduction (right). Note the bisegmental IR path, with an inflection corresponding to the IR pulley. For this 73⬚ horizontal gaze shift, there was a corresponding 36⬚ shift in IR muscle path anterior to the inflection at its pulley. By permission
from Demer [19].
septum’, a time-honored but not functionally specific term that may be eventually supplanted by more specific terminology. Electron microscopy demonstrates the fibrils of collagen in the pulleys to have an interlaced configuration
suited to high internal rigidity [13]. There are bands of smooth muscle (SM) in
Mechanics of the Orbita
135
Pulley ring
Globa
Orbit l layer
al lay
er
yer
ital la yer
Orblo
la
l
a
G b
Pulley
sling
Smooth muscle
Collagen
Elastin
Trochlea
LPS
SO
SR
LR
Pulley
sling
IO
Pulley
ring
MR
IO
IR
Orbital layer
Fig. 2. Diagram of the orbita. Coronal views are depicted at levels indicated on axial
view. Functional pulleys are at level depicted at lower right. LG ⫽ Lacrimal gland; LPS ⫽
levator palpebrae superioris muscle; SOT ⫽ superior oblique tendon. By permission from
Demer [31].
the pulley suspensions [14, 15], and particularly in a distribution called the
inframedial peribulbar SM between the MR and IR pulleys [16]. The overall
structure of the orbital connective tissues in schematized in figure 2.
The IR pulley is coupled to the IO pulley in a bond forming part of
Lockwood’s ligament, the connective tissue ‘hammock’ across the inferior orbit
[8, 16]. The IR and IO pulleys are composed of a common collagenous sheath
stiffened by dense elastin. The OL of the IR inserts on its pulley and does not
continue anteriorly. The OL of the IO muscle inserts partly on the conjoined
IO-IR pulleys, partly on the IO sheath temporally and partly on the inferior
aspect of the LR pulley. Elastin and SM occur in the Lockwood’s ligament
region of posterior Tenon’s fascia supporting the IR-IO pulley. The inframedial
peribulbar SM originates on the nasal aspect of this conjoint pulley, and is
positioned upon contraction to displace the pulley nasally. The SM retractors of
Demer
136
the lower eyelid (‘Muller’s inferior tarsal muscle’) and connective tissues
extending to the inferior tarsal plate are also coupled to the conjoint IR-IO pulley, coordinating lower eyelid position with vertical eye position during vertical
gaze shift. The SM of the pulley system has autonomic innervation, including
three likely pathways: (1) sympathetic with a norepinephrine projection from
the superior cervical ganglion; (2) cholinergic parasympathetic, probably from
the ciliary ganglion, and (3) nitroxidergic, probably from the pterygopalatine
ganglion [15].
Although the rigid SO pulley – the trochlea – has been known since antiquity [17, 18], its immobility is exceptional, and also unique that the SO’s OL
inserts via the SO sheath on the SR pulley’s medial aspect [5]. Net SO pulling
direction probably changes half as much as duction despite an immobile
pulley, because of the uniquely thin, broad SO tendon wrapping over the globe
[19].
Most of these anatomical relationships are evident in gross dissections and
surgical exposures. After surgical transposition of a rectus tendon (for the treatment of, e.g., strabismus due to LR palsy), the path of the transposed EOM
continues to be obliquely toward the original pulley location. The effect of rectus EOM transposition can be improved by suture fixation from a posterior
point on the transposed EOM belly to the sclera adjacent to the palsied EOM
[20], a maneuver shown by MRI to displace the pulley further in the transposed
direction [21].
Functional Anatomy of Pulleys
The insertion of each rectus EOM’s OL on its pulley appears to be the main
driving force translating (linearly moving) that pulley posteriorly during EOM
contraction. There is consensus that, in both humans and monkeys, fibers on the
orbital surface of each rectus EOM insert into the dense encircling tissue [4, 6]
in a distributed manner over an anteroposterior region in which successive bundles of fibers extend up to 1 mm into the surrounding connective tissue1 [7].
1
While they may properly be said to have dual insertions, the OL and GL insertions are
not widely displaced. The OLs and GLs of EOMs do not bifurcate widely before inserting as
might have been misunderstood from the diagrammatic implications of some authors who
intended to emphasize the differing neural control and possible proprioception of the two
layers [22]. The concept of dual insertions does not necessarily imply that every fiber in each
layer terminates in that layer’s insertion, since fibers may terminate on one another short of
the insertion in myomyous junctions [23].
Mechanics of the Orbita
137
Imaging by MRI suggests that these enveloping tissues move in coordination
with the insertion and underlying sclera, although histological examinations
show the absence of direct connections between these tissues. The connective
tissue sleeves themselves have a substantial anteroposterior extent along which
connective tissue thickness varies [14], and it has not been possible to histologically identify the precise sites causing EOM path inflections. Consequently,
actual pulley locations have been determined from functional imaging by MRI
in vivo, rather than by histological examination of dead tissues not subjected to
physiological striated and smooth EOM forces.
Since the EOMs must pass through their pulleys, and since pulleys encircle
the EOMs, pulley locations may be inferred from EOM paths even if pulley
connective tissues cannot be imaged directly. Quantitative determinations of
pulley locations and shifts during ocular rotation have been obtained from coronal MRIs in secondary and tertiary gazes associated with EOM path inflection
at the pulleys. Imaging in tertiary (combined horizontal and vertical) gaze positions is particularly informative, since such images show changes in the anteroposterior position of the EOM path inflections [12]. These data have confirmed
that all four rectus pulleys move anteroposteriorly in coordination with their
scleral insertions, by the same anteroposterior amounts. Being partially coupled
to the mobile IR pulley, the IO pulley shifts anteriorly in supraduction, and posteriorly in infraduction. Quantitative MRI shows that the IO pulley moves
anteroposteriorly by half as much as the IR insertion [8]. To date, the MRI studies in living subjects have been consistent with histological examinations of the
same regions in cadavers that were also examined by MRI prior to embedding
and sectioning [16].
Although MRI indicates that rectus pulleys are mobile along the axes of
their respective EOMs, pulleys are located stably and stereotypically in the
planes transverse to the EOM axes. The 95% confidence intervals for the horizontal and vertical coordinates of normal rectus pulleys range over less
than ⫾ 0.6 mm [22]. Precise placement of rectus pulleys is important since the
pulleys act as the EOM’s functional mechanical origins. Pulley stability in the
coronal plane implies a high degree of stiffness of the suspensory tissues of
the pulleys. The Active Pulley Hypothesis (APH) supposes that the anteroposterior mobility of the pulleys is accomplished by application of substantial force
by the OL of each EOM (fig. 2). Aging causes cause inferior sagging of horizontal rectus pulley positions, which shift downward by 1–2 mm from young
adulthood to the seventh decade [23]. Vertical rectus pulley positions change
little with aging [23].
The globe itself makes small translations – linear shifts – during ocular
duction, as determined by high-resolution MRI in normal humans [23]. For
example, the globe translates 0.8 mm inferiorly from 22⬚ downward gaze to 22⬚
Demer
138
upward gaze, and it also translates slightly nasally in both abduction and adduction. While small, these translations affect EOM force directions since the
globe center is only 8 mm anterior to the plane of the rectus pulleys.
Pulleys prevent EOM sideslip during globe rotations, but physiologic
transverse shifts of rectus pulleys can also occur. Gaze-related changes in rectus
pulley positions have been determined by tracing EOM paths with coronal MRI
using a coordinate system relative to the center of the orbit [24]. The MR pulley
translates 0.6 mm superiorly from 22⬚ infraduction to 22⬚ supraduction. The LR
pulley translates 1.5 mm inferiorly from infraduction to supraduction. The IR
pulley shifts 1.1 mm medially in supraduction, but moves 1.3 mm temporally in
infraduction. The SR pulley is relatively stable in the mediolateral direction, but
moves inferiorly in supraduction, and superiorly in infraduction. Gaze-related
shifts in rectus pulley positions are uniform among normal people.
Kinematics of Pulleys
Joel M. Miller first suggested that orbitally fixed pulleys would make the
eye’s rotational axis dependent on eye position [11]. Miller’s crucial insight has
proved fundamental to ocular kinematics, the rotational properties of the eye.
Sequential rotations are not mathematically commutative, so that final eye orientation depends on the order of rotations [25]. Each combination of horizontal
and vertical orientations could be associated with infinitely many torsional
positions [26], but the eye is constrained (when the head is upright and immobile) by Listing’s law (LL): ocular torsion in any gaze direction is that which the
eye would have it if it had reached that gaze direction by a single rotation from
primary eye position about an axis lying in Listing’s plane (LP) [27]. LL is satisfied if the ocular rotational velocity axis shifts by half of the shift in ocular
duction [28]. For example, if the eye supraducts 20⬚, then the vertical velocity
axis about which it rotates for subsequent horizontal movement should tip back
by 10⬚. This is called the ‘half-angle rule’, or the velocity domain formulation
of LL. Conformity to the half angle rule makes the sequence of ocular rotations
appear commutative to the brain [29]. Commutativity is the critical feature of
the pulley system.
The APH explains how rectus pulley position can implement the half angle
kinematics required by LL [2, 6, 12, 19]. The EOMs rotate the globe about axes
perpendicular to the tendon paths near the insertion. In figure 3a, b, it is seen
from simple small angle trigonometry that a horizontal rectus EOM’s pulling
direction tilts posteriorly by half the angle of supraduction if the pulley is
located as far posterior to globe center as the insertion is anterior to globe center. If all rectus EOMs and their pulleys are arranged similarly, this configuration
Mechanics of the Orbita
139
Rotational
axis
Rotational
axis
Straight
ahead
LR
Insert.
LR
Pulley
a
D1 ⫽ D2
b
Primary position
Nasal
r
laye
ital
Orb
r
laye
bal
Glo
Glo
bal
Orb
ital
sion
en
Susp
laye
Temporal
Nasal
O
Suspension
d
ital
er
laye
Temporal
Primary position
e
c
nsion
Suspe
Primary
position
10 D1 D2
Suspension
Gaze
n
nsion
Suspe
r
laye
ital
r
Orb bal laye
lo
g
R
S
D1
D2
f
␣
␣/2
Supraduction
10
IR glo
bal la
Orbityer
al lay
er
Inferior
10 axis
␣/2
LR global layer
r
Suspension
Adduction
10 axis
LR axis
er
al lay
r
IR g
Orb lobal laye
r
ital
laye
r
ensio
Glob
Orb
␣
l lay
ba
Glo
r
r
laye yer
ital
la
Orb lobal
g
R
S
LR global layer
2
Susp
yer
rbi
laye
␣/2
D1 D
Supraduction
la
tal
D1 D2
Superior
␣/2
D3/2
D2
D1
D3
Fig. 3. Diagram of EOM and pulley behavior for half angle kinematics conforming to
LL. a Lateral view. Rotational velocity axis of the EOM is perpendicular to the segment from
pulley to scleral insertion. The velocity axis for the LR is vertical in primary position.
b Lateral view. In supraduction to angle alpha, the LR velocity axis tilts posteriorly by angle
alpha/2 if distance D1 from pulley to globe center is equal to distance D2 from globe center to
insertion. c Lateral view. In primary position, terminal segment of the IO muscle lies in the
plane containing the LR and IR pulleys into which the IO’s orbital layer inserts. The IO
velocity axis parallels primary gaze. d Superior view of rectus EOMs and pulleys in primary
position, corresponding to a. e Superior view. In order for adduction to maintain D1 ⫽ D2 in
an oculocentric reference, the MR pulley must shift posteriorly in the orbit, and the LR pulley anteriorly. This is proposed to be implemented by the orbital layers of these EOMs, working against elastic pulley suspensions. f Lateral view similar to c. In supraduction to angle
alpha, the IR pulley shifts anteriorly by distance D3, as required by the relationship shown in
e. The IO pulley shifts anteriorly by D3/2, shifting the IO velocity axis superiorly by alpha/2.
By permission from Demer [19].
mechanically enforces LL since all the rectus forces rotating the globe observe
half angle kinematics.
If only primary and secondary gaze positions were required, rectus pulleys
could be rigidly fixed to the orbit. However, it has been proven mathematically
that perfect agonist-antagonist EOM alignment is possible only if pulley locations move in the orbit [30]. Tertiary gazes such as adducted supraduction
require the rectus pulleys actively to shift anteroposteriorly in the orbit along
Demer
140
the EOM’s length, maintaining a fixed oculocentric relationship (fig. 3d, e). The
APH proposes that pulley shifts are generated by the contraction of the OLs acting against the elasticity of the pulley suspensions [1, 6, 12, 31]. This behavior
could not be due to attachment of rectus pulleys to the sclera. Not only does serial section histology show no such attachment, but also the sclera moves freely
relative to pulleys transverse to the EOM axes. Anteroposterior rectus pulley
movements persist even after enucleation [32], when the MR path inflection at
its pulley continues to shift anteroposteriorly with horizontal versions, but the
angle of inflection sharpens to as much as 90⬚ at the pulley [32].
Despite coordinated movements, however, it is supposed that ocular rotation by the OL and pulley translation by the GL require different EOM actions
and neural commands. The mechanical load on the GL is predominantly the
viscosity of the relaxing antagonist EOM, proportional to rotational speed [33].
The load on the OL, however, is due to the pulley suspension elasticity, which is
independent of rotational speed, but proportional to the angle of eccentric gaze.
Laminar electromyography in humans shows high, phasic activity in the GL
during saccades, with only a small maintained change in activity in eccentric
gaze [33]. In the OL, electromyography shows sustained, high activity in eccentric gaze, but no phasic activity during saccades. In cat, the most powerful and
fatigue-resistant LR motor units, comprising 27% of all units, innervate both
the OL and GL [34]. These ‘bilayer’ motor units would command similar tonic
contraction in the two layers, an arrangement convenient to maintain pulley
position relative to the EOM insertion. Other motor units project selectively to
either the OL or GL [34], as might be appropriate for control of differing viscous loads.
While the rectus EOMs by themselves seem capable of implementing LL
[35], some important eye movements do not conform to LL. Violations of LL
occur during the vestibulo-ocular reflex (VOR) [36, 37] and during convergence [38, 39]. These violations may be due to the action of the oblique EOMs.
The IO muscle’s functional anatomy also appears suited to half angle kinematics. The IO pulley shifts anteroposteriorly by half of vertical ocular duction [8],
shifting the IO’s rotational axis by half of vertical duction (fig. 3d, f) [8]. The
broad, thin SO insertion on the sclera resists sideslip by virtue of its shape. The
SO approximates half angle kinematics because the distance from trochlea to
globe center is approximately equal to the distance from globe center to insertion, the SO rotational axis shifts by half the horizontal duction [19].
Optimal stereopsis requires torsional cyclovergence to align corresponding
retinal meridia [40]. In central gaze, excyclotorsion occurs in convergence that
violates LL [41]. During asymmetrical convergence to a target aligned to one
eye, this extorsion occurs in both eyes, interpretable as temporal tilting of LP
for each eye [38]. A form of Herring’s law of equal innervation probably exists
Mechanics of the Orbita
141
for the vergence system, such that both eyes receive symmetric version commands for remote targets, and mirror symmetric vergence commands for near
targets [42].
MRI during convergence to a target aligned to one eye has been performed
using mirrors and has allowed the effect of convergence to be distinguished
from that of adduction [43]. In the aligned orbit, there was a 0.3–0.4 mm
extorsional shift of most rectus pulleys corresponding to about 1.9⬚ [43], similar to globe extorsion [44]. It appears that during convergence, the rectus pulley
array rotates about the long axis of the orbit in coordination with ocular torsion,
changing the torsional pulling directions of all rectus EOMs but maintaining
half angle dependence on horizontal and vertical duction. This would cause a
parallel, torsional offset in LP.
While it is possible that globe torsion might passively rotate the rectus pulley array, the high stiffness of the rectus pulley suspensions necessary to stabilize them against sideslip would severely limit such passive torsional shifts,
always to less than ocular torsion [43]. An active mechanism has been suggested for the torsional pulley shifts in convergence that equal ocular torsion.
The OL of the IO muscle inserts on the IR pulley and, at least in younger specimens, also on the LR pulley [8]. Contraction of the IO OL would directly
extorsionally shift the LR and IR pulleys. Contractile IO thickening has been
directly demonstrated by MRI during convergence [43]. Inferior LR pulley shift
could be coupled to lateral SR pulley shift via the dense connective tissue band
between them [45]. The OL of the SO muscle inserts on the SO sheath posterior
to the trochlea, with both tendon and sheath reflected at that rigid pulley [5].
Anterior to the trochlea, the SO sheath inserts on the SR pulley’s nasal border.
Relaxation of the SO OL during convergence is consistent with single unit
recordings in the monkey trochlear nucleus [46], and could contribute to extorsion of the pulley array. The inframedial peribulbar SM might also contribute to
rectus pulley extorsion in convergence [16].
Controversy Concerning Pulleys
Because of their distributed nature, some doubt the existence of EOM pulleys of Miller, with the alternative suppositions being that the penetrations of
the rectus EOMs through Tenon’s fascia are unimportant, or that the connective
tissues serve only to limit the range of ductions [47]. Histological evidence has
previously been presented suggesting the presence of EOM pulleys in rodents
[48]. Ruskell et al. [7] have proposed that OL insertion into connective tissue
sleeves may be a general feature of all mammals. They studied isolated human
and monkey rectus EOMs near their pulleys, reporting tendons leaving the
Demer
142
orbital surface of the EOMs to insert in sleeves or other surrounding connective
tissues. Ruskell et al. [7] considered their results to confirm and extend the
observation that the OL fibers separate from the GL fibers and insert in the
sheath, and that OL fibers are unlikely to contribute much to duction.
Histological study in rat, including 3-D reconstruction, suggested insertion of
the OL of the IR on a pulley [49], consistent with the APH.
Dimitrova et al. [50] electrically stimulated eye movements from central to
secondary gazes in anesthetized cats and monkeys before and after removal of
the LR pulley. Although this surgery predictably increased the amplitude and
velocity of horizontal eye movements, there was no significant effect on vertical eye movements [50]. Dimitrova et al. [50] interpreted the increase in eye
movement size to transmission of OL force to the tendon, although they also
noted that reduction in elastic load associated with pulley removal would also
increase eye movement. Their experiment was not a test of the APH’s implications for LL, which would have required investigation of tertiary gazes.
Listing’s Law (LL) Is Mechanical
Long regarded as an organizing principle of ocular motility, LL reduces
ocular rotational freedom from three (horizontal, vertical, and torsional) to only
two degrees (horizontal and vertical) during visually guided eye movements
with the head upright and stationary [28]. The classic formulation of LL states
that, with the head upright and immobile, any eye position can be reached from
primary position by rotation about one axis lying in LP. Conformity with LL
can be demonstrated by expressing ocular rotational axes as ‘quaternions’ that
can be directly plotted to form LP [25].
Unlike 1-D velocity that is the time derivative of position, 3-D eye velocity
is a mathematical function both of eye position and its derivative. The time
derivative of each component of 3-D eye position is called coordinate velocity,
but this differs from 3-D velocity in a way critical to neural control of saccades
[29, 51–53]. Tweed et al. [54] have pointed out that the ocular position axis will
be constrained to a plane if, in the velocity domain, the ocular velocity axis
changes by half the amount of duction. This can be expressed as a tilt angle
ratio of one half. Since in most situations the eye begins in LP, a tilt angle ratio
of one half constrains the eye to remain in LP, and so satisfies LL. However, if
eye position were somehow to begin outside LP at the onset of an eye movement that subsequently conforms to the velocity domain formulation of LL, eye
position would remain in a plane parallel to but displaced from LP.
Violation of LL during the VOR occurs since the VOR compensates for
head rotation about any arbitrary axis [37, 55, 56]. The VOR does not violate
Mechanics of the Orbita
143
LL ideally, but has a non-half angle dependency of rotational velocity axis on
eye position. The ideal tilt angle ratio for the VOR would be zero. However,
ocular torsion during the VOR does depend on eye position in the orbit; the
VOR axis shifts by about one quarter of duction relative to the head, and thus a
tilt angle ratio near 0.25 [37, 55, 56]. During well-controlled, whole-body transient yaw rotation at high acceleration, the VOR exhibits quarter angle behavior beginning at a time indistinguishable for the earliest VOR response [57,
58]. Such kinematics would be consistent with neural drive to a mechanical
implementation of quarter angle VOR kinematics as part of the minimum
latency reflex, and a different mechanical specification of saccadic half angle
behavior.
Neural and mechanical roles in determination of ocular kinematics have
been controversial. Before modern descriptions of the orbita, it seemed obvious
that LL was implemented neurally in premotor circuits as an intrinsic feature of
central ocular motor control [59–63]. The APH then proposed to account for LL
mechanically, but physiologic violations of LL continued to suggest a role for
central neural control [64]. A neural role in LL appeared tenable given the
observation of ocular extorsion and temporal tilting of LP during convergence
[39, 65] associated with torsional repositioning of the rectus EOM pulley array
[43] and alteration in discharge of trochlear motoneurons [46].
Crane et al. [66] studied the transition between the angular VOR’s quarter
angle strategy and saccades’ half-angle behavior. These investigators used the
yaw angular VOR to drive ocular torsion out of LP, and then used a visual target
to evoke a vertical saccade. This is an unusual situation in which the velocity
and position domain formulations of LL are no longer equivalent. To return the
saccade’s position domain rotational axis to LP would require that the saccade’s
velocity axis violate the half angle rule in the process of canceling the initial
non-LP torsion. If instead the saccade’s velocity axis conformed to the half
angle rule, the saccade would begin and end with the non-LP torsion induced by
the VOR. Crane et al. [66] showed that saccades observed half angle kinematics
in the velocity domain, and maintained any non-LL initial torsion. This result
suggests that the half angle velocity relationship is the fundamental principle
underlying LL, as would be expected from coordinated APH behavior of the
rectus pulleys. However, torsion returning the eye to LP has been observed during both horizontal and vertical saccades after torsional optokinetic nystagmus
had driven the eye out of LP [67], a difference perhaps related to the entrainment of quick phases during nystagmus, and seemingly impossible to implement with a purely mechanical system [67]. Reconciliation of these findings
would require differences in neural control of visual saccades vs. vestibular
quick phases, a possibility [66] given the known ability of the vestibular system
to drive saccades [68].
Demer
144
Upright
Contralateral
to head tilt
Rotational
axis
Lateral
view
Rotational
axis
MR
Insert.
MR
Pulley
Pulley
Insert.
Extorsion
SR
SR
Frontal
view
LR
LR
MR
MR
Extorsion
IR
IR
Fig. 4. Diagram of effects of head tilt on rectus pulleys in lateral (top row) and frontal
(bottom row) views. With head upright, the IR, LR, MR, and SR pulleys are arrayed in
frontal view in a cruciate pattern. The MR passes through its pulley, represented as a ring, to
its scleral insertion. The rotational velocity axis imparted by the MR is perpendicular to the
segment from pulley to insertion. The pulley array extorts during contralateral head tilt.
Since during head tilt the MR pulley shifts superiorly by the half the distance the insertion
shifts, the MR’s velocity axis changes by one fourth the ocular torsion. By permission from
Demer and Clark [69].
The functional anatomy of human EOMs has been examined by MRI during ocular counterrolling (OCR), a static torsional VOR mediated by the
otoliths [69]. The coronal plane positions of the rectus EOMs shifted torsionally
in the same direction as OCR. While OCR was not measured, the torsion of the
rectus pulley array was roughly half of OCR reported by other eye movement
studies. The torsional shift of the rectus pulley array half of OCR would change
rectus EOM pulling directions by one quarter of OCR (fig. 4), ideal for quarter
angle VOR kinematics. During OCR, oblique EOMs exhibited changes in cross
section consistent with their possible roles in torsional positioning of rectus
pulleys [69]. This finding, considered in the context of saccade kinematics during the VOR [66], suggests that the array of the four rectus pulleys constitute a
kind of ‘inner gimbal’ that conforms to Listing’s half angle kinematics for visually guided movements such as fixations and saccades, but which is rotated by
the oblique EOMs to implement eye movements such as the slow and quick
phases of the VOR.
Mechanics of the Orbita
145
Older recordings of trochlear motoneuron discharge suggest that ocular
extorsion during convergence is neurally commanded [46]. If the ocular torsion
specified by LL were similarly neurally commanded, torsional commands
should be reflected in discharge patterns of neurons innervating the oblique and
vertical rectus EOMs. Ghasia and Angelaki [70] recorded activities of
motoneurons and nerve fibers innervating the vertical rectus and oblique EOMs
in monkeys during smooth pursuit conforming to LL. There were no neural
commands for LL torsion in motor units innervating the cyclovertical EOMs
[51]. This evidence for a mechanical basis of LL was also supported by the
experiment of Klier et al. [71] in which electrical stimulation was delivered to
the abducens nerve (CN6) of alert monkeys to evoke saccade-like movements.
Klier et al. [71] demonstrated that the evoked saccades had half angle kinematics conforming to LL. The decisive conclusion from these two experiments is
that LL has a mechanical basis, and is not specified by the instantaneous neural
commands. These two results were predicted by the APH [6], while the neural
theory of LL predicted opposite results in both cases [62]. However, the neurons driving the cyclovertical EOMs not only did not command half angle LL
torsion, but also did not command quarter angle kinematics for the VOR [70].
This suggests that quarter angle VOR kinematics are also mechanical, rather
than neural. An early suggestion had been made than quarter angle behavior
could be implemented mechanically by retraction of rectus pulleys [6], but subsequent recognition that this idea would be unrealistic [61] led to abandonment
of the concept of pulley retraction [2, 43]. Furthermore, uncoordinated anteroposterior shift in pulley location would be inconsistent with the recent experiments of Crane et al. [66] demonstrating transition between quarter angle VOR,
and half angle saccade behavior without measurable latency. The foregoing
results seemingly require that quarter angle VOR behavior arise from mechanical phenomena not previously considered.
Implications for Neural Control
Some tentative conclusions can now be reached concerning neural control
of eye movements generally, and some older data probably should be reinterpreted. Central neural signals correlated with all types of eye movements
would be expected to reflect effects of torsional reconfiguration of rectus pulleys during the VOR. Recordings from burst neurons in monkeys appear compatible with the torsional shift of rectus pulleys transverse to the EOM axes in
the direction of OCR induced by head tilt [72]. In monkeys, the displacement
plane for 3-D eye positions during pursuit and saccades shifts opposite to
changes in head orientation relative to gravity [73], and such shifts may be
Demer
146
dynamic during semicircular canal stimulation [74, 75]. Hess and Angelaki
have suggested that shift in LP is mediated by the otolith input to the 3-D
neural integrator [73], but the finding may be reconciled with the observation
that lesion of the integrator in the rostral interstitial nucleus of the medial longitudinal fasciculus also abolishes the torsional shift in LP associated with
OCR [76] if the torsional shift of pulleys is mediated by the 3-D neural integrator. If so, it would be predicted that integrator lesion would abolish counterroll of the pulleys during vestibular stimulation, by blocking polysynaptic
vestibular input to the oblique EOMs whose tonic activity presumably maintains torsional pulley array orientation.
In monkeys, the preferred directions of saccadic neurons in the superior
colliculus shift in the opposite direction, and by slightly more than half the
amount, of head tilt [77]. Based on simultaneous measurements of OCR and
preferred directions of superior collicular neurons, Frens et al. [77] concluded
that the changes in EOM pulling directions are probably about two thirds of
ocular torsion.
Regardless of the ocular motor subsystem involved, torsional rectus pulley
shifts during the VOR would preserve the advantage of apparent commutativity
of the peripheral ocular motor apparatus for concurrent saccades and pursuit.
This commutativity would be valuable even though higher-level sensorimotor
transformations must account for 3-D geometrical effects of eye and head orientation [64, 77–79], and is incorporated in some modern models of ocular
motor control [29, 52, 76, 78, 80]. Neural processing for the VOR must be generated in 3-D, based on transduction of head motion in three degrees of freedom, and on 3-D eye orientation in the head.
Some low level visuomotor processing may be simpler than previously
believed. In saccade programming, retinal error could be mapped onto corresponding zero-torsion motor error commands within LP as modeled by the ‘displacement-feedback’ model of Crawford and Guitton [81]. This model, with a
downstream mechanism for half angle behavior, can simulate the visuomotor
transformations necessary for accurate and kinematically correct saccades
within a reasonable oculomotor range, but had been rejected by Crawford and
Guitton who supposed that saccades from non-LL torsional starting positions
return to LP [81]. Recent demonstration by Crane et al. [66] that such saccades
maintain their initial non-LL torsion while nevertheless conforming to half
angle kinematics suggests that the ‘displacement-feedback’ model, lacking in a
neural representation of LL, is plausible for control of visual saccades. In the
context of realistic mechanical properties of EOM pulleys, sensorimotor integration of saccades does not require explicit neural computation of ocular torsion. This simplification solves some complexity, but merely moves other
kinematic problems to a higher level. When head movements are involved,
Mechanics of the Orbita
147
neural consideration of torsion is geometrically unavoidable for accurate localization of visual targets [78, 81].
Several aspects of ocular kinematics are thus implemented by an intricate
mechanical arrangement, rather than by complex neural commands to a simpler
mechanical arrangement. This insight alters the interpretation of common
situations, and offers hope of mechanical (i.e., surgical) solutions to clinical
disorders that might earlier have been believed to have neural origins. If the
APH were correct, oblique EOM function would not be critical for LL [35],
although oblique tone might set initial LP orientation. This is supported by the
finding in chronic SO paralysis that LL is observed, albeit with temporal tilting
of LP [82, 83], and that this temporally tilted LP is not changed by vergence as
is normally the case [84]. The orientation of LP varies considerably both among
individuals, and between eyes of the same individuals, making it unlikely that
absolute LP orientation is very important to either vision of ocular motor
control [58]. Although oblique EOMs do not actively participate in generation
of LL, elastic tensions arising from stretching and relaxation or oblique EOMs
would create torques violating LL unless their innervations were adjusted to
compensate [51]. Consequently, recordings of small changes in oblique EOM
innervations during pursuit movements conforming to LL [70, 85] do not
negate a pulley contribution, nor do dynamic violations of LL during saccades
in SO palsy [82].
Implications for Strabismus
Thinking about cyclovertical strabismus has been dominated by the historical concept of EOM weakness, typified by the terms ‘paresis’ and ‘paralysis’
[86]. This is likely because cranial nerves innervating EOMs are susceptible to
damage by trauma and compression, and because when the concept of EOM
weakness became dominant, neuroscience was too primitive to offer alternative
explanations [86]. Deeply engrained clinical concepts require modification.
Prototypic for cyclovertical strabismus is SO palsy. Theoretical, experimental, and much clinical evidence supports the idea that acute, unilateral SO
palsy produces a small ipsilateral hypertropia that increases with contralateral
gaze, and with head tilt to the ipsilateral shoulder [87, 88]. The basis of this ‘3step test’ is traditionally believed related to OCR, so that the eye ipsilateral to
head tilt is normally intorted by the SO and SR EOMs whose vertical actions
cancel [89]. However, ipsilateral to a palsied SO, unopposed SR elevating
action is supposed to create hypertropia. The 3-step test has been the cornerstone of diagnosis and classification of cyclovertical strabismus for generations
of clinicians [90, 91]. When the 3-step test is positive, strabismologists infer SO
Demer
148
weakness and attribute the large amount of interindividual alignment variability
to secondary changes [83] such as ‘IO overaction’ and ‘SR contracture’. The 3step test’s mechanism is generally misunderstood. Kushner [92] has pointed out
that were traditional teaching true, then IO weakening, the most common
surgery for SO palsy, should increase the head tilt-dependent change in hypertropia; the opposite is observed. Among numerous inconsistencies with common clinical observations [92], bilateral SO palsy should cause greater head
tilt-dependent change in hypertropia than unilateral SO palsy; however, the
opposite is found [93]. Modeling and simulation of putative effects of head tilt
in SO palsy suggest that SO weakness alone cannot account for typical 3-step
test findings [94, 95].
High-resolution MRI has quantified normal changes in SO cross-section
with vertical gaze, and SO atrophy and loss of gaze-related contractility typical
of SO palsy [96–99]. Neurosurgical SO denervation rapidly produces neurogenic atrophy and ablates contractile thickening normally observed in infraduction. A striking and consistent MRI finding has been the nonspecificity of the
3-step test for structural abnormalities of the SO belly, tendon, and trochlea,
found in only in ⬃50% of patients [100]. Even in patients selected because
MRI demonstrated profound SO atrophy, there was no correlation between clinical motility and IO size or contractility [99]. A possible explanation for some
of this discrepancy might be putative SO tendon laxity, assessed intraoperatively by a qualitative and perhaps unreliable judgment made during application
of traction with forceps [101–103]. Multiple conditions can simulate the ‘SO
palsy’ pattern of incomitant hypertropia [104]. Vestibular lesions cause head-tilt
dependent hypertropia, also known as skew deviation [105] that can mimic SO
palsy by the 3-step test [106]. Pulley heterotopy can simulate SO palsy [107],
and is probably not its result, since SO atrophy is not associated with significant
alterations in pulley position in central gaze [108].
Craniosynostosis is a congenital disorder in which skull shape is distorted
by premature fusion of the sutures among cranial bones. While various
eponyms have been attached based on variable expressivity (e.g. Crouzon,
Pfeiffer), these are largely due to known gene mutations affecting bone formation [109]. Strabismus is prevalent in craniosynostosis, particularly large V and
A patterns [110, 111], yet responds poorly to oblique EOM surgery [112].
Rectus EOM paths may be markedly abnormal in craniosynostosis [107, 113],
imparting abnormal pulling directions. It has been proposed that because the
EOM pulley array is anchored to the bony orbit at discrete points [45], bony
abnormality alters EOM pulling directions by malpositioning pulleys.
Typically, the heterotopic array of rectus pulleys is extorted or intorted, not necessarily symmetrically. Computer simulations suggest rectus pulley malpositioning as in craniosynostosis can produce incomitant strabismus [114, 115].
Mechanics of the Orbita
149
Extorsion of the pulley array is associated with V patterns, and intorsion associated with A patterns [116].
Surgical Treatment of Pulley Pathology
Surgery for pulley disorders has recently emerged for treatment of three
types of pathologies [19].
Pulley Heterotopy
Milder pulley heterotopy not apparently associated with craniosynostosis
may involve the stable malpositioning of one or several rectus pulleys [114,
115]. Initial efforts to treat heterotopy involved transpositions of the scleral
insertions of EOMs whose pulleys were heterotopic [19], later augmented by
fixations of EOM bellies to the underlying sclera ⬃8 mm posteriorly [113].
While MRI has demonstrated that this does shift the involved rectus pulley in
the desired direction [21, 117], because the pulley does not shift as far as the
insertion, the operation introduces undesirable ocular torsion opposite the
direction of transposition. Since normal pulleys are not fixed to sclera, posterior
fixation also compromises normal pulley kinematics and introduces abnormal
globe translation during duction [117]. Newer approaches to pulley heterotopy
involve surgery on connective tissues suspending the pulleys. A technically
convenient approach to treatment of inferior displacement of the LR pulley is to
shorten and stiffen the ligament coupling the LR and SR pulleys. Extreme pulley heterotopy is associated with esotropia and hypotropia in axial high myopia
[118, 119]. In this condition, historically misnamed the ‘heavy eye syndrome,’
the LR pulley shifts inferiorly to approach the IR, and the globe correspondingly shifts superotemporally out of the rectus pulley array. It has been recently
reported that surgical anastomosis of the lateral margin of the IR belly with the
superior margin of the LR belly is highly effective in correcting esotropia associated with the ‘heavy eye syndrome,’ since the procedure normalizes EOM
paths relative to the globe in a manner impossible for more conventional strabismus surgery [120].
Pulley Instability
Normal pulleys shift only slightly in the coronal plane even during large
ductions [24]. Large gaze-related shifts or one or more pulleys are associated
with incomitant strabismus [19, 121]. Pulley instability has also been termed
‘gaze-related pulley shift’ [122]. Inferior LR pulley shift in adduction produces
restrictive hypotropia closely resembling Brown syndrome caused by hindrance
of SO travel in the trochlea [123], or ‘X’ pattern exotropia characterized by
Demer
150
greater deviation in both up and down than in central gaze [121]. Early efforts
to treat pulley instability consisted of posterior fixation of the involved EOM to
the underlying sclera, and were intended to prevent posterior sideslip of the
EOM belly. More recent physiologically driven approaches involve pulley suspensions directly, tightening lax connective tissue bands that presumably permitted the pulley shift.
Pulley Hindrance
The third recognized pathology is pulley hindrance, in which normal posterior shift with EOM contraction is mechanically impeded [124], often inducing abnormal globe translation. Intentionally created hindrance can be
therapeutic, as long known for posterior fixation (also known as ‘retroequatorial myopexy’ and ‘fadenoperation’) of an EOM to the underlying sclera. An
operation intended to reduce an EOM’s effect in its field of action, posterior
fixation was originally supposed to work by reduction in the EOM’s arc of contact, reducing its rotational lever arm [125]. Imaging by MRI demonstrates this
mechanism incorrect, but several lines of evidence indicate that posterior fixation actually works by hindering posterior shift of the contracting EOM’s pulley,
mechanically restricting EOM action [126]. A technically simpler and safer
modification of posterior fixation has recently been introduced by us in which
the MR pulley suspension is placed under tension and the MR pulley sutured to
the EOM belly; this operation is at least as effective as posterior fixation with
scleral suturing in treatment of accommodative esotropia with excessive
accommodative convergence [127].
Central to the initial recognition of pulleys was the stability of rectus EOM
paths after large surgical transpositions of the scleral insertions. Only slight
shifts of pulleys are observed by MRI after transposition [21, 117]. Posterior
suture fixation of the transposed EOMs as described by Foster [20] shifts the
pulley farther into the direction of the transposed insertion. This changes the
pulling direction to mimic more closely that of the paralyzed EOM, increasing
the effectiveness of transposition [117].
Conclusion
The fundamental anatomy of the ocular motor effector apparatus fundamentally differs from traditional teaching. The following encapsulates this
author’s broad concept of the orbita, simplified here for heuristic purposes.
Rather than consisting of mechanically simple EOMs rotating the eye under
explicit neural control of every kinematic nuance, the ocular motor system consists of a rather intricate mechanical arrangement comprised of a trampoline-like
Mechanics of the Orbita
151
suspension supported by the rectus EOMs and their associated connective tissues, which in turn is circumferentially controlled by the obliques. Rectus
EOMs and their pulleys constitute the inner suspension that implements kinematics in 2-D corresponding largely to the 2-D organization of the retina and
subcortical visual system, and so mechanically implements LL without additional neural specification. The inner suspension has effectively commutative
properties. Analogous to a gimbal arrangement (but importantly different from
a gimbal in some respects), the outer suspension moves the inner under the
drive from the oblique EOMs to generate torsion not conforming to LL, and
noncommutatively influences the inner suspension. The degree to which neural
adaptations can compensate for ocular kinematics that normally are mechanically determined is a crucial question, since the answer will inform us about the
clinical significance of many disorders of ocular motility, and the degree to
which they may be amenable to surgical treatment.
Acknowledgement
This work was supported by US Public Health Service grants EY08313, EY00331, and
DC005224. J. Demer received an award from Research to Prevent Blindness and is Leonard
Apt Professor of Ophthalmology.
References
1
2
3
4
5
6
7
8
9
10
11
12
Demer JL: Extraocular muscles; in Jaeger EA, Tasman PR (eds): Duane’s Clinical Ophthalmology.
Philadelphia, Lippincott, 2000, vol 1, chapter 1, pp 1–23.
Demer JL: Anatomy of strabismus; in Taylor D, Hoyt C (eds): Pediatric Ophthalmology and
Strabismus, ed 3. London, Elsevier, 2005, pp 849–861.
Porter JD, Baker RS, Ragusa RJ, Brueckner JK: Extraocular muscles: basic and clinical aspects of
structure and function. Surv Ophthalmol 1995;39:451–484.
Oh SY, Poukens V, Demer JL: Quantitative analysis of rectus extraocular muscle layers in monkey
and humans. Invest Ophthalmol Vis Sci 2001;42:10–16.
Kono R, Poukens V, Demer JL: Superior oblique muscle layers in monkeys and humans. Invest
Ophthalmol Vis Sci 2005;46:2790–2799.
Demer JL, Oh SY, Poukens V: Evidence for active control of rectus extraocular muscle pulleys.
Invest Ophthalmol Vis Sci 2000;41:1280–1290.
Ruskell GL, Kjellevold Haugen IB, Bruenech JR, van der Werf F: Double insertions of extraocular rectus muscles in humans and the pulley theory. J Anat 2005;206:295–306.
Demer JL, Oh SY, Clark RA, Poukens V: Evidence for a pulley of the inferior oblique muscle.
Invest Ophthalmol Vis Sci 2003;44:3856–3865.
Sappey PC: Traite D’Anatomie Descriptive Avec Figures Intercalees Dans Le Texte.Paris, Delahaye
et Lecrosnier, 1888.
Sappey PC: The motor muscles of the eyeball [translation from the French]. Strabismus 2001;9:
243–253.
Miller JM: Functional anatomy of normal human rectus muscles. Vision Res 1989;29:223–240.
Kono R, Clark RA, Demer JL: Active pulleys: magnetic resonance imaging of rectus muscle paths
in tertiary gazes. Invest Ophthalmol Vis Sci 2002;43:2179–2188.
Demer
152
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
Porter JD, Poukens V, Baker RS, Demer JL: Cytoarchitectural organization of the medial rectus
muscle pulley in man. Invest Ophthalmol Vis Sci 1995;36:S960.
Demer JL, Miller JM, Poukens V, Vinters HV, Glasgow BJ: Evidence for fibromuscular pulleys of
the recti extraocular muscles. Invest Ophthalmol Vis Sci 1995;36:1125–1136.
Demer JL, Poukens V, Miller JM, Micevych P: Innervation of extraocular pulley smooth muscle in
monkeys and humans. Invest Ophthalmol Vis Sci 1997;38:1774–1785.
Miller JM, Demer JL, Poukens V, Pavlowski DS, Nguyen HN, Rossi EA: Extraocular connective
tissue architecture. J Vis 2003;3:240–251.
Fink WH. Surgery of the Vertical Muscles of the Eye. Springfield (IL), Thomas, 1962, pp 37–121.
Helveston EM, Merriam WW, Ellis FD, Shellhamer RH, Gosling CG: The trochlea: a study of the
anatomy and physiology. Ophthalmology 1992;80:124–133.
Demer JL: Pivotal role of orbital connective tissues in binocular alignment and strabismus. The
Friedenwald lecture. Invest Ophthalmol Vis Sci 2004;45:729–738.
Foster RS: Vertical muscle transposition augmented with lateral fixation. J AAPOS 1997;1:20–30.
Clark RA, Rosenbaum AL, Demer JL: Magnetic resonance imaging after surgical transposition
defines the anteroposterior location of the rectus muscle pulleys. J AAPOS 1999;3:9–14.
Clark RA, Miller JM, Demer JL: Three-dimensional location of human rectus pulleys by path
inflections in secondary gaze positions. Invest Ophthalmol Vis Sci 2000;41:3787–3797.
Clark RA, Demer JL: Effect of aging on human rectus extraocular muscle paths demonstrated by
magnetic resonance imaging. Am J Ophthalmol 2002;134:872–878.
Clark RA, Miller JM, Demer JL: Location and stability of rectus muscle pulleys inferred from
muscle paths. Invest Ophthalmol Vis Sci 1997;38:227–240.
Haslwanter T: Mathematics of three-dimensional eye rotations. Vision Res 1995;35:1727–1739.
van den Berg AV: Kinematics of eye movement control. Proc R Soc Lond 1995;260:191–197.
Ruete CGT: Ocular physiology. Strabismus 1999;7:43–60.
Tweed D, Vilis T: Geometric relations of eye position and velocity vectors during saccades. Vision
Res 1990;30:111–127.
Quaia C, Optican LM: Commutative saccadic generator is sufficient to control a 3-D ocular plant
with pulleys. J Neurophysiol 1998;79:3197–3215.
Koene AR, Erklens CJ: Properties of 3D rotations and their relation to eye movement control. Biol
Cybern 2004;90:410–417.
Demer JL: The orbital pulley system: a revolution in concepts of orbital anatomy. Ann N Y Acad
Sci 2002;956:17–32.
Detorakis ET, Engstrom RE, Straatsma BR, Demer JL: Functional anatomy of the anophthalmic
socket: insights from magnetic resonance imaging. Invest Ophthalmol Vis Sci 2003;44:
4307–4313.
Collins CC: The human oculomotor control system; in Lennerstrand G, Bach-y-Rita P (ed): Basic
Mechanisms of Ocular Motility and Their Clinical Implications. New York, Pergamon, 1975, pp
145–180.
Shall MS, Goldberg SJ: Lateral rectus EMG and contractile responses elicited by cat abducens
motoneurons. Muscle Nerve 1995;18:948–955.
Porrill J, Warren PA, Dean P: A simple control laws generates Listing’s positions in a detailed
model of the extraocular muscle system. Vision Res 2000;40:3743–3758.
Smith MA, Crawford JD: Neural control of rotational kinematics within realistic vestibuloocular
coordinate systems. J Neurophysiol 1998;80:2295–2315.
Crane BT, Tian J, Demer JL: Human angular vestibulo-ocular reflex initiation: relationship to
Listing’s law. Ann NY Acad Sci 2005;1039:1–10.
Steffen H, Walker MF, Zee DS: Rotation of Listing’s plane with convergence: Independence from
eye position. Invest Ophthalmol Vis Sci 2000;41:715–721.
Kapoula Z, Bernotas M, Haslwanter T: Listing’s plane rotation with convergence: role of disparity,
accommodation, and depth perception. Exp Brain Res 1999;126:175–186.
Schreiber K, Crawford JD, Fetter M, Tweed D: The motor side of depth vision. Nature
2001;410:819–822.
Bruno P, van den Berg AV: Relative orientation of primary positions of the two eyes. Vision Res
1997;37:935–947.
Mechanics of the Orbita
153
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
van Rijn LJ, van den Berg AV: Binocular eye orientation during fixations: Listing’s law extended
to include eye vergence. Vision Res 1993;33:691–708.
Demer JL, Kono R, Wright W: Magnetic resonance imaging of human extraocular muscles in convergence. J Neurophysiol 2003;89:2072–2085.
Allen MJ, Carter JH: The torsional component of the near reflex. Am J Optom Arch Am Acad
Optom 1967;44:343–349.
Kono R, Poukens V, Demer JL: Quantitative analysis of the structure of the human extraocular
muscle pulley system. Invest Ophthalmol Vis Sci 2002;43:2923–2932.
Mays LE, Zhang Y, Thorstad MH, Gamlin PD: Trochlear unit activity during ocular convergence.
J Neurophysiol 1991;65:1484–1491.
van den Bedem SPW, Schutte S, van der Helm FCT, Simonsz HJ: Mechanical properties and functional importance of pulley bands or ‘faisseaux tendineux’. Vis Res 2005;45:2710–2714.
Khanna S, Porter JD: Evidence for rectus extraocular muscle pulleys in rodents. Invest
Ophthalmol Vis Sci 2001;42:1986–1992.
Felder E, Bogdanovich S, Rubinstein NA, Khana TS: Structural details of rat extraocular muscles
andd three-dimensional reconstruction of the rat inferior rectus muscle and muscle-pulley interface. Vision Res 2005;45:1945–1955.
Dimitrova DM, Shall MS, Goldberg SJ: Stimulation-evoked eye movements with and without the
lateral rectus muscle pulley. J Neurophysiol 2003;90:3809–3815.
Quaia C, Optican LM: Dynamic eye plant models and the control of eye movements. Strabismus
2003;11:17–31.
Raphan T: Modeling control of eye orientation in three dimensions. I. Role of muscle pulleys in
determining saccadic trajectory. J Neurophysiol 1998;79:2653–2667.
Raphan T: Modeling control of eye orientation in three dimensions; in Fetter M, Haslwanter T,
Misslisch H, Tweed D (eds): Three-dimensional Kinematics of Eye, Head, and Limb Movements.
Amsterdam, Harwood, 1997, pp 359–374.
Tweed D, Cadera W, Vilis T: Computing three-dimensional eye position quaternions and eye
velocity from search coil signals. Vision Res 1990;30:97–110.
Misslisch H, Tweed D, Fetter M, Sievering D, Koenig E: Rotational kinematics of the human
vestibuloocular reflex. III. Listing’s law. J Neurophysiol 1994;72:2490–2502.
Thurtell MJ, Black RA, Halmagyi GM, Curthoys IA, Aw ST: Vertical eye position-dependence of
the human vestibuloocular reflex during passive and active yaw head rotations. J Neurophysiol
1999;81:2415–2428.
Crane BT, Tian JR, Demer JL: Temporal dynamics of ocular position dependence of the initial
human vestibulo-ocular reflex. Invest Ophthalmol Vis Sci 2005 (in revision).
Crane BT, Tian JR, Demer JL: Human angular vestibulo-ocular reflex initiation: relationship to
Listing’s law. Ann N Y Acad Sci 2005;1039:26–35.
Crawford JD, Vilis T: Symmetry of oculomotor burst neuron coordinates about Listing’s plane.
J Neurophysiol 1992;68:432–448.
Tweed D: Visual-motor optimization in binocular control. Vision Res 1997;37:1939–1951.
Misslisch H, Tweed D: Neural and mechanical factors in eye control. J Neurophysiol 2001;86:
1877–1883.
Angelaki DE, Hess BJ: Control of eye orientation: where does the brain’s role end and the
muscle’s begin? Eur J Neurosci 2004;19:1–10.
Angelaki DE: Three-dimensional ocular kinematics during eccentric rotations: evidence for
functional rather than mechanical constraints. J Neurophysiol 2003;89:2685–2696.
Klier EM, Crawford JD: Human oculomotor system acounts for 3-D eye orientation in the visualmotor transformation for saccades. J Neurophysiol 1998;80:2274–2294.
Mok D, Ro A, Cadera W, Crawford JD, Vilis T: Rotation of Listing’s plane during vergence. Vision
Res 1992;32:2055–2064.
Crane BT, Tian J, Demer JL: Kinematics of vertical saccades during the yaw vestibulo-ocular
reflex in humans. Invest Ophthalmol Vis Sci 2005;46:2800–2809.
Lee C, Zee DS, Straumann D: Saccades from torsional offset positions back to Listing’s plane.
J Neurophysiol 2000;83:3141–3253.
Demer
154
68 Tian JR, Crane BT, Demer JL: Vestibular catch-up saccades in labyrinthine deficiency. Exp Brain
Res 2000;131:448–457.
69 Demer JL, Clark RA: Magnetic resonance imaging of human extraocular muscles during static
ocular counter-rolling. J Neurophysiol 2005;94:3292–3302.
70 Ghasia FF, Angelaki DE: Do motoneurons encode the noncommutativity of ocular rotations?
Neuron 2005;47:281–293.
71 Klier EM, Meng H, Angelaki DE: Abducens nerve/nucleus stimulation produces kinematically
correct three-dimensional eye movements. Soc Neurosci Abstr 2005:abstract #475.4.
72 Scherberger H, Cabungcal J-H, Hepp K, Suzuki Y, Straumann D, Henn V: Ocular counterroll
modulates the preferred direction of saccade-related pontine burst neurons in the monkey.
J Neurophysiol 2001;86:935–949.
73 Hess BJM, Angelaki DE: Gravity modulates Listing’s plane orientation during both pursuit and
saccades. J Neurophysiol 2003;90:1340–1345.
74 Hess BJM, Angelaki DE: Kinematic principles of primate rotational vestibulo-ocular reflex II.
Gravity-dependent modulation of primary eye position. J Neurophysiol 1997;78:2203–2216.
75 Hess BJM, Angelaki DE: Kinematic principles of primate rotational vestibulo-ocular reflex. I.
Spatial organization of fast phase velocity axes. J Neurophysiol 1997;78:2193–2202.
76 Crawford JD, Tweed DB, Vilis T: Static ocular counterroll is implemented through the 3-D neural
integrator. J Neurophysiol 2003;90:2777–2784.
77 Frens MA, Suzuki Y, Scherberger H, Hepp K, Henn V: The collicular code of saccade direction
depends on the roll orientation of the head relative to gravity. Exp Brain Res 1998;120:283–290.
78 Crawford JD, Martinez-Trujillo JC, Kleier EM: Neural control of three-dimensional eye and head
movements. Cur Opin Neurosci 2003;13:655–662.
79 Van Opstal AJ, Hepp K, Hess BJ, Straumann D, Henn V: Two- rather than three-dimensional representation of saccades in monkey superior colliculus. Science 1991;252:1313–1315.
80 Glasauer S, Dieterich M, Brandt T: Central positional nystagmus simulated by a mathematical
ocular motor model of otolith-dependent modification of Listing’s plane. J Neurophysiol
2001;86:1456–1554.
81 Crawford JD, Guitton D: Visual-motor transformations required for accurate and kinematically
correct saccades. J Neurophysiol 1997;78:1447–1467.
82 Wong AMF, Sharpe JA, Tweed D: Adaptive neural mechanism for Listing’s law revealed in
patients with fourth nerve palsy. Invest Ophthalmol Vis Sci 2002;43:1796–1803.
83 Straumann D, Steffen H, Landau K, et al: Primary position and Listing’s law in acquired and congenital trochlear nerve palsy. Invest Ophthalmol Vis Sci 2003;44:4282–4292.
84 Migliaccio AA, Cremer PD, Sw ST, Halmagyi GM: Vergence-mediated changes in Listing’s plane
do not occur in an eye with superior oblique palsy. Invest Ophthalmol Vis Sci 2004;45:3043–3047.
85 Angelaki DE, Dickman DJ: Premotor neurons encode torsional eye velocity during smooth-pursuit eye movements. J Neurosci 2003;23:2971–2979.
86 Demer JL: Clarity of words and thoughts about strabismus. Am J Ophthalmol 2001;132:757–759.
87 Bielschowsky A: Lectures on motor anomalies. XI. Etiology, prognosis, and treatment of ocular
paralyses. Am J Ophthalmol 1939;22:723–734.
88 von Noorden GK, Murray E, Wong SY: Superior oblique paralysis. A review of 270 cases. Arch
Ophthalmol 1986;104:1771–1776.
89 Adler FE: Physiologic factors in differential diagnosis of paralysis of superior rectus and superior
oblique muscles. Arch Ophthalmol 1946;36:661–673.
90 Scott WE, Kraft SP: Classification and treatment of superior oblique palsies: II. Bilateral superior
oblique palsies; in Caldwell D (ed): Pediaric Ophthalmology and Strabismus: Transactions of the
New Orleans Academy of Ophthalmology. New York, Raven Press, 1986, pp 265–291.
91 Scott WE, Parks MM: Differential diagnosis of vertical muscle palsies; in von Noorden GK (ed):
Symposium on Strabismus: Transactions of the New Orleans Academy of Ophthalmology. St.
Louis, Mosby, 1978, pp 118–134.
92 Kushner BJ: Ocular torsion: rotations around the ‘WHY’ axis. J AAPOS 2004;8:1–12.
93 Kushner BJ: The diagnosis and treatment of bilateral masked superior oblique palsy. Am J
Ophthalmol 1988;105:186–194.
Mechanics of the Orbita
155
94 Robinson DA: Bielschowsky head-tilt test – II. Quantitative mechanics of the Bielschowsky headtilt test. Vision Res 1985;25:1983–1988.
95 Simonsz HJ, Crone RA, van der Meer J, Merckel-Timmer CF, van Mourik-Noordenbos AM:
Bielschowsky head-tilt test I – ocular counterrolling and Bielschowsky head-tilt test in 23 cases of
superior oblique palsy. Vision Res 1985;25:1977–1982.
96 Demer JL, Miller JM: Magnetic resonance imaging of the functional anatomy of the superior
oblique muscle. Invest Ophthalmol Vis Sci 1995;36:906–913.
97 Chan TK, Demer JL: Clinical features of congenital absence of the superior oblique muscle as
demonstrated by orbital imaging. J AAPOS 1999;3:143–150.
98 Velez FG, Clark RA, Demer JL: Facial asymmetry in superior oblique palsy and pulley heterotopy.
J AAPOS 2000;4:233–239.
99 Kono R, Demer JL: Magnetic resonance imaging of the functional anatomy of the inferior oblique
muscle in superior oblique palsy. Ophthalmology 2003;110:1219–1229.
100 Demer JL, Miller MJ, Koo EY, Rosenbaum AL, Bateman JB: True versus masquerading superior
oblique palsies: muscle mechanisms revealed by magnetic resonance imaging; in Lennerstrand G
(ed): Update on Strabismus and Pediatric Ophthalmology. Boca Raton (FL), CRC Press, 1995, pp
303–306.
101 Plager DA: Traction testing in superior oblique palsy. J Pediatr Ophthalmol Strabismus 1990;27:
136–140.
102 Plager DA: Tendon laxity in superior oblique palsy. Ophthalmology 1992;99:1032–1038.
103 Plager DA, Helveston EM, Fahad B: Superior oblique muscle atrophy/hypodevelopment in superior oblque palsy. Abstr of 22nd Annual AAPOS Mtg. 1996:papers 10.
104 Kushner BJ: Errors in the three-step test in the diagnosis of vertical strabismus. Ophthalmology
1987;96:127–132.
105 Brodsky ME: Three dimensions of skew deviation. Br J Ophthalmol 2003;87:1440–1441.
106 Donahue SP, Lavin PJ, Hamed LM: Tonic ocular tilt reaction simulating a superior oblique palsy:
diagnostic confusion with the 3-step test. Arch Ophthalmol 1999;117:347–352.
107 Clark RA, Miller JM, Rosenbaum AL, Demer JL: Heterotopic muscle pulleys or oblique muscle
dysfunction? J AAPOS 1998;2:17–25.
108 Clark RA, Miller JM, Demer JL: Displacement of the medial rectus pulley in superior oblique
palsy. Invest Ophthalmol Vis Sci 1998;39:207–212.
109 Lajeunie E, Catala M, Renier D. Craniosynostosis: from a clinical description to an understanding
of bone formation of the skull. Childs Nerv Syst 1999;15:276–280.
110 Limon de Brown E, Monasterio FO, Feldman MS: Strabismus in plagiocephaly. J Pediatr
Ophthalmol Strabismus 1998;25:180–190.
111 Khan SH, Nischal KK, Dean F, Hayward RD, Walker J: Visual outcomes and amblyogenic risk
factors in craniosynostotic syndromes: a review of 141 cases. Br J Ophthalmol 2003;87:
999–1003.
112 Coats DK, Paysse EA, Stager DR: Surgical management of V-pattern strabismus and oblique dysfunction in craniofacial dysostosis. J AAPOS 2000;4:338–342.
113 Velez FG, Thacker N, Britt MT, Rosenbaum AL: Cause of V pattern strabismus in craniosynostosis: a case report. Br J Ophthalmol 2004;88:1598–1599.
114 Clark RA, Demer JL, Miller JM, Rosenbaum AL: Heterotopic rectus extraocular muscle pulleys
simulate oblique muscle dysfunction. Abstracts of the American Association for Pediatric
Ophthalmology and Strabismus. 1997, p 39.
115 Demer JL, Clark RA, Miller JM: Heterotopy of extraocular muscle pulleys causes incomitant strabismus; in Lennerstrand G (ed). Advances in Strabismology. Buren (Netherlands), Aeolus Press,
1999, pp 91–94.
116 Demer JL: A 12 year, prospective study of extraocular muscle imaging in complex strabismus.
J AAPOS 2003;6:337–347.
117 Clark RA, Demer JL: Rectus extraocular muscle pulley displacement after surgical transposition
and posterior fixation for treatment of paralytic strabismus. Am J Ophthalmol 2002;133:119–128.
118 Krzizok TH, Schroeder BU: Measurement of recti eye muscle paths by magnetic resonance imaging in highly myopic and normal subjects. Invest Ophthalmol Vis Sci 1999;40:2554–2560.
Demer
156
119 Demer JL, Miller JM: Orbital imaging in strabismus surgery; in Rosenbaum AL, Santiago AP
(eds): Clinical Strabismus Management: Principles and Techniques. Philadelphia, WB Saunders,
1999, pp 84–98.
120 Wong IBY, Leo SW, Khoo BK: Surgical correction of myopia strabismus fixus. Abstracts of 31th
Annual Meeting of the American Association for Pediatric Ophthalmology and Strabismus. 2005,
p 50.
121 Oh SY, Clark RA, Velez F, Rosenbaum AL, Demer JL: Incomitant strabismus associated with
instability of rectus pulleys. Invest Ophthalmol Vis Sci 2002;43:2169–2178.
122 Demer JL, Kono R, Wright W, Oh SY, Clark RA: Gaze-related orbital pulley shift: A novel cause
of incomitant strabismus; in de Faber JT (ed): Progress in Strabismology. Lisse, Swets and
Zeitlinger, 2002, pp 207–210.
123 Bhola R, Rosenbaum AL, Ortube MC, Demer JL: High resolution magnetic resonance imaging
demonstrates varied anatomic abnormalities in Brown’s syndrome. J AAPOS 2004 (in revision).
124 Piruzian A, Goldberg RA, Demer JL: Inferior rectus pulley hindrance: orbital imaging mechanism
of restrictive hypertropia following lower lid surgery. J AAPOS 2004;8:338–344.
125 Scott AB: The faden operation: mechanical effects. Am Orthoptic J 1977;27:44–47.
126 Clark RA, Isenberg SJ, Rosenbaum SJ, Demer JL: Posterior fixation sutures: a revised mechanical
explanation for the fadenoperation based on rectus extraocular muscle pulleys. Am J Ophthalmol
1999;128:702–714.
127 Clark RA, Ariyasu R, Demer JL: Medial rectus pulley posterior fixation is as effective as scleral
posterior fixation for acquired esotropia with a high AC/A ratio. Am J Ophthalmol 2004;137:
1026–1033.
Joseph L. Demer, MD, PhD
Jules Stein Eye Institute, Departments of Ophthalmology and Neurology, David Geffen Medical
School at the University of California
100 Stein Plaza, UCLA
Los Angeles, CA 90095-7002 (USA)
Tel. ⫹1 310 825 5931, Fax ⫹1 310 206 7826, E-Mail [email protected]
Mechanics of the Orbita
157
Straube A, Büttner U (eds): Neuro-Ophthalmology.
Dev Ophthalmol. Basel, Karger, 2007, vol 40, pp 158–174
Current Models of the Ocular
Motor System
Stefan Glasauer
Center for Sensorimotor Research, Department of Neurology,
Ludwig-Maximilian University Munich, Munich, Germany
Abstract
This chapter gives a brief overview of current models of the ocular motor system.
Beginning with models of the final ocular pathway consisting of eye plant and the neural
velocity-to-position integrator for gaze holding, models of the motor part of the saccadic system, models of the vestibulo-ocular reflexes (VORs), and of the smooth pursuit system are
reviewed. As an example, a simple model of the 3-D VOR is developed which shows why the
eyes rotate around head-fixed axes during rapid VOR responses such as head impulses, but
follow a compromise between head-fixed axes and Listing’s law for slow VOR responses.
Copyright © 2007 S. Karger AG, Basel
The ocular motor system is one of the best examined motor systems. Not
only are there numerous studies on behavioral data, but also the neurophysiology and anatomy of the ocular motor system is well documented. This knowledge makes the ocular motor system a perfect candidate for modeling. Models
of the ocular motor system span the range from models at the systems level to
detailed neural networks using firing rate neurons. Spiking neuron models are,
at present, rare. The main reason is that the ocular motor system is composed of
a wealth of neuronal structures which makes a detailed implementation using
spiking neuron models computationally difficult. Moreover, the impressive
explanatory power of models at the systems level has not yet raised the need for
more detailed modeling at the level of single neurons except for restricted subsets of the ocular motor circuitry.
The present chapter attempts to give an overview of the most recent models related to the ocular motor system, without trying to compile a complete
bibliography or referring to the whole seminal work by D.A. Robinson, starting
in the 1960s, which still is the basis for models of the ocular motor system. The
focus is on the motor system, therefore, models of visual cortical mechanisms
such as computation of motion from retinal sensory inputs will only briefly be
touched upon. However, one should not forget that the question of how retinal
input represented on retinotopic maps is neurally transformed by the brain to
finally result in a motor command for an eye movement is an important aspect
which should not be neglected. In the following, the various models will be presented in the reverse order, that is, the chapter begins with models focused on
the biomechanics of the eye. Subsequently, models of the neural velocity-toposition integrator, which is common to all types of eye movements, are considered. Finally, models of the various types of eye movements and their neural
control are presented.
Eye Plant
The term ‘eye plant’ covers the kinematic and dynamic behavior of the eye.
Thus, models of the eye plant (for review, see also [1]) focus on the relationship
between a motor command generated in the ocular motor nuclei of the brainstem and the resulting eye movement. Evidently, this transformation from
motor command to eye movement is determined by the biomechanics of the eye
globe, the extraocular eye muscles, the muscle pulleys (connective tissue pulleys that serve as the functional mechanical origin of the muscles), and the
orbital tissues [see Demer, this vol, pp 132–157]. Most models focusing on the
eye plant explicitly deal with the 3-D geometry and kinematics of the eye, and
with specific properties of the plant such as the force-length relationship of the
muscles or the placement of the pulleys. In contrast, models dealing with the
neural control implemented in brainstem structures and above very often treat
the eye plant as a lumped element. Two types of eye plant models can be distinguished: static models, concerned with the anatomy of the eye plant, and
dynamic models, also considering the temporal properties involved (e.g. time
constants of the eye plant).
Static models, derived from Robinson’s work [2, 3] have resulted in software packages, i.e. Orbit [4], SEE [5], designed to help the ophthalmologist, for example, in strabismus surgery. Other authors have designed static
models to evaluate the role of the eye plant in Listing’s law [6–9]. For a review
on Listing’s law, see Wong [10]. This question is closely related to the problem
of noncommutativity of 3-D rotations. From these theoretical studies, especially after the existence of muscle pulleys was established [see Demer, this vol,
pp 132–157], it was concluded that, given specific pulley configurations,
Listing’s law (i.e. if eye orientation is expressed as rotation vectors or quaternions,
Ocular Motor Models
159
torsion depends linearly on gaze direction) may be implemented by the eye
plant. In other words, a 2-D innervation of the six extraocular eye muscles
would be sufficient to achieve the torsional eye orientations required by
Listing’s law (see also below) in tertiary positions (off the horizontal and vertical meridians). This view has recently been supported by recordings from the
motoneurons during smooth pursuit [11]. This does not mean that the eye plant
constricts eye movements to obey Listing’s law, but it simplifies its implementation to a great extent.
Dynamics have been implemented mostly in simplified, lumped eye plant
models [12–16], since detailed experimental studies of the 3-D dynamics have
been missing. Recently, the dynamics of the eye plant have been re-evaluated
[17], suggesting that in contrast to previous assumptions of a dominant time
constant of 200 ms, the dynamics have to be described by a wide range of time
constants ranging from about 10 ms to 10 s. A possibly more severe shortcoming of the lumped eye plant models is that they do not account for the fact that
muscle force is a function of innervation and length. According to a more realistic model of 3-D dynamics [1], this leads to passive eye position-dependent
torque that has to be compensated for by additional innervation. Thus, while
models using simplified eye plant approximations are useful and valid in many
cases, a more adequate implementation of the eye plant will be necessary to
fully understand the neural mechanisms controlling eye movements.
The Neural Velocity-to-Position Integrator
Together with the ocular motor nuclei in the brainstem, the neural velocityto-position integrator [for review, see 18] forms the final neural structure common to all types of eye movements. The neural commands for eye movements,
which are also sent to the ocular motor nuclei, consist of phasic signals coding
eye velocity (e.g. the saccadic burst command). However, if this were the only
signal sent to the muscles, the eye would not remain in an eccentric position, but
drift back to the equilibrium position determined by the eye plant. Therefore, an
additional signal is necessary to generate the tonic muscle force to hold the eye.
This signal comes from the neural velocity-to-position integrators located in the
brainstem (nucleus prepositus hypoglossi and medial vestibular nucleus) for
horizontal eye movements and the midbrain (interstitial nucleus of Cajal) for
vertical eye movements. Additionally, the cerebellar flocculus plays an important role in neural integration in mammals, as shown by lesion experiments in
different species such as rats, cats, and nonhuman primates [19]. As for the eye
plant, many models consider the neural integrator as lumped element, which is
described by a so-called leaky integrator with a time constant of more than 2 s
Glasauer
160
for primates, which determines the residual centripetal drift. This lumped
description is useful and valid for models interested in other aspects of the ocular motor system. However, it does not allude as to how the integrator is implemented neurally, or which additional properties it may need.
Specifically when considering 3-D eye movements, it has been shown that
simply using three leaky integrators (as an extension to 1-D models) may not
suffice depending on the coding of velocity information to be integrated,
because 3-D rotations do not commute. This poses a problem especially for the
vestibulo-ocular reflex (VOR): the semicircular canal afferent signal codes
angular velocity, but the integral of angular velocity does not yield orientation
[15]. This problem can, however, be circumvented if the signal to be integrated
is first converted to the derivative of eye orientation (which is not angular
velocity). Thus, in such case, a commutative integrator composed of three parallel 1-D integrators can be used [13, 15, 16], and will produce a correct tonic
signal to hold the eye eccentrically, given that the eye plant has the property of
converting this neural command to actual eye orientation. Such a configuration
will also maintain the eye orientation in Listing’s plane if the command is 2-D.
Notably, as mentioned above, eye movements violating Listing’s law (e.g. during
the VOR, or during active eye-head gaze shifts) are still possible, but necessarily require a full 3-D neural command. Additionally, Listing’s law is modified
by vergence and head tilt. Such a modification requires changes in the central
nervous commands, either by altering the pulley configuration or the commands sent to the extraocular muscles. Therefore, an extension to the neural
integrator scheme has been proposed which incorporates additional input from
the otoliths to achieve accurate fixations during head tilt [20, 21].
The neural implementation of the integration is the topic of a considerable
number of studies. It has been suggested that a network of reciprocal inhibition
forms a positive feedback loop which effectively prolongs the short time constants of single neurons to the desired long time constant of the integrating network [18, 22, 23]. Other related models proposed that the positive feedback
loop forming the integrator is excitatory and contains an internal model of the
eye plant dynamics [24, 25]. One of the problems of the original reciprocal
feedback hypothesis was that fine tuning of the synaptic strength is implausible
given that membrane time constants of about 5 ms have to be extended to the
20 s of the network [26]. A possible solution [27] is that the intrinsic time constant of processing is determined by synaptic time constants with values around
100 ms (corresponding to NMDA receptors). Alternative models suggest that
single cell properties determine integration [28, 29].
While the models above mostly assume that the known integrator brainstem regions exclusively perform the integration, it has been shown by several
studies that, in mammals, lesions of the cerebellar floccular lobe or the parts of
Ocular Motor Models
161
the inferior olive projecting to it decrease the integrator time constant to less
than 2 s. This means that the brainstem integrator alone only needs to achieve
weak integration, the remainder is done by the cerebellum. Models of how the
cerebellum may contribute to the integrator function are relatively sparse, but
suggest that recurrent feedback loops are responsible for this function [19,
30–33].
Saccadic Eye Movements
Saccades rapidly redirect gaze, for example in response to a visual stimulus
[see Thier, this vol, pp 52–75]. The function of the saccadic burst generator in
the brainstem (horizontal: paramedian pontine reticular formation; vertical: rostral interstitial nucleus of the medial longitudinal fasciculus) and its input structures are the focus of numerous modeling studies. While the first models by
Robinson focused on how the burst generator and the neural integrator cooperate
to achieve an inverse dynamic model of the eye plant to produce rapid and accurate saccades without postsaccadic drift, later studies concentrated, for example,
on how saccadic accuracy is achieved by local feedback loops (e.g. [34]). Such
feedback loops have been proposed since, during an ongoing saccade, visual
feedback for fine endpoint corrections is not available due to the long latency of
visual processing. Subsequently, these 1-D models have been extended to three
dimensions [35, 16, 20] to explain how the 2-D visual input, the retinal error, is
converted to an accurate 3-D motor command, which obeys Listing’s law [10].
Neural network models of the saccadic burst generator, inspired by
Robinson’s work, have shown how the various cell types in the brainstem, such
as omnipause neurons and burst neurons, may interact to generate the saccadic
burst command [36–39].
Another problem tackled by modelers is how the transformation necessary
to generate a temporal, vector-coded command (the saccadic burst) from a spatial representation of retinal error coded in a retinotopic map (e.g. the superior
colliculus) is achieved [40]. Since the exact mechanism of this spatiotemporal
transformation is unknown to date, these models provide important testable
hypotheses [37]. Detailed modeling of map-like structures such as the superior
colliculus necessitates the use of neural network models to represent the spatial
distribution of neural activity. For the superior colliculus, this has been done in
various ways, e.g. as 1-D simplification [41], to complex networks which represent the collicular map, propose feedback mechanism [42], and also implement
the above-mentioned visuomotor transformation [43]. Even more complex
models of the superior colliculus and saccade generation, such as the ones by
Grossberg et al. [44], incorporate aspects such as multimodality, model cortical
Glasauer
162
regions such as the frontal eye fields (FEFs), and have been proposed to formulated hypotheses about how the brain may allow for reactive vs. planned saccades, how target selection may work, and how the behavioral differences in
common saccade paradigms, such as gap, overlap, or delayed saccades may be
explained [45].
Another important region implicated in saccade generation, the oculomotor vermis and the fastigial nucleus of the cerebellum, are the focus of only a
few models so far. Their focus is either mainly on the functional role of the
cerebellum [46, 47], or on explaining the possible interaction of superior colliculus and cerebellum for saccade generation [32, 48–50]. One of the tests for
the realism of these models is simulation of the profound effects of cerebellar
lesions on saccade execution, thereby providing and testing hypotheses on cerebellar function for on-line motor control of rapid movements. The most recent
of these models [50] proposes that the role of the cerebellum goes beyond controlling eye movement in that the cerebellum is considered to control gaze, that
is, the combined action of eye and head in achieving accurate gaze shifts. While
lesion studies have demonstrated the importance of these cerebellar structures
for adaptive modification of saccadic amplitude, even less modeling studies
have touched upon this issue [51–53]. However, since recent experimental studies [54] on saccade adaptation challenge the prevailing theories of the adaptive
function of the cerebellum and inferior olive [55, 56], an increasing interest in
modeling of these structures can be expected.
Perceptual aspects of the saccadic system, which are further upstream from
motor processing, are also a topic of current models. To name one example,
Niemeier et al. [57] explained the saccadic suppression of displacement by
Bayesian integration of sensory and motor information, thus suggesting that an
apparent flaw in trans-saccadic processing of visual information is, in fact, an
optimal solution.
For readers with deeper interest in computational modeling of the saccadic
system from cortical structures to brainstem, a recent review article [58] providing a comprehensive overview is recommended.
Vestibulo-Ocular Reflexes
The VOR is the phylogenetically oldest eye movement system and serves
to stabilize the eye in space, and thus the visual image on the retina [see Fetter,
this vol, pp 35–51]. There are two distinct VOR systems, the angular VOR driven by the semicircular canals stabilizing the retinal image during head rotation, and the translational VOR which gets input from the otolith systems and
compensates for translations. Additionally, the so-called static VOR, which is
Ocular Motor Models
163
also driven by the otoliths, compensates for head tilt with respect to gravity and
results in static ocular counterroll and a compensatory tilt of Listing’s plane.
The static VOR plays a minor role in primates due to its weak gain (only about
5 of counterroll for a 90 head tilt in roll), but is of interest for the clinicians,
since peripheral and central vestibular imbalance causes ocular counterroll. It
has thus been of interest not only to model the static VOR, but also to formalize
hypotheses about possible lesion sites causing pathological counterroll [59, 60].
Another study of interest for clinicians is concerned with the angular VOR after
unilateral or bilateral vestibular lesions [61].
Practically all ocular motor models are based on a firing rate description of
the underlying neural structure. However, there is one exception, a model of the
horizontal angular VOR in the guinea pig which uses realistic spiking neurons
[62]. The model consists of separate brainstem circuits for generation of slow
and quick phases, and thus allows simulation of nystagmus. Due to the bilateral
layout of the network, a simulation of unilateral peripheral vestibular lesions
was also possible.
While the three-neuron arc of the angular VOR and its indirect pathway via
the neural integrator, first modeled by Robinson, has been an excellent example
of an inverse internal model, modeling it regained interest only after considering the 3-D properties of the VOR [12, 15] (see also the modeling example
below). In parallel to these attempts, models of canal-otolith interaction considered how the VOR response is influenced by gravity [63, 64], e.g. why there are
differences in pitch VOR if performed in upright vs. supine positions. This
question is closely related to the more general question of how the brain
resolves the ambiguity of otolith signals which do not differentiate between linear acceleration and gravity, a problem for which various solutions based on
canal-otolith senory fusion have been offered so far [63–67]. While these models focused on the necessary underlying computations of the proposed interaction of semicircular canal and otolith information for VOR responses, others
investigated how these signals could interact at the brainstem level [68–70].
Some of these models also included visual-vestibular interaction [64, 67],
which played a major role in early models of the angular VOR [71–73], since
the dynamics of the semicircular canals are insufficient to generate the ongoing
nystagmus observed in light in response to continuous whole-body rotation.
This response, called optokinetic nystagmus [see Büttner, this vol, pp 76–89],
and its intimate link to the VOR via the so-called velocity-storage mechanism
have been treated by various models [64, 74, 75].
Of ongoing interest is another feature of the VOR, its adaptability [76]. The
gain of the VOR in darkness can be adapted by changing the visual input during
training, for example, rotating a visual scene with the subject will decrease the
VOR gain. Since adaptability depends on the cerebellum [77], several models
Glasauer
164
have been proposed which explain gain adaptation by assuming synaptic plasticity at the level of the cerebellar flocculus [78]. Other models suggest on the
basis of experimental evidence that plasticity also occurs at the level of the
vestibular nuclei [75, 79, 80]. Recent papers suggest that VOR adaptation may,
in fact, be ‘plant adaptation’, since the experimental modification is applied to
the visual rather than the vestibular input [30, 33]. Consequently, in those models the adaptation takes place in a floccular feedback loop carrying an efference
copy of the motor command rather than changing the weights of the vestibular
input.
A Modeling Example: A 3-D Model of the Angular VOR
As an example of how a model is formulated in mathematical terms, I shall
now develop a model of the 3-D rotational VOR. 3-D eye position can be
expressed by rotation vectors [6]. The rotation vector expresses the rotation of
the eye with respect to a reference direction, e.g. straight ahead. The direction
of the rotation vector corresponds to the rotation axis, and its length is approximately proportional to half the angle of the rotation. Since the VOR is driven by
the afferent signal from the semicircular canals, which is proportional to angular head velocity, we need a relation between rotational position and angular
velocity. This relation is given by a differential equation which expresses the
temporal derivative of a rotation vector r· dr/dt by angular velocity and the
rotation vector r [81]:
r ( ( 䊊 r) r r)/2
(1)
From this differential equation, angular position is obtained by integration.
The model developed below is based on work by Tweed [15], who originally used quaternions to describe rotations. Note that, for our purpose, both
methods are equivalent. According to the linear plant hypothesis (see above),
the extraocular motor neurons code a weighted combination of eye position, the
output of the neural integrator, and its temporal derivative (rather than angular
velocity). The brain has thus to convert the angular velocity vector supplied by
the semicircular canal system to the temporal derivative of eye position. This
conversion can be performed by equation 1. Tweed [15] suggested a simplified
version of quaternion multiplication, which, expressed in rotation vectors, leads
to the following formulation:
r 艐 ( r)/2 艐 R : ½ [1 rx ry; rz 1 0; ry 0 1] (2)
with r being an eye position in Listing’s plane, i.e. rx ⬇ 0. The latter prerequisite is fulfilled for real VOR eye movements, since frequent vestibular
Ocular Motor Models
165
quick phases keep the eye close to Listing’s plane [82, 83]. Equation 2 also
shows that using this relation there is no longer a difference between Tweed’s
3-component quaternions [15] and the rotation vector computation. Even
though this formula is sufficient for most purposes, it does not capture a main
feature of the VOR, the quarter-angle rule [84]. Therefore, instead of equation
2, the following relationship is proposed
r j [½ 0 0; 0 1 0; 0 0 1] R (3)
which sets the gain of the torsional component of the derivative of eye
position to 0.5. R is the eye position-dependent matrix defined in equation 2.
Note that this is not equivalent to setting the gain of the torsional
angular velocity to 0.5. This equation already reproduces both the low gain of
the torsional VOR and the quarter-angle rule (on close inspection, this is
exactly what is proposed by Tweed [15] in the simulation source code in his
appendix A).
However, it was shown that the rapid VOR, for example in response to
head impulses, does not follow the quarter-angle rule but remains head fixed
[85]. This finding, which is not explained by Tweed’s model, can easily be
accounted for by the combination of a direct pathway carrying an accurate
derivative of eye position (equation 2) and the integrator pathway following
equation 3. This results in the following motor command m:
m R r r j
(4)
with r being computed according to equation 3, and being the dominant
time constant of the eye plant (200 ms). The so-called linear plant can be
expressed by
e· (m – e)/
(5)
with e being true eye position (in contrast to r, which signifies an internal
estimate of eye position). Equations 2–5 thus constitute a simple dynamical
model, which captures the main features of the 3-D VOR: low torsional VOR
gain, quarter-angle rule for low frequencies, and head-fixed rotation axes for
high frequencies.
The model necessarily requires feedback connections from the neural integrators to vestibular nuclei to achieve the conversion from angular velocity to
the derivative of eye position (fig. 1). Indeed, feedback connections to the
vestibular nuclei have been shown anatomically from both the nucleus prepositus hypoglossi and the interstitial nucleus of Cajal. For a numerical simulation
of the model comparing responses to slow and fast head movements, see figure 2.
This modeling example not only demonstrates the importance of taking into
account that eye movements are 3-D, but also that models based on eye velocity
as model output are often not sufficient.
Glasauer
166
rI
Semicircular
canals
Vestibular
nuclei
Head rotation
Ocular motor
nuclei
.
rI
Neural
integrator
r
I
m
+
Eye plant
+
.
·R·r
e
Eye rotation
Direct pathway
Fig. 1. Block diagram of the model of the VOR described in the main text. The symbols correspond to the variables used in the mathematical description (equations 1–5); the
boxes contain the differential equations or other mathematical relations translating input to
output.
Straight ahead
250
30˚ down
30˚ up
6
5
Horizontal (degrees/s)
Horizontal (degrees/s)
200
150
100
4
3
2
50
1
0
50
a
0
0
Torsional (degrees/s)
1
50
b
0
1
Torsional (degrees/s)
Fig. 2. Simulation of VOR responses to purely horizontal head rotations (amplitude 5)
with a model of the 3-D VOR (see text). a Rapid VOR, duration 50 ms. b Slow VOR, duration
2 s. Solid lines: horizontal angular eye velocity plotted over torsional angular eye velocity.
Note the difference in velocity scales. Black: gaze straight ahead; dark grey: gaze 30° down;
light grey: gaze 30° up. Dashed lines: quarter-angle rule prediction for relation between torsional and horizontal eye velocity at the respective gaze elevation. The model thus simulates
how rapid VOR responses can be purely head fixed, while slow VOR follows the quarterangle rule, as demonstrated experimentally [85].
Ocular Motor Models
167
Retina
Target motion
Retinal
slip
Afferent
pathways
Efferent
pathways
Pursuit
command
Motor
pathways
a
Internal
model
Retina
Target motion
Retinal
slip
Afferent
pathways
Reconstructed
target motion
Efferent
pathways
Efference
copy
Pursuit
command
Motor
pathways
b
Fig. 3. Two basic hypotheses for the processing of retinal slip information for smooth
pursuit [after 89]. a The pursuit command is generated in a simple feedback loop. b An internal model of motor pathways and afferent pathways driven by an efference copy of the pursuit command generates a signal suited to reconstruct target motion. This signal is used to
generate the pursuit command.
Smooth Pursuit Eye Movements
The smooth pursuit system [for overview, see Büttner, this vol, pp 76–89]
has received considerable interest by modelers. In contrast to saccadic eye
movements, it has to be modeled as a closed-loop system, since the pursuit eye
movement changes the visual input by attempting to stabilize the target on the
retina. Even though it shares some pathways and properties with the saccadic
system (for review, see [86]), most of its structure can be regarded as implementing a separate stream of processing [review: 87]. Most importantly,
smooth pursuit relies on an intact cerebellum (flocculus, paraflocculus, and
dorsal vermis), while saccades are possible even without it. One group of models assumes that the eye movement response is based on a combination of eye
acceleration, eye velocity, and sometimes eye position signals, which are combined to drive the pursuit controller (e.g. [88]). Alternatively, a positive feedback loop within the visual cortex is proposed (fig. 3) which has a similar
effect as using combined retinal velocity and acceleration signals [90].
Another group building on the earliest modeling attempts [91, 92] assumes an
internal reconstruction of target velocity from retinal slip and an efference
Glasauer
168
copy of eye velocity, which then drives pursuit (e.g. [93]). The latter approach
has some advantages, especially regarding the problem of the long latency of
visual processing, which makes the use of a simple high-gain feedback loop
problematic. It is also supported by recent experimental evidence: it has been
shown that the cortical middle superior temporal area (MST) contains neurons
which code target motion in space (for review, see [87]), and that thalamic neurons carry smooth pursuit signals which are suited to convey an efference copy
to the cortex [94].
While figure 2 shows the basic information processing of the two hypotheses, the various boxes in this processing scheme may contain mathematical
descriptions of the underlying processing from simple gain elements, delays or
linear differential equations, as in [91], to more complex systems of nonlinear
differential equations which are used to model neural networks. It is worth to
note that all dynamic computational models, whether on a systems level or
describing in detail the dynamics of ion channels of single neurons, rely on the
same basic building blocks, coupled differential equations.
All pathways for pursuit pass through the cerebellum; therefore, most
models have concentrated on the role of the cerebellar pathways, especially
those passing through the floccular lobe. The role of the cortical structures (pursuit region of the FEFs and MST), their downstream pathways (dorsolateral
pontine nuclei and nucleus reticularis tegmenti pontis), and their specific contribution has received less attention so far. Neurophysiology suggests that the
FEF pathway is more related to signals on eye acceleration, i.e. changes in pursuit velocity, while MST is thought to convey signals related to ongoing pursuit
[95]. FEF has also been implicated in pursuit gain control [96]: rapid variations
in target velocity have a greater effect if pursuit velocity is high. Similarly, pursuit onset is slower than pursuit offset. While earlier models assumed a switch
in pursuit pathways [97], one pathway for pursuit onset, and one for offset, a
continuous gain control is now discussed [98, 99].
Gain control may also be related to another relevant feature of smooth pursuit, its predictive nature. Despite the visual latency, pursuit tracking of simple
motions, such as ramp-like or sinusoidal target movement, can reach unity gain
with zero latency. Thus, some form of predictive control must take place.
Current models propose memory-based mechanisms [100] or adaptive control
implementing a predictive model of target dynamics [101] to explain the experimental findings. It is also not clear whether the predictive aspects of pursuit
control are implemented in cortical areas [101], or in the cerebellum [102], or
in both.
Since pursuit movements are almost always accompanied by saccadic eye
movements, a recent model proposes how switching between both modes can
be achieved together with predictive aspects of saccades and pursuit [103].
Ocular Motor Models
169
Combined Eye-Head Movements
Combined eye-head movements occur when the head is passively perturbed and the eyes compensate by the VOR. However, under natural circumstances saccadic gaze shifts and smooth pursuit consist of a combination of eye
and head movements, especially when the target eccentricity is too large to be
reached with the eye alone. Active combined eye-head movements raise several
questions [104], for example whether the VOR is active during the gaze shift, or
whether the local feedback loops in the saccadic system operate on gaze (eye
plus head) or eye-in-head signals. While it is usually accepted that the VOR is
shut off during the gaze shift, models on combined eye-head gaze shifts reached
different conclusions concerning the feedback loops: while most models
assume that gaze is the controlled variable [105–107], others propose that eye
and head movements are controlled separately with the head controller influencing the saccadic burst generator for the eye [108]. The 3-D behavior of eye
and head during gaze shifts has successfully been explained by an elegant
model [109] which shows how the eye may anticipate the final head position.
Finally, a recent neural network model showed how superior colliculus and
cerebellum may interact for combined eye-head gaze shifts [50].
Conclusions
Basically for all aspects of eye movement control, computational models do
exist. The vast majority of these models are based on a systems level approach or
use neural networks with firing rate neurons. While most models concentrate on
specific aspects of eye movements, there are some attempts to provide models
putting together several of the ocular motor subsystems. To be useful, future models need to pursue such a holistic approach to eye movements, and at the same
time try to link the systems level approach to the underlying neural mechanisms.
References
1
2
3
4
5
Quaia C, Optican LM: Dynamic eye plant models and the control of eye movements. Strabismus
2003;11:17–31.
Robinson DA: A quantitative analysis of extraocular muscle cooperation and squint. Invest
Ophthalmol Vis Sci 1975;14:801–825.
Miller JM, Robinson DA: A model of the mechanics of binocular alignment. Comput Biomed Res
1984;17:436–470.
Miller JM, Pavlovski DS, Shamaeva I: OrbitTM 1.8 Gaze Mechanics Simulation. Eidactics, Suite
404, 1450 Greenwich St., San Francisco, CA 94109, USA, 1999.
Haslwanter T, Buchberger M, Kaltofen T, Hoerantner R, Priglinger S: SEE: a biomechanical
model of the oculomotor plant. Ann N Y Acad Sci 2005;1039:9–14.
Glasauer
170
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Haustein W: Considerations on listing’s law and the primary position by means of amatrix description of eye position control. Biol Cybern 1989;60:411–420.
Porrill J, Warren PA, Dean P: A simple control law generates Listing’s positions in a detailed
model of the extraocular muscle system. Vision Res 2000;40:3743–3758.
Koene AR, Erkelens CJ: Properties of 3D rotations and their relation to eye movement control.
Biol Cybern 2004;90:410–417.
Warren PA, Porrill J, Dean P: Consistency of Listing’s law and reciprocal innervation with pseudoinverse control of eye position in 3-D. Biol Cybern 2004;91:1–9.
Wong AM: Listing’s law: clinical significance and implications for neural control. Surv
Ophthalmol 2004;49:563–575.
Ghasia FF, Angelaki DE: Do motoneurons encode the noncommutativity of ocular rotations?
Neuron 2005;47:281–293.
Schnabolk C, Raphan T: Modeling three-dimensional velocity-to position transformation in oculomotor control. J Neurophysiol 1994;71:623–638.
Tweed D, Misslisch H, Fetter M: Testing models of the oculomotor velocity-to-position transformation. J Neurophysiol 1994;72:1425–1429.
Raphan T: Modeling control of eye orientation in three dimensions; in Fetter M, Haslwanter T,
Misslisch H, Tweed D (eds): Three-Dimensional Kinematics of Eye, Head, and Limb Movements.
The Netherlands, Harwood Academic Publishing, 1997, pp 359–374.
Tweed D: Velocity-to-position transformation in the VOR and the saccadic system; in Fetter M,
Haslwanter T, Misslisch H, Tweed D (eds): Three-Dimensional Kinematics of Eye, Head, and
Limb Movements. The Netherlands, Harwood Academic Publishing, 1997, pp 375–386.
Quaia C, Optican LM: Commutative saccadic generator is sufficient to control a 3-D ocular plant
with pulleys. J Neurophysiol 1998;79:3197–3215.
Sklavos S, Porrill J, Kaneko CR, Dean P: Evidence for wide range of time scales in oculomotor
plant dynamics: implications for models of eye-movement control. Vision Res 2005;45:1525–1542.
Robinson DA: Integrating with neurons. Annu Rev Neurosci 1989;12:33–45.
Zee D, Yamazaki A, Butler PH, Gücer G: Effects of ablation of flocculus and paraflocculus on eye
movements in primate. J Neurophysiol 1981;46:878–899.
Glasauer S, Dieterich M, Brandt T: Central positional nystagmus simulated by a mathematical
ocular motor model of otolith-dependent modification of Listing’s plane. J Neurophysiol 2001;86:
1546–1554.
Crawford JD, Tweed DB, Vilis T: Static ocular counterroll is implemented through the 3-D neural
integrator. J Neurophysiol 2003;90:2777–2784.
Anastasio TJ: Nonuniformity in the linear network model of the oculomotor integrator produces
approximately fractional-order dynamics and more realistic neuron behavior. Biol Cybern 1998;
79:377–391.
Sklavos SG, Moschovakis AK: Neural network simulations of the primate oculomotor system IV.
A distributed bilateral stochastic model of the neural integrator of the vertical saccadic system.
Biol Cybern 2002;86:97–109.
Galiana HL, Outerbridge JS: A bilateral model for central neural pathways in vestibuloocular
reflex. J Neurophysiol 1984;51:210–241.
Green AM, Galiana HL: Hypothesis for shared central processing of canal and otolith signals.
J Neurophysiol 1998;80:2222–2228.
Seung HS: How the brain keeps the eyes still. Proc Natl Acad Sci USA 1996;93:13339–13344.
Seung HS, Lee DD, Reis BY, Tank DW: Stability of the memory of eye position in a recurrent network of conductance-based model neurons. Neuron 2000;26:259–271.
Koulakov AA, Raghavachari S, Kepecs A, Lisman JE: Model for a robust neural integrator. Nat
Neurosci 2002;5:775–782.
Loewenstein Y, Sompolinsky H: Temporal integration by calcium dynamics in a model neuron.
Nat Neurosci 2003;6:961–967.
Dean P, Porrill J, Stone JV: Decorrelation control by the cerebellum achieves oculomotor plant
compensation in simulated vestibulo-ocular reflex. Proc Biol Sci 2002;269:1895–1904.
Ebadzadeh M, Darlot C: Cerebellar learning of bio-mechanical functions of extra-ocular muscles:
modeling by artificial neural networks. Neuroscience 2003;122:941–966.
Ocular Motor Models
171
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
Glasauer S: Cerebellar contribution to saccades and gaze holding: a modeling approach. Ann NY
Acad Sci 2003;1004:206–219.
Porrill J, Dean P, Stone JV: Recurrent cerebellar architecture solves the motor-error problem. Proc
Biol Sci 2004;271:789–796.
Jürgens R, Becker W, Kornhuber HH: Natural and drug-induced variations of velocity and duration of human saccadic eye movements: evidence for a control of the neural pulse generator by
local feedback. Biol Cybern 1981;39:87–96.
Crawford JD, Guitton D: Visual-motor transformations required for accurate and kinematically
correct saccades. J Neurophysiol 1997;78:1447–1467.
Scudder CA: A new local feedback model of the saccadic burst generator. J Neurophysiol
1988;59:1455–1475.
Moschovakis AK: Neural network simulations of the primate oculomotor system. II. Frames of
reference. Brain Res Bull 1996;40:337–345.
Gancarz G, Grossberg S: A neural model of the saccade generator in the reticular formation.
Neural Netw 1998;11:1159–1174.
Jackson ME, Litvak O, Gnadt JW: Analysis of the frequency response of the saccadic circuit:
numerical simulations. Neural Netw 2001;14:1357–1376.
Moschovakis AK, Highstein SM: The anatomy and physiology of primate neurons that control
rapid eye movements. Annu Rev Neurosci 1994;17:465–488.
Bozis A, Moschovakis AK: Neural network simulations of the primate oculomotor system. III. An
one-dimensional, one-directional model of the superior colliculus. Biol Cybern 1998;79:215–230.
Arai K, Das S, Keller EL, Aiyoshi E: A distributed model of the saccade system: simulations of temporally perturbed saccades using position and velocity feedback. Neural Netw 1999;12:1359–1375.
Smith MA, Crawford JD: Distributed population mechanism for the 3-D oculomotor reference
frame transformation. J Neurophysiol 2005;93:1742–1761.
Grossberg S, Roberts K, Aguilar M, Bullock D: A neural model of multimodal adaptive saccadic
eye movement control by superior colliculus. J Neurosci 1997;17:9706–9725.
Brown JW, Bullock D, Grossberg S: How laminar frontal cortex and basal ganglia circuits interact
to control planned and reactive saccades. Neural Netw 2004;17:471–510.
Dean P: Modelling the role of the cerebellar fastigial nuclei in producing accurate saccades: the
importance of burst timing. Neuroscience 1995;68:1059–1077.
Enderle JD, Engelken EJ: Effects of cerebellar lesions on saccade simulations. Biomed Sci
Instrum 1996;32:13–21.
Lefevre P, Quaia C, Optican LM: Distributed model of control of saccades by superior colliculus
and cerebellum. Neural Netw 1998;11:1175–1190.
Quaia C, Lefèvre P, Optican LM: Model of the control of saccades by superior colliculus and
cerebellum. J Neurophysiol 1999;82:999–1018.
Wang X, Jin J, Jabri M: Neural network models for the gaze shift system in the superior colliculus
and cerebellum. Neural Netw 2002;15:811–832.
Schweighofer N, Arbib MA, Dominey PF: A model of the cerebellum in adaptive control of
saccadic gain. I. The model and its biological substrate. Biol Cybern 1996;75:19–28.
Schweighofer N, Arbib MA, Dominey PF: A model of the cerebellum in adaptive control of
saccadic gain. II. Simulation results. Biol Cybern 1996;75:29–36.
Ebadzadeh M, Darlot C: Cerebellar learning of bio-mechanical functions of extra-ocular muscles:
modeling by artificial neural networks. Neuroscience 2003;122:941–966.
Catz N, Dicke PW, Thier P: Cerebellar complex spike firing is suitable to induce as well as to
stabilize motor learning. Curr Biol 2005;15:2179–2189.
Marr D: A theory of cerebellar cortex. J Physiol 1969;202:437–470.
Albus JS: A theory of cerebellar function. Math Biosci 1971;10:5–61.
Niemeier M, Crawford JD, Tweed DB: Optimal transsaccadic integration explains distorted spatial
perception. Nature 2003;422:76–80.
Girard B, Berthoz A: From brainstem to cortex: computational models of saccade generation
circuitry. Prog Neurobiol 2005;77:215–251.
Glasauer S, Dieterich M, Brandt T: Three-dimensional modeling of static vestibulo-ocular
brainstem syndromes. Neuroreport 1998;9:3841–3845.
Glasauer
172
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
Glasauer S, Dieterich M, Brandt T: Simulation of pathological ocular counterroll and skew-torsion
by a 3-D mathematical model. Neuroreport 1999;10:1843–1848.
Galiana HL, Smith HL, Katsarkas A: Modelling non-linearities in the vestibulo-ocular reflex (VOR)
after unilateral or bilateral loss of peripheral vestibular function. Exp Brain Res 2001;137:369–386.
Cartwright AD, Gilchrist DP, Burgess AM, Curthoys IS: A realistic neural-network simulation of
both slow and quick phase components of the guinea pig VOR. Exp Brain Res 2003;149:299–311.
Merfeld DM, Young LR: The vestibulo-ocular reflex of the squirrel monkey during eccentric rotation and roll tilt. Exp Brain Res 1995;106:111–122.
Zupan LH, Merfeld DM, Darlot C: Using sensory weighting to model the influence of canal,
otolith and visual cues on spatial orientation and eye movements. Biol Cybern 2002;86:209–230.
Glasauer S: Interaction of semicircular canals and otoliths in the processing structure of the subjective zenith. Ann NY Acad Sci 1992;656:847–849.
Mergner T, Glasauer S: A simple model of vestibular canal-otolith signal fusion. Ann NY Acad Sci
1999;871:430–434.
Reymond G, Droulez J, Kemeny A: Visuovestibular perception of self-motion modeled as a
dynamic optimization process. Biol Cybern 2002;87:301–314.
Green AM, Galiana HL: Hypothesis for shared central processing of canal and otolith signals.
J Neurophysiol 1998;80:2222–2228.
Green AM, Angelaki DE: Resolution of sensory ambiguities for gaze stabilization requires a second neural integrator. J Neurosci 2003;23:9265–9275.
Green AM, Angelaki DE: An integrative neural network for detecting inertial motion and head orientation. J Neurophysiol 2004;92:905–925.
Robinson DA: Vestibular and optokinetic symbiosis: an example of explaining by modeling; in Baker
R, Berthoz A (eds): Control of Gaze by Brain Stem Neurons. Elsevier, Amsterdam, 1977, pp 49–58.
Furman JM, Hain TC, Paige GD: Central adaptation models of the vestibulo-ocular and optokinetic systems. Biol Cybern 1989;61:255–264.
Raphan T, Sturm D: Modeling the spatiotemporal organization of velocity storage in the vestibuloocular reflex by optokinetic studies. J Neurophysiol 1991;66:1410–1421.
Schweigart G, Mergner T, Barnes G: Eye movements during combined pursuit, optokinetic and
vestibular stimulation in macaque monkey. Exp Brain Res 1999;127:54–66.
Hirata Y, Takeuchi I, Highstein SM: A dynamical model for the vertical vestibuloocular reflex and
optokinetic response in primate. Neurocomputing 2003;52–54:531–540.
Miles FA, Lisberger SG: Plasticity in the vestibulo-ocular reflex: a new hypothesis. Annu Rev
Neurosci 1981;4:273–299.
Blazquez PM, Hirata Y, Highstein SM: The vestibulo-ocular reflex as a model system for motor
learning: what is the role of the cerebellum? Cerebellum 2004;3:188–192.
Gomi H, Kawato M: Adaptive feedback control models of the vestibulocerebellum and spinocerebellum. Biol Cybern 1992;68:105–114.
Lisberger SG: Neural basis for motor learning in the vestibuloocular reflex of primates. III.
Computational and behavioral analysis of the sites of learning. J Neurophysiol 1994;72:974–998.
Galiana HL, Green AM: Vestibular adaptation: how models can affect data interpretations.
Otolaryngol Head Neck Surg 1998;119:231–243.
Hepp K: Oculomotor control: Listing’s law and all that. Curr Opin Neurobiol 1994;4:862–868.
Lee C, Zee DS, Straumann D: Saccades from torsional offset positions back to listing’s plane.
J Neurophysiol 2000;83:3241–3253.
Schneider E, Glasauer S, Dieterich M, Kalla R, Brandt T: Diagnosis of vestibular imbalance in the
blink of an eye. Neurology 2004;63:1209–1216.
Misslisch H, Tweed D, Fetter M, Sievering D, Koenig E: Rotational kinematics of the human
vestibulo-ocular reflex III. Listing’s law. J Neurophysiol 1994;72:2490–2502.
Palla A, Straumann D, Obzina H: Eye-position dependence of three-dimensional ocular rotationaxis orientation during head impulses in humans. Exp Brain Res 1999;129:127–133.
Krauzlis RJ: The control of voluntary eye movements: new perspectives. Neuroscientist 2005;11:
124–137.
Thier P, Ilg U: The neural basis of smooth-pursuit eye movements. Curr Opin Neurobiol 2005;15:
645–652.
Ocular Motor Models
173
88 Krauzlis RJ, Lisberger SG: A model of visually-guided smooth pursuit eye movements based on
behavioral observations. J Comput Neurosci 1994;1:265–283.
89 Lisberger SG, Morris EJ, Tychsen L: Visual motion processing and sensory-motor integration for
smooth pursuit eye movements. Annu Rev Neurosci 1987;10:97–129.
90 Tabata H, Yamamoto K, Kawato M: Computational study on monkey VOR adaptation and smooth
pursuit based on the parallel control-pathway theory. J Neurophysiol 2002;87:2176–2189.
91 Robinson DA, Gordon JL, Gordon SE: A model of the smooth pursuit eye movement system. Biol
Cybern 1986;55:43–57.
92 Yasui S, Young LR: Perceived visual motion as effective stimulus to pursuit eye movement system.
Science 1975;190:906–908.
93 Marti S, Straumann D, Glasauer S: The origin of downbeat nystagmus: an asymmetry in the distribution of on-directions of vertical gaze-velocity Purkinje cells. Ann N Y Acad Sci 2005;1039:
548–553.
94 Tanaka M: Involvement of the central thalamus in the control of smooth pursuit eye movements.
J Neurosci 2005;25:5866–5876.
95 Ono S, Das VE, Economides JR, Mustari MJ: Modeling of smooth pursuit-related neuronal
responses in the DLPN and NRTP of the rhesus macaque. J Neurophysiol 2005;93:108–116.
96 Chou IH, Lisberger SG: The role of the frontal pursuit area in learning in smooth pursuit eye
movements. J Neurosci 2004;24:4124–4133.
97 Huebner WP, Saidel GM, Leigh RJ: Nonlinear parameter estimation applied to a model of smooth
pursuit eye movements. Biol Cybern 1990;62:265–273.
98 Keating EG, Pierre A: Architecture of a gain controller in the pursuit system. Behav Brain Res
1996;81:173–181.
99 Nuding U, Glasauer S, Büttner U: Nonlinear Systems Analysis of the Smooth-Pursuit Gain-Control
Mechanism. Abstract for the Japan-Germany Symposium on Computational Neuroscience, Tokio,
2006
100 Barnes G, Grealy M: Modelling prediction in ocular pursuit; in Becker W, Deubel H, Mergner T
(eds): Current Oculomotor Research. New York, Plenum Press, 1999, pp 97–107.
101 Shibata T, Tabata H, Schaal S, Kawato M: A model of smooth pursuit in primates based on learning the target dynamics. Neural Netw 2005;18:213–224.
102 Kettner RE, Suh M, Davis D, Leung HC: Modeling cerebellar flocculus and paraflocculus
involvement in complex predictive smooth eye pursuit in monkeys. Ann N Y Acad Sci 2002;978:
455–467.
103 Lee WJ, Galiana HL: An internally switched model of ocular tracking with prediction. IEEE Trans
Neural Syst Rehabil Eng 2005;13:186–193.
104 Crawford JD, Martinez-Trujillo JC, Klier EM: Neural control of three-dimensional eye and head
movements. Curr Opin Neurobiol 2003;13:655–662.
105 Galiana HL, Guitton D: Central organization and modeling of eye-head coordination during orienting gaze shifts. Ann N Y Acad Sci 1992;656:452–471.
106 Goossens HH, Van Opstal AJ: Human eye-head coordination in two dimensions under different
sensorimotor conditions. Exp Brain Res 1997;114:542–560.
107 Wagner R, Galiana HL: Hybrid gaze control: ffusing visual/vestibular senses, slow/fast processes,
and eye/head coordination. Proc 31st Int Symp Robotics ISR 2000;220–225.
108 Freedman EG: Interactions between eye and head control signals can account for movement kinematics. Biol Cybern 2001;84:453–462.
109 Tweed D: Three-dimensional model of the human eye-head saccadic system. J Neurophysiol
1997;77:654–666.
Stefan Glasauer
Department of Neurology
Klinikum Grosshadern
Marchioninistrasse 15
DE–81377 Munich (Germany)
Tel. 49 89 7095 4835, Fax 49 89 7095 4801, E-Mail [email protected]
Glasauer
174
Straube A, Büttner U (eds): Neuro-Ophthalmology.
Dev Ophthalmol. Basel, Karger, 2007, vol 40, pp 175–192
Therapeutic Considerations for Eye
Movement Disorders
A. Straube
Department of Neurology, University of Munich, Munich, Germany
Abstract
Advances made in understanding the pathophysiology of eye movement disorders have
only recently with the publication of the first well-planned studies been translated into better
treatment strategies. The following chapter summarizes the pharmacological treatment options
for a variety of oculomotor syndromes. Cortisone is useful, for example, for acute vestibular
neuritis to improve the restitution of the labyrinthine function. For the widespread benign
paroxysmal positioning nystagmus, a series of liberatory movements that free the semicircular
canal from the causative otoconia is now a well-established therapy. Treatment for the central
vestibular syndrome of up- and downbeat nystagmus consists of drugs like the potassium canal
blocker 4-aminopyridine, which influence the cerebellar circuits involved in the disorder’s
pathophysiology. Acquired pendular nystagmus, one of the oculomotor syndromes often caused by multiple sclerosis, results in the severe impairment of reduced visual acuity. Memantine,
a weak NMDA antagonist, has now been proven effective here. Finally, anticonvulsants like
carbamazepine are the drugs of choice for disorders involving a nerve-blood vessel contact that
induces symptoms of vestibular paroxysmia or superior oblique myokymia.
Copyright © 2007 S. Karger AG, Basel
The common goal of voluntary as well as most reflexive eye movements is
to stabilize images on the retina (especially the central fovea, the area of the
highest resolution) in order to prevent retinal slip. Abnormal involuntary eye
movements may cause excessive motion of images on the retina, leading to
blurred vision and to the illusion that the perceived world is moving (oscillopsia). Clinical examination of such pathological eye movements often allows the
topological diagnosis of the lesion causing the abnormalities. Despite our extensive knowledge of the anatomy and physiology of eye movements, very little is
known about pharmacological aspects of the ocular motor system. Thus, our
treatment options for abnormal eye movements remain fairly limited. Most drug
treatments are based on case reports. Only recently have a few controlled trials
Table 1. Practical treatment of oculomotor signs/syndromes
Ocular sign/disorder
Substance
Dosage
Contraindications
Vestibular neuritis
Acute: dimenhydrinate
Prednisolone
50–100 mg
1 mg/kg body weight
per day for 5 days,
or starting with 100 mg
General
contraindications for
cortisone and
dimenhydrinate
Menière’s disease
Acute: dimenhydrinate
Prophylaxis: betahistine
Gentamicin
50–100 mg
8/16–32 mg/day
Locally in the middle ear
General
contraindications for
dimenhydrinate and
betahistine
Ototoxic (hearing loss)
Vestibular paroxysmia
Carbamazepine
2 ⫻ 200–600 mg slowrelease formulation
3–4 ⫻ 300–600 mg
Drowsiness, ataxia
Vertigo, dry mouth
Enzyme induction
Drowsiness, ataxia
Vertigo, dry mouth
Enzyme induction
Gabapentin
Gabapentin
2 ⫻ 200–600 mg slowrelease formulation
3–4 ⫻ 300–600 mg
Downbeat nystagmus
Clonazepam
Baclofen
4-aminopyridine
2 ⫻ 0.5–1 mg daily
3 ⫻ 5–10 mg daily
3 ⫻ 10 mg
Sedation
Ataxia, weakness
Seizures
Upbeat nystagmus
Baclofen
4-aminopyridine
3 ⫻ 5–10 mg
Sedation; weakness
Seizures
Periodic alternating
nystagmus
Baclofen
3 ⫻ 5–10 mg
Sedation
Ataxia, weakness
Acquired pendular
nystagmus
Memantine
Gabapentin
3–4 ⫻ 10 mg
3–4 ⫻ 300–600 mg
Somnolence, confusion,
dry mouth, edema
Superior oblique
myokymia
Carbamazepine
been published (overview in [1–5]). Several drugs can themselves cause nystagmus, for example, anticonvulsants, sedatives, and antihistaminergic drugs
induce gaze-evoked nystagmus; nicotinergic substances induce a nystagmus that
can disclose an underlying vestibular tone imbalance; and intoxication due to
lithium or phenytoin can lead to downbeat nystagmus as well as opsoclonus.
This chapter summarizes the most recent publications on pharmacological
treatment options for the different eye movement syndromes and also gives a
short overview of the clinical aspects and pathophysiology of these syndromes.
Eye movement syndromes are generally differentiated into those characterized by a pathological jerk nystagmus, pendular nystagmus, atypical nystagmus,
or saccadic oscillations. All interfere with the normal foveal fixation of a target.
Straube
176
Peripheral and Central Vestibular Disorders
Pathophysiology
The vestibulo-ocular reflex (VOR) is one of the most basic reflexes. It can
even be observed in fish. After a short latency, the VOR generates eye rotations
in the same plane as the head rotation that elicits them [6]. To do this, the oculomotor system uses information provided by the three pairs of orthogonally
oriented semicircular canals. The right and left sides work together in a tradeoff
manner (i.e. when one labyrinth increases the neuronal activity, the other
decreases it) [6]. Disorders of the vestibular periphery cause nystagmus in a
direction that is determined by the pattern of labyrinthine semicircular canals
involved [6]. The complete, unilateral loss of one labyrinth causes a mixed horizontal-torsional nystagmus that is suppressed by visual fixation. Another consequence of peripheral vestibular lesions is a change in the size (gain) of the
overall dynamic VOR response, i.e. the gain of the VOR for head movements
toward the affected ear becomes smaller, and the subject has to refixate the
object after the head movement by a saccade. The head-impulse test uses this
feature clinically. As a result, patients may complain of oscillopsia during rapid
head movements.
Central vestibular disorders are caused by lesions of pathways or areas
involved in the adjustment of the VOR (e.g. the cerebellar connections to the
vestibular nuclei) [2, 6]. These lesions result in upbeat, downbeat, torsional nystagmus or central positional vertigo.
Vestibular Neuritis
Clinical Aspects
The presenting sign of vestibular neuritis is an acute onset of severe rotatory vertigo that lasts for hours to days [7]. Hearing loss is normally not a sign
of vestibular neuritis [7]. The horizontal contraversive beating spontaneous nystagmus has a torsional component and causes postural instability with a tendency to fall to the ipsiversive side.
Etiology
Recent findings support the view that an inflammation of parts of the
vestibular nerve is the cause of vestibular neuritis and acute labyrinthitis. Most
studies have shown the presence of latent herpes simplex virus type 1 in human
vestibular ganglia [8, 9]. The imaging of 2 patients with vestibular neuritis using
3-tesla MRI and high-dose contrast medium revealed isolated enhancement of
Treatment of Oculomotor Disorders
177
the vestibular nerve only on the affected side [10], a sign of a disturbed bloodbrain barrier due to the inflammation.
Treatment
Treatment options consist primarily of vestibular sedatives (e.g. dimenhydrinate, 50–100 mg) [11] in the first 3 days administered in combination with
steroids. Kitahara et al. [12] examined 36 patients who were treated for up to 2
years after onset either with or without steroids. Although the treatment onset
was rather late, the group on steroids showed a tendency for more improvement. A more detailed study published in 2004 [13] reported on a total of 141
patients who were randomized within 3 days after onset of symptoms to one of
four treatment options – placebo, methylprednisolone (starting with 100 mg
daily), valacyclovir , or a combination of valacyclovir and methylprednisolone.
The main finding of this study was that the groups receiving methylprednisolone had a better final outcome (caloric testing showed about 60%
recovery of peripheral vestibular function) after 12 months than the placebo/
valacyclovir groups (36–39%). The combination of valacyclovir and
methylprednisolone provided no additional benefit. It has also been reported
that patients should be mobilized early to accelerate the recovery of vestibulospinal function [14].
Menière’s Disease
Clinical Aspects
Menière’s disease is characterized by spontaneous attacks of vertigo, fluctuating sensorineural hearing loss, aural fullness, and tinnitus that lasts for
hours to a few days [11, 15]. Key symptoms of such an attack are a horizontal
rotatory nystagmus, postural instability, and nausea/vomiting. The symptoms
only rarely include the opposite ear. Only 5 of 101 patients in a 2-year followup developed symptoms in the contralateral ear [16]. In addition to a typical
history, the finding of a unilateral hearing deficit on the audiogram and a
reduced reaction to caloric vestibular testing also support the diagnosis [15].
Etiology
The cause of Menière’s disease is still not known. It has been shown
histopathologically that endolymphatic hydrops and concomitant distortion of
the membranous labyrinth can cause Menière’s disease [15]. Other candidates
include immunological causes and inflammation. An increased prevalence of
migraine has also been described in patients with Menière’s disease [17]. The
pathophysiological link between both diseases may be allergic mechanisms [17].
Straube
178
Treatment
In the daily practice it is useful to administer vestibular sedatives such as
dimenhydrinate during acute self-limiting attacks [11, 15, 18]. One popular
prophylactic treatment regimen tries to reduce the endolymph by low-salt diet
or diuretics; another option is to administer betahistine (8–16 mg/day). Higher
dosages (up to 3 ⫻ 48 mg) seem to be more effective than lower ones [15],
although the efficacy of betahistine has not been proven [18]. No randomized
studies on these treatment options have yet been conducted. A retrospective survey of the outcome of 22 patients revealed that intratympanic steroid perfusion
was only of short-term benefit [19]. A systematic review of published uncontrolled studies found that gentamicin reduced vestibular function in the treated
ear and achieved overall vertigo control (complete or substantial control) in
89% of the patients (range 73–100%); hearing worsened in 26% (0–90%) [20].
A meta-analysis examined the application of gentamicin, which poses the lowest risk of hearing loss [21]. The titration technique with daily or weekly doses
until onset of vestibular symptoms, change in vertigo, or hearing loss showed
the best rate of vertigo control. Complete ablation of the vestibular function is
not typically required for such control [21], as this is also not achieved for a
long time with gentamicin instillation [22].
Superior Canal Dehiscence Syndrome
Clinical Aspects
Patients with a so-called superior canal dehiscence syndrome [23, 24]
complain of vertigo and oscillopsia, which are induced by intense sound stimuli, a Valsalva maneuver, or in some cases even the heart beat, when nystagmus
beats synchronously with the pulse in the plane of the involved vestibular canal
[25]. The accompanying jerk nystagmus has vertical and torsional components
[23, 24].
Etiology
The superior canal dehiscence syndrome is a special form of inner-ear perilymph fistula [23]. High-resolution computed tomography has shown that the
cause is a missing bone coverage between the superior canal and the middle cranial
fossa. This results in increased pressure on the superior canal when the intracranial
pressure increases. In some patients, the dehiscence may be bilateral [23].
Treatment
Surgical plugging of the canal or resurfacing of the dehiscence can prevent
the pressure-induced oscillopsia [23]. Aftereffects are not long lasting.
Treatment of Oculomotor Disorders
179
Vestibular Paroxysmia
Clinical Aspects
If patients complain of short, repeated, paroxysmal attacks of vertigo lasting for seconds to minutes, which can sometimes be provoked by particular
head positions, a vestibular paroxysmia is suspected. Spontaneous nystagmus is
observed during the attack [26]. Other possible symptoms include unilateral
tinnitus, hyperacusis, or facial contractions. Clinical examination in the attackfree intervals may in some patients reveal slight signs of permanent vestibular
deficit, hypoacusis, or facial paresis on the affected side [26, 27].
Etiology
High-resolution MR imaging may show the compression of the 8th nerve
by an artery (most often AICA) or more rarely by a vein in the region of the root
entry zone of the vestibular nerve. However, such a result does not prove the
diagnosis of paroxysmia, since such contacts can also be found in healthy subjects. The proposed mechanism is similar to that of nerve-blood vessel contact
in trigeminal neuralgia.
Treatment
As in other neurovascular compression syndromes, an anticonvulsant (carbamazepine, slow-release formulation, 2 ⫻ 200 to 2 ⫻ 800 mg p.o. daily; phenytoin
1 ⫻ 250 to 1 ⫻ 400 mg p.o. daily; lamotrigine 100–400 mg p.o. daily) should be
given initially [26, 27]. All drugs should be first administered in the lowest recommended dose and only gradually increased in order to prevent side effects. In general, a positive response to antiepileptic drugs can be achieved with low dosages
and after a few days. If the symptoms do not resolve, a surgical approach may be
considered [28]. There are no satisfactory follow-up studies on any of these treatment options, and the diagnostic criteria have not yet been fully established.
Downbeat Nystagmus
Clinical Aspects
Downbeat nystagmus is a central nystagmus that occurs during fixation and
increases on downward gaze, especially on lateral gaze [6, 29, 30]. The head
position relative to the earth’s vertical may play a role in some patients [31].
Convergence may suppress or enhance the nystagmus or even change its nystagmus toward an upbeat nystagmus in certain patients. Most patients also have
vestibulocerebellar ataxia. Lesions that cause downbeat nystagmus occur in the
vestibular cerebellum bilaterally and rarely in the underlying medulla [6].
Straube
180
Etiology
The main pathophysiological mechanism of downbeat nystagmus is a central imbalance of the vertical VOR [28] in combination with an abnormality of
the vertical-torsional gaze-holding mechanism – the ‘neural integrator for eye
movements’ [32]. The neural integrator is a network consisting of the medial
vestibular complex and its connection to the cerebellum. The most common
cause of downbeat nystagmus is cerebellar degeneration (hereditary, sporadic, or
paraneoplastic). Recently, a report was published on a patient with glutamic-acid
decarboxylase antibodies and a downbeat nystagmus in addition to signs of a
stiff person syndrome [33]. Other important causes are Arnold-Chiari malformation and drug intoxication (especially anticonvulsants and lithium). In everyday
practice, cerebellar atrophy, Arnold-Chiari malformation, various cerebellar
lesions (multiple sclerosis, vascular, tumors), and idiopathic causes account for
approximately one fourth each of cases of downbeat nystagmus [30, 34].
Treatment
Since a loss of inhibitory cerebellar influence on the vestibular nuclei is one
of the main pathophysiological mechanisms of downbeat nystagmus, it seems
expedient to investigate substances that may help re-establish such cerebellar
influence on the brainstem. The vestibulocerebellar efferences to the vestibular
nuclei are gabaergic; thus, most drugs investigated were GABA-A agonists. The
GABA-A agonist clonazepam (2 ⫻ 1 mg daily) was recently reported to have a
positive effect on so-called idiopathic downbeat nystagmus (e.g. no pathological
findings on MRI) [35]. This supports older observations that clonazepam (0.5 mg
p.o. three times daily) and the GABA-B agonist baclofen (10 mg p.o. three times
daily) [36, 37] reduce the velocity in downbeat nystagmus. Gabapentin (an alpha2-delta calcium channel antagonist) [38] might also have weak positive effects
and reduces in some patients downbeat nystagmus. A placebo-controlled, doubleblind study with a crossover design investigated the effect of the potassium channel blocker 3,4-diaminopyridine in 17 patients with downbeat nystagmus [39].
Potassium channel blockers can increase the spontaneous firing rate of the cerebellar Purkinje cells and therefore the inhibitory effect on the vestibular nuclei.
On average, the potassium channel blocker reduced the slow-phase velocity of the
nystagmus by more than 50% [39]. The same group reported a similar effect of 4aminopyridine (10 mg orally) in a single patient [40]. This substance penetrates
the blood-brain barrier better than 3,4-diaminopyridine and may therefore be
more effective. The potassium channel blockers also seem to have a specific
influence on the gravity-dependent component of the vertical velocity bias of
downbeat nystagmus [41]. This might explain why patients who do not show such
a vertical velocity bias and have more offset in the null position (e.g. the position
at which the nystagmus velocity is minimal) do not seem to benefit in the same
Treatment of Oculomotor Disorders
181
way from the treatment. The patients in whom the influence of the gravity-dependent component is more pronounced also seem to benefit more from a supine
head position [41]. In isolated patients with a craniocervical anomaly, a surgical
decompression involving the removal of part of the occipital bone in the region of
the foramen magnum was beneficial [42, 43].
As a practical rule, treatment should be started by trying clonazepam. If
this option does not improve the nystagmus satisfactorily, 4-aminopyridine
(10 mg three times daily) should be tried.
Upbeat Nystagmus
Clinical Aspects
Upbeat nystagmus occurs when the eyes are close to the central position
and usually increases during upgaze [44]. The nystagmus usually disrupts vertical smooth pursuit. In some patients, the upbeat nystagmus changes to downbeat nystagmus during convergence. An upbeat nystagmus has in general a
better prognosis than a downbeat nystagmus and is often only a temporary
problem [11].
Etiology
A central vestibular imbalance is involved in upbeat nystagmus as in
downbeat nystagmus. The most frequently seen lesions are medullary lesions
[44]. Probable causes of upbeat nystagmus are lesions in the ascending pathways from the anterior canals (and/or the otoliths) at the pontomesencephalic or
pontomedullary junction, near the perihypoglossal nuclei [44, 45]. The main
causes are multiple sclerosis, tumors of the brainstem, Wernicke’s encephalopathy, intoxication (e.g. nicotine), and seldom cerebellar degeneration.
Treatment
Treatment with baclofen (5–10 mg p.o. three times daily) caused an
improvement in several patients [37]. Probably 4-aminopyridine will also
improve the upbeat nystagmus in some patients [46].
Seesaw Nystagmus
Clinical Aspects
Seesaw nystagmus is a rare pendular or jerk oscillation around the line of gaze.
A half-cycle consists of elevation and intorsion of one eye with synchronous
Straube
182
depression and extorsion of the other eye [6, 47]. During the next half-cycle,
there is a reversal of the vertical and torsional movements. The frequency is
lower in the pendular (2–4 Hz) than in the jerk variety.
Etiology
Jerk hemi-seesaw nystagmus has been attributed to unilateral mesodiencephalic lesions [48], which affect the interstitial nucleus of Cajal and its
vestibular afferents from the vertical semicircular canals [49]. The pendular
form is associated with lesions that affect the optic chiasm; it can be congenital.
Loss of crossed visual input seems to be the crucial element in the pathophysiology of pendular seesaw nystagmus [50].
Therapeutic Recommendations
Alcohol was reported to have a beneficial effect (1.2 g/kg body weight) in
2 patients [51, 52], as does clonazepam [1]. More recently, Averbuch-Heller
reported on 3 patients with a seesaw component to their pendular nystagmus,
who improved with gabapentin [53].
Periodic Alternating Nystagmus
Clinical Aspects
Periodic alternating nystagmus is a spontaneous horizontal beating nystagmus which periodically changes direction after 100–240 s [6]. Consequently,
the patients complain of increasing/decreasing oscillopsia. When the nystagmus amplitude gradually decreases, the nystagmus reverses its direction, and
then the amplitude increases again. Periodic alternating nystagmus also disrupts
visual fixation. During the nystagmus, patients often complain of increasing/
decreasing oscillopsia [11].
Etiology
Animal and human experiments show that the disinhibition of the GABAergic velocity-storage mechanism, which is mediated by the vestibular nuclei,
is responsible for the nystagmus [54, 55]. Patients with periodic alternating
nystagmus commonly have vestibulocerebellar lesions or, very rarely, intoxications [56, 57]. The underlying etiologies are craniocervical anomalies,
multiple sclerosis, cerebellar degenerations or tumors, anticonvulsant therapy,
and bilateral visual loss. Recently, autoantibodies directed against glutamic
acid decarboxylase were described in a patient with progressive cerebellar
ataxia and periodic alternating nystagmus, suggesting an autoimmune mechanism [58].
Treatment of Oculomotor Disorders
183
Therapeutic Recommendations
In general, periodic alternating nystagmus does not improve spontaneously. Several case reports describe a positive effect of baclofen, a GABA-B
agonist, in a dose of 5–10 mg p.o. three times daily [1, 57, 59, 60].
Other Supranuclear Oculomotor Disorders
Acquired Pendular Nystagmus
Clinical Aspects
Acquired pendular nystagmus is a visually distressing form of nystagmus,
in which oscillopsia and impaired vision are common. Acquired pendular nystagmus is a quasi-sinusoidal oscillation that may have a predominantly horizontal, vertical, or mixed trajectory (i.e. circular, elliptical, or diagonal); it can be
either predominantly monocular or predominantly binocular [6, 61, 62]. The
frequency of this type of nystagmus is 2–7 Hz [63]. It is often associated with
head titubation (a kind of head tremor with small amplitude and not synchronized with the nystagmus), trunk and limb ataxia, or visual impairment. The
amplitude is small and can often be only seen with an ophthalmoscope.
Etiology
Acquired pendular nystagmus occurs with several myelin disorders (e.g. multiple sclerosis, toluene abuse, Pelizaeus-Merzbacher disease). It is also a component
of the syndrome of oculopalatal tremor (myoclonus) and is observed in Whipple’s
disease [6, 62]. Common etiologies in adults are multiple sclerosis and brainstem
stroke [62, 64]. On the basis of observations that the nystagmus is often dissociated
and that eye movements other than optokinetic nystagmus and voluntary saccades
are also disturbed, it has been suggested that a lesion in the brainstem near the oculomotor nuclei is the cause [61]. Alternative candidates such as an inhibition of the
inferior olive due to lesions of the ‘Mollaret triangle’ or an instability of the gazeholding network (neural integrator) have also been proposed [64].
Treatment
The first reported treatment option was anticholinergic treatment with trihexyphenidyl (20–40 mg p.o. daily) [65, 66]; however, Leigh et al. [67] reported
in a double-blind study that only 1 of 6 patients improved during this oral treatment. Starck et al. [68] reported that nystagmus improved with memantine, a glutamate antagonist, in all 9 tested patients (15–60 mg p.o. daily). Gabapentin, an
alpha-2-delta calcium channel antagonist, substantially improved the nystagmus
(and visual acuity) in 10 of 15 patients (3 ⫻ 300–400 mg daily) [53]. Gabapentin
Straube
184
was superior to vigabatrin in a small series of patients [69]; others have also
reported an improvement due to gabapentin [70, 71]. Cannabis, which acts as a
retrograde presynaptic inhibitory transmitter and in this way is similar to
gabapentin, which also acts presynaptically, was recently reported to be equally
effective [72, 73]. A bilateral retrobulbar botulinum toxin injection was successfully used in some patients to induce a complete external ophthalmoplegia,
thereby diminishing the acquired pendular nystagmus [74, 75]; however, it proved
unsatisfactory in other patients [76].
Opsoclonus and Ocular Flutter
Clinical Aspects
Opsoclonus consists of repetitive bursts of conjugate saccadic oscillations,
which have horizontal, vertical, and torsional components. During each burst of
these high-frequency oscillations, the movement is continuous, without any
intersaccadic interval. These oscillations are often triggered by eye closure, convergence, pursuit, and saccades; amplitudes range up to 2–15⬚ [6]. The same pattern is restricted in ocular flutter to the horizontal plane. The ocular symptoms
are often accompanied by cerebellar signs, such as gait and limb myoclonus (the
‘dancing feet, dancing eyes syndrome’). Most of the patients complain of very
disturbing oscillopsias during these saccadic oscillations [6, 77].
Etiology
A functional disturbance of active saccadic suppression by the pontine
omnipause neurons is the most probable pathophysiological mechanism. Since
histological abnormalities of these neurons have not been shown [78], a functional lesion of the glutaminergic cerebellar projections from the fastigial
nuclei to the omnipause cells is the likely cause of their disinhibition.
Opsoclonus can be observed in benign cerebellar encephalitis (postviral, e.g.
Coxsackie B37; postvaccinal) or as a paraneoplastic symptom (infants, neuroblastoma; adults, carcinoma of the lung, breast, ovary, or uterus) [77].
Treatment
In addition to therapy for any underlying process such as tumor or
encephalitis, treatment with immunoglobulins or prednisolone may occasionally be effective [79]. Four of 5 patients with square-wave oscillations, probably
a related fixation disturbance, showed an improvement on therapy with valproic
acid [80]. In single cases, an improvement has been observed during treatment
with propranolol (40–80 mg p.o. three times daily), nitrazepam (15–30 mg p.o.
daily), and clonazepam (0.5–2.0 mg p.o. three times daily) [1, 77, 81].
Treatment of Oculomotor Disorders
185
Infranuclear Oculomotor Disorders
Superior Oblique Myokymia
Clinical Aspects
Superior oblique myokymia is characterized by paroxysmal monocular
high-frequency oscillations [6, 82, 83]. These oscillations are mainly torsional
in the primary gaze position and in abduction, but when the eyes are in adduction the oscillations have a vertical component [83]. The patients usually complain of oscillopsia during these paroxysmal attacks.
Etiology
The pathophysiology of this condition is not totally clear, but vascular compression of the 4th nerve [84, 85] may be responsible. The same mechanism is
suspected in vestibular paroxysmia. Alternative causes may include spontaneous
discharges in the 4th nerve nucleus or of the superior oblique muscle.
Treatment
Like trigeminal neuralgia (another putative neurovascular compression
disorder), superior oblique myokymia frequently remits spontaneously for periods of a few months to years. If it does not, a number of drugs have been
reported to be beneficial, including the anticonvulsants carbamazepine [82] and
gabapentin [86, 87]. In chronic cases that did not improve with anticonvulsants,
tenotomy of the superior oblique muscle has been performed, but usually it
necessitates inferior oblique surgery as well. Surgical decompression of the 4th
nerve has also been reported to help, but this treatment should be reserved for
the most vexing cases, as it may result in superior oblique palsy [88, 89] and
bears a risk of suboccipital craniotomy. Treatment should always be started with
one of the anticonvulsants.
Benign Paroxysmal Positional Vertigo
Clinical Aspects
One of the most frequent types of vertigo as well as oculomotor syndromes
is benign paroxysmal positional vertigo (BPPV) [11, 90]. BPPV occurs when
particles in one of the semicircular canals move freely when the head is turned
in the plane of the affected canal. Theoretically, all three canals can be affected,
but in practice the posterior vertical canal (p-BPPV) is affected most often [11,
90]. The positioning of the head towards the affected canal plane induces a rotatory nystagmus that beats to the undermost ear with a crescendo-decrescendo
Straube
186
time course. Horizontal BPPV (h-BPPV) is characterized by a nonfatiguable
bilateral horizontal beating nystagmus that occurs while the patient lies supine
and turns his/her head to the side of the affected canal [11, 91].
h-BPPV was reported to occur in about 12% of a series of 300 patients [91].
BPPV of the anterior vertical canal probably occurs much more seldom
than that of the posterior or horizontal canal. The associated nystagmus characteristically has less of a torsional component than in p-BPPV [92].
Etiology
BPPV is caused by the displacement of calcium-rich particles from the
utricle into one of the canals [11, 90]. These particles change the function of the
canal, which normally only detects angular acceleration. If the head is positioned in the plane of the affected canal, the particles move within the semicircular canal according to the gravitational force, causing an endolymph flow that
is followed by a displacement of the cupula of the canal. Predisposing conditions are older age, head trauma, labyrinthitis, Menière’s disease, migraine, or
longer periods of immobilization.
A differential diagnosis of positional vertigo is migrainous vertigo; it may
mimic BPPV. Several groups recently reported an association of migraine and
vertigo. A study published this year classified 10 patients of 362 consecutive
patients who had positional vertigo as well as migrainous. Diagnostic factors
that distinguish the migrainous form from idiopathic positional vertigo are
short duration of the attacks, frequent recurrences, early manifestation in life,
other migrainous symptoms like photo-/phonophobia and headache during the
vertigo episodes, and atypical nystagmus [93]. Central positional vertigo due to
lesions of the vestibular cerebellum can mimic peripheral positional vertigo
sometimes, but normally the nystagmus is less pronounced and does not show
habituation [94].
Treatment
Treatment consists of so-called liberatory maneuvers. The rationale is to
redirect the particles out of the affected canal. There are two repositioning treatments for p-BPPV: Epley’s and Semont’s maneuvers. Both require active movements by the patients; this may be difficult for older patients. Another possibly
effective therapeutic procedure is the so-called prolonged forced position. It
requires the patient to maintain a position in which the affected ear remains
uppermost for several hours. This is thought to allow the floating particles to
slip out of the canal into labyrinthine recesses, where they no longer have any
impact on the cupula [95].
The question as to which liberatory maneuver is superior for benign
positional paroxysmal vertigo of the posterior canal was recently addressed in
Treatment of Oculomotor Disorders
187
several published studies and meta-analyses. Updating the Cochrane database,
Hilton and Pinder [96] reanalyzed randomized trials of adult patients with
p-BPPV to determine the extent of improvement of the vertigo after the Epley
maneuver, no treatment, or other repositioning maneuvers. Using only 3 of 15
trials for the final analysis, the authors concluded that there is some evidence
that the Epley maneuver is a safe and effective treatment option, but the available data were insufficient to compare the Epley maneuver with other repositioning maneuvers [96]. Another study on the best liberatory maneuver
compared the self-applied Semont maneuver with the self-applied Epley procedure. Patients who performed the Epley maneuver had a significantly higher
success rate than the group using the Semont maneuver (95 vs. 58%). Thus, the
Epley procedure, as a home-based self-applied liberatory maneuver, seems to
be the better choice [97].
For h-BPPV, the maneuver involves a 360⬚ horizontal head and body (‘barbecue’) rotation (e.g. rotation about the longitudinal body axis in a supine
position) [91].
A small group of patients who were followed for 60 months had a recurrence rate of 26% for posterior canal and 50% for horizontal canal BPPV [98].
Patients with trauma or labyrinthitis had lower initial success rates of the repositioning maneuver, whereas patients with endolymphatic hydrops were predicted to have higher recurrence rates [99, 100].
References
1
2
3
4
5
6
7
8
9
10
11
12
Carlow TJ: Medical treatment of nystagmus and ocular motor disorders. Int Ophthalmol Clin
1986;26:251–264.
Straube A, Leigh RJ, Bronstein A, Heide W, Riordan-Eva P, Tijssen CC, Dehaene I, Straumann D:
EFNS task force – therapy of nystagmus and oscillopsia. Eur J Neurol 2004;11:83–89.
Leigh RJ, Tomsak RL: Drug treatments for eye movement disorders. J Neurol Neurosurg
Psychiatry 2003;74:1–4.
Rucker JC: Current treatment of nystagmus. Curr Treat Options Neurol 2005;7:69–77.
Büttner U, Fuhry L: Drug therapy of nystagmus and saccadic intrusions; in Büttner U (ed):
Vestibular Dysfunction and Its Therapy. Adv Otorhinolaryngol. Basel, Karger, 1999, pp 195–227.
Leigh RJ, Zee DS: The Neurology of Eye Movements, ed 3. New York, Oxford University Press,
1999.
Straube A: Nystagmus: an update on treatment in adults. Expert Opin Pharmacother 2005;6:
583–590.
Furuta Y, Takasu T, Fukuda S, Inuyama Y, Sato KC, Nagashima K: Latent herpes simplex virus
type 1 in human vestibular ganglia. Acta Otolaryngol Suppl 1993;503:85–89.
Arbusow V, Theil D, Strupp M, Mascolo A, Brandt T: HSV-1 not only in human vestibular ganglia
but also in the vestibular labyrinth. Audiol Neurootol 2001;6:259–262.
Karlberg M, Annertz M, Magnusson M: Acute vestibular neuritis visualized by 3-T magnetic resonance imaging with high-dose gadolinium. Arch Otolaryngol Head Neck Surg 2004;130:229–232.
Brandt T: Vertigo. Its Multisensory Syndromes, ed 2. London, Springer Verlag, 1999.
Kitahara T, Kondoh K, Morihana T, Okumura S, Horii A, Takeda N, Kubo T: Steroid effects on
vestibular compensation in human. Neurol Res 2003;25:287–289.
Straube
188
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
Strupp M, Zingler VC, Arbusow V, Niklas D, Maag KP, Dieterich M, Bense S, Theil D, Jahn K,
Brandt T: Methylprednisolone, valacyclovir, or the combination for vestibular neuritis. N Engl J
Med 2004;351:354–361.
Strupp M, Arbusow V, Maag KP, Gall C, Brandt T: Vestibular exercises improve central vestibulospinal compensation after vestibular neuritis. Neurology 1998;51:838–844.
Minor LB, Schessel DA, Carey JP: Meniere’s disease. Curr Opin Neurol 2004;17:9–16.
Perez R, Chen JM, Nedzelski JM: The status of the contralateral ear in established unilateral
Meniere’s disease. Laryngoscope 2004;114:1373–1376.
Sen P, Georgalas C, Papesch M: Co-morbidity of migraine and Meniere’s disease – is allergy the
link? J Laryngol Otol 2005;119:455–460.
James AL, Burton MJ: Betahistine for Meniere’s disease or syndrome. Cochrane Database Syst
Rev 2001;CD001873.
Dodson KM, Woodson E, Sismanis A: Intratympanic steroid perfusion for the treatment of
Meniere’s disease: a retrospective study. Ear Nose Throat J 2004;83:394–398.
Diamond C, O’Connell DA, Hornig JD, Liu R: Systematic review of intratympanic gentamicin in
Meniere’s disease. J Otolaryngol 2003;32:351–361.
Chia SH, Gamst AC, Anderson JP, Harris JP: Intratympanic gentamicin therapy for Meniere’s disease: a meta-analysis. Otol Neurotol 2004;25:544–552.
Atlas J, Parnes LS: Intratympanic gentamicin for intractable Meniere’s disease: 5-year follow-up.
J Otolaryngol 2003;32:288–293.
Minor LB: Superior canal dehiscence syndrome. Am J Otol 2000;21:9–19.
Banerjee A, Whyte A, Atlas MD: Superior canal dehiscence: review of a new condition. Clin
Otolaryngol 2005;30:9–15 (review).
Tilikete C, Krolak-Salmon P, Truy E, Vighetto A: Pulse-synchronous eye oscillations revealing
bone superior canal dehiscence. Ann Neurol 2004;56:556–560.
Straube A, Büttner U, Brandt T: Recurrent attacks with skew deviation, torsional nystagmus and
contraction of the left frontalis muscle. Neurology 1994;44:177–178.
Brandt T, Dieterich M: Vestibular paroxysmia: vascular compression of the eighth nerve? Lancet
1994;343:798–799.
Jannetta PJ, Møller MB, Møller AR: Disabling positional vertigo. N Engl J Med 1984;310:
1700–1705.
Baloh RW, Spooner JW: Downbeat nystagmus. A type of central vestibular nystagmus. Neurology
1981;31:304–310.
Bronstein AM, Miller DH, Rudge P, Kendall BE: Down beating nystagmus: magnetic resonance
imaging and neuro-otological findings. J Neurol Sci 1987;81:173–184.
Marti S, Palla A, Straumann D: Gravity dependence of ocular drift in patients with cerebellar
downbeat nystagmus. Ann Neurol 2002;52:712–721.
Glasauer S, Hoshi M, Kempermann U, Eggert T, Büttner U: Three-dimensional eye position and
slow phase velocity in humans with downbeat nystagmus. J Neurophysiol 2003;89:338–354.
Ances BM, Dalmau JO, Tsai J, Hasbani MJ, Galetta SL: Downbeating nystagmus and muscle
spasms in a patient with glutamic-acid decarboxylase antibodies. Am J Ophthalmol 2005;140:
142–144.
Halmagyi MG, Rudge P, Gresty MA, Sanders MD: Downbeating nystagmus. A review of 62
cases. Arch Neurol 1983;40:777–784.
Young YH, Huang TW: Role of clonazepam in the treatment of idiopathic downbeat nystagmus.
Laryngoscope 2001;111:1490–1493.
Currie J, Matsuo V: The use of clonazepam in the treatment of nystagmus induced oscillopsia.
Ophthalmology 1986;93:924–932.
Dieterich M, Straube A, Brandt T, Paulus W, Büttner U: The effects of baclofen and cholinergic drugs on upbeat and downbeat nystagmus. J Neurol Neurosurg Psychiatry 1991;54:
627–632.
Averbuch-Heller L, Tusa RJ, Fuhry L, Rottach KG, Ganser GL, Heide W, Büttner U, Leigh RJ: A
double-blind controlled study of gabapentin and baclofen as treatment for acquired nystagmus.
Ann Neurol 1997;41:818–825.
Treatment of Oculomotor Disorders
189
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
Strupp M, Schuler O, Krafczyk S, Jahn K, Schautzer F, Büttner U, Brandt T: Treatment of downbeat nystagmus with 3,4-diaminopyridine: a placebo-controlled study. Neurology 2003;61:
165–170.
Kalla R, Glasauer S, Schautzer F, Lehnen N, Büttner U, Strupp M, Brandt T: 4-aminopyridine
improves downbeat nystagmus, smooth pursuit, and VOR gain. Neurology 2004;62:1228–1229.
Helmchen C, Sprenger A, Rambold H, Sander T, Kömpf D, Straumann D: Effect of 3,4diaminopyridine on the gravity dependence of ocular drift in downbeat nystagmus. Neurology
2004;63:752–753.
Pedersen RA, Troost BT, Abel LA, Zorub D: Intermittent down beat nystagmus and oscillopsia
reversed by suboccipital craniectomy. Neurology 1980;30:1232–1242.
Spooner JW, Baloh RW: Arnold-Chiari malformation. Improvement in eye movements after surgical treatment. Brain 1981;104:51–60.
Stahl JS, Averbuch-Heller L, Leigh RJ: Acquired nystagmus. Arch Ophthalmol 2000;118:
544–549.
Fisher A, Gresty M, Chambers B, Rudge P: Primary position upbeating nystagmus: a variety of
central positional nystagmus. Brain 1983;106:949–964.
Glasauer S, Kalla R, Büttner U, Strupp M, Brandt T: 4-aminopyridine restores visual ocular motor
function in upbeat nystagmus. J Neurol Neurosurg Psychiatry 2005;76:451–453.
Endres M, Heide W, Kömpf D: See-saw nystagmus. Clinical aspects, diagnosis, pathophysiology:
observations in 2 patients. Nervenarzt 1996;67:484–489.
Halmagyi GM, Aw ST, Dehaene I, Curthoys IS, Todd MJ: Jerk-waveform see-saw nystagmus due
to unilateral meso-diencephalic lesion. Brain 1994;117:775–788.
Rambold H, Helmchen C, Büttner U: Unilateral muscimol inactivations of the interstitial nucleus
of Cajal in the alert rhesus monkey do not elicit seesaw nystagmus. Neurosci Lett 1999;272:
75–78.
Stahl JS, Averbuch-Heller L, Leigh RJ: Acquired nystagmus. Arch Ophthalmol 2000;118:
544–549.
Frisèn L, Wikkelso C: Posttraumatic seesaw nystagmus abolished by ethanol ingestion. Neurology
1986;36:841–844.
Lepore FE: Ethanol-induced resolution of pathologic nystagmus. Neurology 1987;37:877.
Averbuch-Heller L, Tusa RJ, Fuhry L, Rottach K, Ganser GL, Heide W, Büttner U, Leigh RJ: A
double-blind controlled study of gabapentin and baclofen as treatment for acquired nystagmus.
Ann Neurol 1997;41:818–825.
Waespe W, Cohen B, Raphan T: Dynamic modification of the vestibuloocular reflex by the nodulus and uvula. Science 1985;228:199–202.
Furman JMR, Wall C, Pang D: Vestibular function in periodic alternating nystagmus. Brain
1990;113:1425–1439.
Lee MS, Lessell S: Lithium-induced periodic alternating nystagmus. Neurology 2003;60:344.
Halmagyi MG, Rudge P, Gresty MA: Treatment of periodic alternating nystagmus. Ann Neurol
1980;8:609–611.
Tilikete C, Vighetto A, Trouillas P, Honnorat J: Anti-GAD antibodies and periodic alternating nystagmus. Arch Neurol 2005;62:1300–1303.
Isago H, Tsuboya R, Kataura A: A case of periodic alternating nystagmus: with special reference
to the efficacy of baclofen treatment. Auris Nasus Larynx 1985;12:15–21.
Nuti D, Ciacci G, Giannini F, Rossi A, Frederico A: Aperiodic alternating nystagmus: report of two
cases and treatment by baclofen. Ital J Neurol Sci 1986;7:453–459.
Gresty M, Ell JJ, Findley LJ: Acquired pendular nystagmus: its characteristics, localising value
and pathophysiology. J Neurol Neurosurg Psychiatry 1982;45:431–439.
Leigh RJ: Clinical features and pathogenesis of acquired forms of nystagmus. Baillieres Clin
Neurol 1992;1:393–416.
Zee DS: Mechanisms of nystagmus. Am J Otolaryngol (Suppl) 1985;30–34.
Lopez LI, Bronstein AM, Gresty MA, Du Boulay EP, Rudge P: Clinical and MRI correlates in 27
patients with acquired pendular nystagmus. Brain 1996;119:465–472.
Herishanu Y, Louzoun Z: Trihexyphenidyl treatment of vertical pendular nystagmus. Neurology
1986;36:82–84.
Straube
190
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
Jabbari B, Rosenberg M, Scherokman B, Gunderson CH, McBurney JW, McClintock W:
Effectiveness of trihexyphenidyl against pendular nystagmus and palatal myoclonus: evidence of
cholinergic dysfunction. Mov Disord 1987;2:93–98.
Leigh RJ, Burnstine TH, Ruff RL, Kasmer RJ: The effect of anticholinergic agents upon acquired
nystagmus: a double-blind study of trihexyphenidyl and tridihexethyl chloride. Neurology
1991;41:1737–1741.
Starck M, Albrecht H, Pöllmann W, Straube A, Dieterich M: Drug therapy of acquired nystagmus
in multiple sclerosis. J Neurol 1997;244:9–16.
Bandini F, Castello E, Mazzella L, Mancardi GL, Solaro C: Gabapentin but not vigabatrin is effective in the treatment of acquired nystagmus in multiple sclerosis: how valid is the GABAergic
hypothesis? J Neurol Neurosurg Psychiatry 2001;71:107–110.
Stahl JS, Rottach KG, Averbuch-Heller L, von Maydell RD, Collins SD, Leigh RJ: A pilot study of
gabapentin as treatment for acquired nystagmus. Neuro-ophthalmology 1996;16:107–113.
Fabre K, Smet-Dieleman H, Zeyen T: Improvement of acquired pendular nystagmus by
gabapentin: case report. Bull Soc Belge Ophtalmol 2001;282:43–46.
Dell’Osso LF: Suppression of pendular nystagmus by smoking cannabis in a patient with multiple
sclerosis. Neurology 2000;13:2190–2191.
Schon F, Hart PE, Hodgson TL, Pambakian AL, Ruprah M, Williamson EM, Kennard C:
Suppression of pendular nystagmus by smoking cannabis in a patient with multiple sclerosis.
Neurology 1999;53:2209–2210.
Menon GJ, Thaller VT: Therapeutic external ophthalmoplegia with bilateral retrobulbar botulinum
toxin – an effective treatment for acquired nystagmus with oscillopsia. Eye 2002;16:804–806.
Leigh RJ, Tomsak RL, Grant MP, Remler BF, Yaniglos SS, Lystad L, Dell’Osso LF: Effectiveness of botulinum toxin administered to abolish acquired nystagmus. Ann Neurol 1992;32:
633–642.
Tomsak RL, Remler BF, Averbuch-Heller L, Chandran M, Leigh RJ: Unsatisfactory treatment of
acquired nystagmus with retrobulbar injection of botulinum toxin. Am J Ophthalmol 1995;119:
489–496.
Büttner U, Straube A, Handke V: Opsoclonus und Okular flutter. Nervenarzt 1997;68:633–637.
Ridley A, Kennard C, Scholtz CL, Büttner-Ennever JA, Summers B, Turnbull A: Omnipause neurons in two cases of opsoclonus associated with oat cell carcinoma of the lung. Brain 1987;110:
1699–1709.
Pless M, Ronthal M: Treatment of opsoclonus-myoclonus with high-dose intravenous immunoglobulin. Neurology 1996;46:583–584.
Traccis S, Marras MA, Puliga MV, Ruiu MC, Masala PG, Carboni A, Aiello I, Pugliatti M, Rosati G:
Square-wave jerks and square-wave oscillations: treatment with valproic acid. Neuro-ophthal Mol
1997;18:51–58.
Leopold HC: Opsoklonus- und Myoklonie-Syndrom. Klinische und elektronystagmographische
Befunde mit Verlaufsstudien. Fortschr Neurol Psychiatr 1985;53:42–54.
Rosenberg MI, Glaser JS: Superior oblique myokymia. Ann Neurol 1983;13:667–669.
Leigh RJ, Tomsak RL, Seidman SH, Dell’Osso LF: Superior oblique myokymia. Quantitative
characteristics of the eye movements in three patients. Arch Ophthalmol 1991;109:1710–1713.
Yousry I, Dieterich M, Naidich TP, Schmid UD, Yousry TA: Superior oblique myokymia: magnetic
resonance imaging support for the neurovascular compression hypothesis. Ann Neurol 2002;51:
361–368.
Hashimoto M, Ohtsuka K, Suzuki Y, Minamida Y, Houkin K: Superior oblique myokymia caused
by vascular compression. J Neuroophthalmol 2004;24:237–239.
Tomsak RL, Kosmorsky GA, Leigh RJ: Gabapentin attenuates superior oblique myokymia. Am J
Ophthalmol 2002;133:721–723.
Deokule S, Burdon M, Matthews T: Superior oblique myokymia improved with gabapentin. J
Neuroophthalmol 2004;24:95–96.
Samii M, Rosahl SK, Carvalho GA, Krzizok T: Microvascular decompression for superior oblique
myokymia: first experience. J Neurosurg 1998;89:1020–1024.
Scharwey K, Krzizok T, Samii M, Rosahl SK, Kaufmann H: Remission of superior oblique
myokymia after microvascular decompression. Ophthalmologica 2000;214:426–428.
Treatment of Oculomotor Disorders
191
90 Bronstein A: Benign paroxysmal positional vertigo (BPPV): Diagnosis and physical treatment.
Adv Clin Neurosci Rehabil 2005;5:13–15.
91 Hornibrook J: Horizontal canal benign positional vertigo. Ann Otol Rhinol Laryngol
2004;113:721–725.
92 Bertholon P, Bronstein AM, Davies RA, Rudge P, Thilo KV: Positional down beating nystagmus in
50 patients: cerebellar disorders and possible anterior semicircular canalithiasis. J Neurol
Neurosurg Psychiatry 2002;72:366–367.
93 von Brevern M, Radtke A, Clarke AH, Lempert T: Migrainous vertigo presenting as episodic positional vertigo. Neurology 2004;62:469–472.
94 Büttner U, Helmchen C, Brandt T: Diagnostic criteria for central versus peripheral positioning
nystagmus and vertigo: a review. Acta Otolaryngol 1999;119:1–5.
95 Crevits L: Treatment of anterior canal benign paroxysmal positional vertigo by a prolonged forced
position procedure. J Neurol Neurosurg Psychiatry 2004;75:779–781.
96 Hilton M, Pinder D: The Epley (canalith repositioning) manoeuvre for benign paroxysmal positional vertigo. Cochrane Database Syst Rev 2004;CD003162.
97 Radtke A, von Brevern M, Tiel-Wilck K, Mainz-Perchalla A, Neuhauser H, Lempert T: Self-treatment of benign paroxysmal positional vertigo: semont maneuver vs Epley procedure. Neurology
2004;63:150–152.
98 Sakaida M, Takeuchi K, Ishinaga H, Adachi M, Majima Y: Long-term outcome of benign paroxysmal positional vertigo. Neurology 2003;60:1532–1534.
99 Del Rio M, Arriaga MA: Benign positional vertigo: prognostic factors. Otolaryngol Head Neck
Surg 2004;130:426–429.
100 Gordon CR, Levite R, Joffe V, Gadoth N: Is posttraumatic benign paroxysmal positional vertigo
different from the idiopathic form? Arch Neurol 2004;61:1590–1593.
A. Straube
Department of Neurology, Klinikum Grosshadern
Marchioninistrasse 15
DE–81377 Munich (Germany)
Tel. ⫹49 89 7095 3900, Fax ⫹49 89 7095 3677, E-Mail [email protected]
Straube
192
Subject Index
Alcohol, seesaw nystagmus management
183
4-Aminopyridine
downbeat nystagmus management 181,
182
upbeat nystagmus management 182
Baclofen
periodic alternating nystagmus
management 184
upbeat nystagmus management 182
Basal ganglia, saccadic eye movement
control 62
Benign paroxysmal positional vertigo
(BPPV)
clinical features 186, 187
etiology 187
treatment 187, 188
Betahistine, Ménière’s disease management
179
Binocular adaptation
Listing’s plane 98
phoria adaptation 97, 98
saccade adaptation 98, 99
Blinking
clinical applications 125
eye movements and effects
blink-associated 114
blink effects 115
disconjugate eye movements 101, 117,
118
saccade-vergence interactions 118,
119
saccadic eye movement 115–117
smooth pursuit eye movements 119, 120
frequency disorders 120, 122
visual consequences 114
Botulinum toxin, acquired pendular
nystagmus management 185
Brainstem saccadic generator
excitatory burst neurons 55, 56
inhibitory burst neurons 56, 57
midbrain reticular formation 55
omnipause neurons 57
paramedian pontine reticular formation 55
tonic neurons 57–60
Caloric testing, vestibulo-ocular reflex
function 45, 46
Carbamazepine
superior oblique myokymia management
186
vestibular paroxysmia management 180
Central caudal nucleus (CCN), eyelid
control 111
Cerebellum
central processing of vestibular signals
39, 40
saccadic eye movement control 66–70
smooth pursuit eye movement role
80–82
Click-evoked myogenic potential, vestibular
function testing 48, 49
Clonazepam
downbeat nystagmus management 181,
182
opsoclonus management 185
seesaw nystagmus management 183
193
Craniosynostosis, strabismus 149
Cyclovergence 92
Dimenhydrimnate
Ménière’s disease management 179
vestibular neuritis management 178
Disconjugate eye movements
binocular adaptation
Listing’s plane 98
phoria adaptation 97, 98
saccade adaptation 98, 99
blinking 101, 117, 118
cyclovergence 92
Hering’s law and asymmetric vergence
movements 95, 96
horizontal vergence movements 91
Listing’s law during convergence 93–95
overview 90, 91
pathology 101, 102
saccade-associated vergence movements
96, 97
vertical vergence movements 92
vestibular stimulation 99–101
Double Purkinje image (DPI) eye tracker,
historical perspective 17
Downbeat nystagmus, see Nystagmus
Electro-oculogram (EOG)
comparison with other eye movement
recording techniques 31, 32
historical perspective 17
infrared reflection device comparison 20,
21
noise and resolution 20
principles 19, 20
single-eye measurement 21
vestibulo-ocular reflex function 45
Epley maneuver, benign paroxysmal
positional vertigo management 187, 188
Extraocular muscles, see Eye muscles
Eye-head movement, ocular motor system
modeling 170
Eyelid, see also Blinking
disorders
blink frequency 120–122
eyelid-eye coordination 124
tonic eyelid position 122, 123
Subject Index
neural control
levator palpebrae muscle innervation
111
lid-eye coordination 111–113
supranuclear disorders 110
Eye movement recordings
comparison of techniques 31, 32
double Purkinje image eye tracker 17
electro-oculogram
infrared reflection device comparison
20, 21
noise and resolution 20
overview 17
principles 19, 20
single-eye measurement 21
historical perspective 16–18
infrared reflection device
calibration 23, 24
overview 17
principles 22, 23
magnetic search coil
accuracy 26
disadvantages 26, 27
error sources 25, 26
noise 26
overview 18
principles 24, 25
video-oculography
calibration 28, 29
noise 30
ocular torsion measurements 30
overview 18, 19
principles 27, 28
Eye muscles
fibers 2–4, 8–11
innervation
central pathways 7
motoneurons 7, 8
premotor circuits 8–10
Listing’s law 139, 140, 143–146, 152
magnetic resonance imaging 134, 138,
139, 142, 145, 149
morphology 2, 133, 134
ocular counterrolling 145
proprioception 10, 11
pulleys
animal studies 142, 143
194
functional anatomy 137–139
kinematics 139–142, 152
neural control 146–148
structure 134–137
surgery
pulley heterotopy 150
pulley hindrance 151
pulley instability 150, 151
sensory receptors
Golgi tendon organs 6
palisade endings 5, 6
spindles 4, 5
skeletal muscle comparison 2
strabismus 148–150
types 133
Eye plant, ocular motor system model 159,
160
Frontal eye field (FEF)
eyelid control 112, 113
smooth pursuit eye movement role 80, 169
Gabapentin
acquired pendular nystagmus
management 184, 185
downbeat nystagmus management 181
seesaw nystagmus management 183
superior oblique myokymia management
186
Golgi tendon organs, eye muscles 6
Hering’s law, asymmetric vergence
movements 95, 96
Infrared reflection device (IRD)
calibration 23, 24
comparison with other eye movement
recording techniques 31, 32
historical perspective 17
principles 22, 23
Lamotrigine, vestibular paroxysmia
management 180
Levator palpebrae muscle, see Eyelid
Listing’s law
Convergence 93–95
mechanical basis 143–146
Subject Index
ocular motor system modeling 162
pulley kinematics 139, 140, 152
violation during vestibulo-ocular reflex
143, 144
Magnetic resonance imaging (MRI), eye
muscles 134, 138, 139, 142, 145, 149
Magnetic search coil
accuracy 26
comparison with other eye movement
recording techniques 31, 32
disadvantages 26, 27
error sources 25, 26
historical perspective 18
noise 26
principles 24, 25
Medulla, smooth pursuit eye movement
pathology 84
Ménière’s disease
clinical features 178
etiology 178, 179
treatment 179
Methylprednisolone, vestibular neuritis
management 178
Neural velocity-to-position integrator,
ocular motor system model 160–162
Nitrazepam, opsoclonus management
185
Nucleus reticularis tegmenti pontis (NRTP),
saccadic eye movement control 62, 64,
65, 66
Nystagmus, see also Optokinetic nystagmus
acquired pendular nystagmus
clinical features 184
etiology 184
treatment 184, 185
bedside clinical evaluation
dynamic disturbances 42, 43
positional testing 43, 44
static imbalance 41, 42
Valsalva- and hyperventilation-induced
nystagmus 44, 45
downbeat nystagmus
clinical features 180
etiology 181
treatment 181, 182
195
Nystagmus (continued)
pathology 177
periodic alternating nystagmus
clinical features 183
etiology 183
treatment 184
seesaw nystagmus
clinical features 182, 183
etiology 183
treatment 183
upbeat nystagmus
clinical features 182
etiology 182
treatment 182
vestibulo-ocular reflex pathology
40, 41
Ocular flutter
clinical features 185
etiology 185
treatment 185
Ocular following response (OFR)
anatomy and physiology 78, 81
features 78
Ocular motor nerve, eye muscle sensory
afferents 7
Oculomotor nucleus, motoneurons 7
Opsoclonus
clinical features 185
etiology 185
treatment 185
Optokinetic nystagmus (OKN)
anatomy and physiology 81
components 77, 78
definition 77
pathology 84
velocities 78
vertical versus horizontal 78
Otoliths, function testing 48
Palisade endings, eye muscles 5, 6
Paramedian pontine reticular formation, see
Brainstem saccadic generator
Parkinson’s disease (PD), eyelid disorders
121, 123, 124
Periodic alternating nystagmus, see
Nystagmus
Subject Index
Phenytoin, vestibular paroxysmia
management 180
Pontine nuclei, saccadic eye movement
control 62, 64, 65
Propranolol, opsoclonus management
185
Pulleys, see Eye muscles
Robinson, D.A., ocular motor system
models 158–160
Rotational testing, vestibulo-ocular reflex
function 45, 46
Saccadic eye movement
antisaccades 53
binocular saccade adaptation 98
blinking
effects 115–117
vergence interactions 118, 119
features 53
latency 53
memory-guided saccades 53
neurocircuitry
basal ganglia 62
brainstem saccadic generator
excitatory burst neurons 55, 56
inhibitory burst neurons 56, 57
midbrain reticular formation 55
omnipause neurons 57
paramedian pontine reticular
formation 55
tonic neurons 57–60
cerebellum 66–70
monkey studies 146, 147
nucleus reticularis tegmenti ponti 62,
64–66
overview 53–55
pontine nuclei 62, 64, 65
superior colliculus 60–62
ocular motor system modeling
162, 163
orienting cascade 53
resting saccades 52
spontaneous saccades 53
target-directed saccades 53
vergence movements 96, 97
Search coil, see Magnetic search coil
196
Seesaw nystagmus, see Nystagmus
Semicircular canal (SCC)
vestibular testing 47, 48
vestibulo-ocular reflex 36
Smooth pursuit eye movements (SPEM)
anatomy and physiology 79–81
blinking effects 119, 120
features 76
latency 76
ocular motor system modeling
168, 169
pathology
cerebellum 82, 84
cortex 82
medulla 84
pontine structures 82
testing 77
Spindles, eye muscles 4, 5
Strabismus
craniosynostosis 149
muscle weakness 148
superior oblique palsy 148, 149
Subjective visual vertical (SVV), otolith
function testing 48
Superior canal dehiscence syndrome
clinical features 179
etiology 179
treatment 179
Superior colliculus
eyelid control 112, 113
saccadic eye movement control 60–62
Superior oblique myokymia
clinical features 186
etiology 186
treatment 186
Supplementary eye field (SEF), smooth
pursuit eye movement role 80
Trigeminal nerve, eye muscle sensory
afferents 7
Trihexyphenidyl, acquired pendular
nystagmus management 184
Upbeat nystagmus, see Nystagmus
Valacyclovir, vestibular neuritis
management 178
Subject Index
Valproic acid, opsoclonus management 185
Vergence eye movements, see Disconjugate
eye movements
Vertigo
benign paroxysmal positional vertigo, see
Benign paroxysmal positional
vertigo
vestibulo-ocular reflex pathology
40, 41
Vestibular neuritis
clinical features 177
etiology 177, 178
treatment 178
Vestibular nuclear complex, central
processing of vestibular signals 39, 40
Vestibular paroxysmia
clinical features 180
etiology 180
treatment 180
Vestibulo-ocular reflex (VOR)
angular reflex 35, 36, 183
bedside clinical evaluation
dynamic disturbances 42, 43
positional testing 43, 44
static imbalance 41, 42
Valsalva- and hyperventilation-induced
nystagmus 44, 45
click-evoked myogenic potential testing
48, 49
components
central processing of vestibular signals
37, 39, 40
motor output 40
overview 36
peripheral sensory apparatus 36, 37
function 35, 77
laboratory testing
caloric testing 45, 46
electro-oculography 45
rotational testing 45, 46
linear reflex 36
ocular motor system modeling
adaptation 164, 165
angular reflex three-dimensional
model 165, 166
overview 163–165
otolith function testing 48
197
Vestibulo-ocular reflex (continued)
pathology 40, 41, 177
semicircular canal function testing 47,
48
Video-oculography (VOG)
calibration 28, 29
Subject Index
comparison with other eye movement
recording techniques 31, 32
historical perspective 18, 19
noise 30
ocular torsion measurements 30
principles 27, 28
198