Verigo and Imbalance: Clinical Neurophysiology Of the Vestiabular System pot

Lateral canal signals synapse in the ipsilateral vestibular nuclear complex and project to the contralateral abducens nucleus innervating the lateral rectus.. Signals from the anterior c

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The Volume Editors

Clinical neurophysiology encompasses the application of a wide variety of electrophysiologic methods to theanalysis and recording of normal function, as well as to the diagnosis and treatment of diseases involvingthe central nervous system, peripheral nervous system, autonomic nervous system and muscles The steadyincrease in growth of subspecialty knowledge and skill in neurology has led to the need for a compilation

of the whole range of physiologic methods applied in each of the major categories of neurologic disease.While some of the methods are applied to a single category of disease, most are useful in multiple clinicalsettings Each volume is designed to serve as the ultimate reference source for academic clinical neurophysiol-ogists and as a reference for specialists in each specific clinical neurophysiology subspecialty It will providethe information needed to fully understand the physiology and pathophysiology of disorders in their patients

As such these volumes will also serve as major teaching texts for trainees in each of the subspecialties.The Handbook volumes cover all of the clinical disorders served by clinical neurophysiology, including themuscle and movement disorders, neuromuscular junction diseases, epilepsy, surgical epilepsy, motor systemdisorders, peripheral nerve disease, sleep disorders, visual and auditory system disorders, vestibular disordersand monitoring neural function Each focuses on advances in one of these major areas of clinical neurophysi-ology Each volume will include critical discussion of new knowledge in basic neurophysiology, and itsapplication to different nervous system diseases

Each volume will include an overview of the field, followed by a section that includes a detailed description

of each of the clinical neurophysiology techniques, and a third section discussing electrophysiologic findings

in specific disorders The latter will include how to evaluate each along with a comparison of the relativecontribution of each of the methods A final section will discuss ongoing research studies and anticipated futureadvances

It is indeed a pleasure to add the latest Handbook volume, Vertigo and Imbalance: Clinical Neurophysiology

of the Vestibular System, application of clinical neurophysiology methods to the series The multiplicity ofboth old and new methods of evaluation demonstrates the vitality of this underappreciated field, as well as

in their many research publications

We are privileged to have David Zee, a pioneer in the development of the study of vestibular disorders,matched with Scott Eggers, who is carrying the field forward, as the volume editors They have done a superbjob of assembling world leaders in the description of the methods and in their application to a wide range ofdiseases and settings

The volume describes the multiplicity of methods that are being applied to the many disorders of balance,coordination, oculomotor function and vestibular function and the neural structures at risk for loss of function

A very special focus is provided on bedside function testing Wherever possible, the information presentedfocuses on evidence-based medicine; the specificity and sensitivity of each modality of testing is providedwhen known, along with comparison of their relative values

Jasper R Daube, MDRochester, MN, USAFranc¸ois Mauguie`re, MD

Lyon, FranceSeries Editors

Baloh, R.W Department of Neurology, UCLA School of Medicine, 710 Westwood Plaza,

Los Angeles, CA 90095-1769, USA

Balough, B.J Department of Otolaryngology, Naval Medical Center San Diego, San Diego,

CA 92134, USA

Bastian, A.J Department of Neurology, The Kennedy Krieger Institute, 707 North

Broad-way, Baltimore, MD 21205, USA

Black, F.O Neurotology Research, Legacy Clinical Research and Technology Center,

1225 NE 2nd Avenue, Portland, OR 97208, USA

Brandt, T Department of Clinical Neurosciences, Ludwig-Maximilians University of

Munich, Marchioninistrasse 15, D-81377 Munich, Germany

Bronstein, A.M Neuro-otology Unit, Imperial College of London, Charing Cross Hospital,

London W6 8RF, UK

Carey, J.P Department of Otolaryngology – Head and Neck Surgery, Johns Hopkins

School of Medicine, 601 N Caroline Street, Room 6255, Baltimore, MD

21287, USA

Cherchi, M Departments of Neurology, Otolaryngology, Physical Therapy and Human

Movement Sciences, Northwestern University Feinberg School of Medicine,Chicago, IL 60611-5800, USA

Clarke, A.H Vestibular Research Laboratory, Charite´ Medical School, Hindenburgdamm

30, D-12200 Berlin, Germany

Colebatch, J.G Department of Neurology and UNSW Clinical School, Prince of Wales

Hospital, High Street, Randwick, Sydney 2031, Australia

Hopkins University, Baltimore, MD 21287, USA

Curthoys, I.S Vestibular Research Laboratory, School of Psychology, University of

Sydney, Sydney, Australia

Dieterich, M Department of Neurology, Ludwig-Maximilians University Munich,

Marchioninistrasse 15, D-81377 Munich, Germany

Earhart, G.M Departments of Neurology, Anatomy and Neurobiology, Program in Physical

Therapy, Campus Box 8502, Washington University School of Medicine, St.Louis, MO 63108, USA

Eggers, S.D.Z Department of Neurology, Mayo Clinic College of Medicine, 200 First St

SW, Rochester, MN 55905, USA

Eisen, M.D Department of Surgery (Otolaryngology), University of Connecticut Health

Center, 85 Seymour Street, Suite 318, Hartford, CT 06106, USA

Fetter, M Department of Neurology and Neurorehabilitation, SRH Clinic Karlsbad–

Langensteinbach, Guttmannstr 1, D-76307 Karlsbad, Germany

Fife, T.D Arizona Balance Center, Barrow Neurological Institute, 222 W Thomas Road,

Suite 110A, Phoenix, AZ 85013, USA

Frohman, E.M Multiple Sclerosis Clinical Center, University of Texas Southwestern

Medi-cal Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.Frohman, T.C Department of Neurology, University of Texas Southwestern Medical Center

at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA

Furman, J.M Eye and Ear Institute, Suite 500, University of Pittsburgh School of

Medi-cine, Pittsburgh, PA 15213, USA

Gibson, W.P.R Department of Surgery/Otolaryngology, University of Sydney, Sydney 2006,

Hain, T.C Departments of Neurology, Otolaryngology and Physical Therapy and

Human Movement Sciences, Northwestern University Feinberg School ofMedicine, 645 N Michigan, Suite 410, Chicago, IL 60611-5800, USA.Halmagyi, G.M Neurology Department, Royal Prince Alfred Hospital, Sydney, Camperdown,

NSW 2050, Australia

Haslwanter, T Upper Austrian University of Applied Sciences, Medical Technology,

Garni-sonstr 21, A-4020 Linz, Austria

Heide, W Department of Neurology, General Hospital Celle, Siemensplatz 4, D-29223

Celle, Germany

Herdman, S.J Division of Physical Therapy, Emory University, 1441 Clifton Road NE,

Atlanta, GA 30322, USA

Hoffer, M.E Department of Otolaryngology, Naval Medical Center San Diego, 34800

Bob Wilson Drive, San Diego, CA 92134-2200, USA

Jen, J.C Department of Neurology, UCLA School of Medicine, 710 Westwood Plaza,

Los Angeles, CA 90095-1769, USA

Kerber, K.A Department of Neurology, University of Michigan Medical School, 1500 E

Medical Center Drive, TC 1920/0316, Ann Arbor, MI 48103, USA

Kim, J.-S Department of Neurology, Seoul National University, Bundang Hospital, 300

Gumi-dong, Bundang-gu, Seongnam-si, Gyeonggi-do 463-707, South Korea.Krafczyk, S Center for Sensorimotor Research, University of Munich, Marchioninistrasse

23, D-81377 Munich, Germany

Lee, H Department of Neurology, Keimyung University School of Medicine, 194

Dongsan dong, Jung-gu, Daegu 700-712, South Korea

Legatt, A.D Department of Neurology, Montefiore Medical Center, 111 East 210th St.,

Bronx, NY 10467, USA

Lempert, T Department of Neurology, Schlosspark-Klinik, Heubnerweg 2, D-14059

Berlin, Germany

Lustig, L.R Department of Otolaryngology – Head and Neck Surgery, University of

Cali-fornia San Francisco, 400 Parnassus Avenue, Room A746, Box 0342, SanFrancisco, CA 94143-0342, USA

McGarvie, L.A Neurology Department, Royal Prince Alfred Hospital, Sydney, Camperdown,

NSW 2050, Australia

Minor, L.B Department of Otolaryngology – Head and Neck Surgery, Johns Hopkins

University School of Medicine, 601 N Caroline St., Room 6210, Baltimore,

MD 21287, USA

Moore, B Department of Otolaryngology, Naval Medical Center San Diego, San Diego,

CA 92134, USA

Niparko, J.K Department of Otolaryngology – Head and Neck Surgery, Division of

Otol-ogy, AudiolOtol-ogy, Neurotology and Skull Base Surgery, Johns Hopkins versity School of Medicine, Baltimore, MD 21287, USA

Uni-Nuti, D Department of Human Pathology and Oncology, Section of Otolaryngology,

Policlinico “Le Scotte”, Viale Bracci 16, 53100 Siena, Italy

Palla, A Neurology Department, Zurich University Hospital, Frauenklinikstr 26,

CH-8091 Zurich, Switzerland

Poling, G.L Medical University of South Carolina, Department of Otolaryngology – Head

and Neck Surgery, Hearing Research Program, 135 Rutledge Avenue, MSC

550, Charleston, SC 29425-5500, USA

Ramat, S Dipartimento di Informatica e Sistemistica, Universita` di Pavia, Via Ferrata

1, 27100 Pavia, Italy

Roberts, D.C Department of Neurology, The Johns Hopkins University School of

Medi-cine, 210 Pathology Bldg., 600 N Wolfe St., Baltimore, MD 21287-6921,USA

Rosengren, S.M Department of Neurology and UNSW Clinical School, Prince of Wales

Hos-pital, High Street, Randwick, Sydney 2031, Australia

Rucker, J.C Departments of Neurology and Ophthalmology, Mount Sinai School of

Med-icine, One Gustave L Levy Place, Box 1052, New York, NY 10029, USA.Schneider, E Center for Sensorimotor Research, University of Munich, Marchioninistrasse

23, D-81377 Munich, Germany

Schubert, M.C Department of Otolaryngology – Head and Neck Surgery, Johns Hopkins

University School of Medicine, 601 N Caroline St, 6th Floor, Baltimore,

MD 21287, USA

Shallop, J.K Department of Otorhinolaryngology, Mayo Clinic and College of Medicine,

Cochlear Implant Program, Rochester, MN 55905, USA

Shelhamer, M Department of Otolaryngology – Head and Neck Surgery and Biomedical

Engineering, The Johns Hopkins University School of Medicine, 210 ogy Bldg., 600 N Wolfe St., Baltimore, MD 21287-6921, USA

Pathol-Shepard, N.T Department of Otolaryngology, Mayo Clinic, 200 First St SE, Rochester,

Strupp, M Department of Neurology, University of Munich, Klinikum Grosshadern,

Marchioninistrasse 15, D-81377 Munich, Germany

Tarnutzer, A Neurology Department, Zurich University Hospital, Frauenklinikstr 26,

Tusa, R.J Neurology and Otolaryngology, Center for Rehabilitation Medicine, Emory

University, 1441 Clifton Road, Atlanta, GA 30322, USA

Von Brevern, M Department of Neurology, Charite´ University Hospital, D-13353 Berlin,

Germany

Woo, D Department of Neurology, The Medical College of Wisconsin, Milwaukee,

WI, USA

Yagi, T Department of Otolaryngology, Nippon Medical School, 1-1-5 Sendagi,

Bunkyo-ku, Tokyo 113-8063, Japan

Zee, D.S Department of Neurology, The Johns Hopkins Hospital, Path 2-210, 600 N

Wolfe St., Baltimore, MD 21287, USA

CHAPTER 1

Overview of vestibular and balance disorders

a

Department of Neurology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905, USA

b

Department of Neurology, The Johns Hopkins Hospital, Path 2-210, 600 N Wolfe St., Baltimore, MD 21287, USA

This volume of the Clinical Neurophysiology

Hand-book Series is devoted to the clinical

neurophysiol-ogy of vestibular and balance disorders This large

subject is covered by 40 chapters written by experts

from around the world As Editors of the volume,

we are indebted to these authors for their unselfish

dedication and far-reaching contributions

Clinicians and scientists involved in the research and

care of patients with dizziness are defined not by an

ana-tomic specialty or disease, but rather by the nature of

their patients’ presenting complaints: vertigo,

disequi-librium, imbalance, and related symptoms Thus,

the target audience for this volume is reflected in

the diverse backgrounds of its authors — neurologists,

otolaryngologists, neuro-ophthalmologists,

audiolo-gists, physical therapists, psychiatrists, and

bioengi-neers Indeed a multidisciplinary approach is essential

for the optimal diagnosis and treatment of patients

with vestibular disorders The goal of this volume is to

review each topic with enough background to be

acces-sible to the non-specialist, while at the same time

providing depth and completeness for the specialist

and methodological detail for the clinician, technician,

or investigator

This volume has been divided into four major

sections:

(1) The Overview section reviews basic vestibular

and ocular motor anatomy and physiology

rele-vant to patients with balance disorders Then

with a foundation of physiological and

anatomi-cal principles in mind, the historianatomi-cal features

and special bedside examination techniques forevaluating the dizzy patient are discussed.(2) The Methodological Techniques section reviews

in depth the great breadth of techniques nowavailable to evaluate the function of the vestibularsystem Beginning with the various techniques ofrecording eye movements, this section coversstandard methods such as rotary chair testing andcaloric testing, as well as recently developed orspecialized tests such as head impulse testing,translational vestibulo-ocular reflex testing, ves-tibular evoked potentials, electrocochleography,and provocative maneuvers Many of theseemerging techniques have not been previouslyreviewed systematically Many have not reachedwidespread clinical use but are in development

or are useful research tools Methodologicaldescriptions are not repeated later in the chapterscovering specific diseases, so the reader will need

to refer back to these chapters for description oftechniques and normal values

(3) Chapters in the Diseases and Treatments sectionaddress the most common conditions and importantissues relevant to care of patients with vestibularand balance disorders Topics range from periph-eral vestibular disorders to neurological disorders,with additional discussion of psychological issues,visual symptoms, and the elderly Both ‘‘new’’diagnoses (e.g., migrainous vertigo and superiorcanal dehiscence) and more traditional causes ofvestibular dysfunction (e.g., Me´nie`re’s disease andvestibular neuritis) are discussed Given the focus

of this volume and series, special attention is paid

to the role of available testing techniques in thediagnosis and management of patients

(4) A final chapter looks back at the historical roots

of the study of vestibular and ocular motor tion Based upon our expanding fundamental

func-*

Correspondence to: Dr Scott D.Z Eggers, Department of

Neurology, Mayo Clinic College of Medicine, 200 First

St SW, Rochester, MN 55905, USA

E-mail:eggers.scott@mayo.edu(S.D.Z Eggers)

Vertigo and Imbalance: Clinical Neurophysiology of the Vestibular System

Handbook of Clinical Neurophysiology, Vol 9

S.D.Z Eggers and D.S Zee (Vol Eds.)

understanding and computational modeling of

these systems, the authors look ahead to the next

decade for methodological approaches and

advances, such as use of artificial neural

net-works to aid diagnosis, development of vestibular

prostheses, study of the perceptual disturbances

often reported by patients with vestibular

dysfunc-tion, and finally treatment approaches based upon

the molecular biology and genetics of vestibular

disease

Evaluating dizzy patients with vertigo and other

‘‘spells’’ of symptoms requires some knowledge in

several areas, including cardiovascular and autonomic

disorders, psychiatry, and areas within neurology such

as cerebrovascular disease, epilepsy, and migraine

Readers may need to consult other textbooks for

further details on cardiovascular diseases, autonomic

disorders, and epilepsy, all of which can sometimes

lead to dizziness and falls

Great advances have been made in the past half

century in the ability to study and quantify the

characteristics of eye movements and the influence

of the vestibular and optokinetic systems on ocularmotor control This, combined with careful clinicalobservation of patients, has led to the discovery ofnew disorders such as superior canal dehiscenceand treatments such as the canalith repositioningprocedure Rational models of the neural basis forvestibular and ocular motor control can be createdand tested experimentally with great precision Yetclinical care of patients with dizziness and vertigo

is still often empiric and messy Many importantbasic and clinical questions remain unanswered.What is the underlying pathophysiological basis forMe´nie`re’s syndrome and migrainous vertigo, andhow are they related? How can we promote regener-ation or engineer alternatives in the setting of vestib-ular damage? Can pharmacogenetics be applied forthe rational treatment of vestibular disorders?The field is ripe for further research Collabora-tion is needed among clinicians, basic scientists,engineers, radiologists, molecular biologists, andgeneticists We hope that this book will provide aframework for basic knowledge and inspiration forfurther study

CHAPTER 2

Overview of anatomy and physiology of the vestibular system

Department of Neurology, University of Arizona College of Medicine, and Arizona Balance Center,

Barrow Neurological Institute, Phoenix, AZ 85013, USA

2.1 Introduction

The vestibular system helps to maintain spatial

orien-tation and stabilize vision for the purpose of

maintain-ing balance, especially durmaintain-ing movement Vestibular

end organs sense angular and linear acceleration and

transduce these forces to electrochemical signals that

can be used by the central nervous system The central

nervous system integrates the information from the

vestibular system to stabilize gaze during head motion

by means of the vestibulo-ocular reflex (VOR) and

to modulate muscle tone by the vestibulocollic and

vestibulospinal reflexes (Fig 1)

The vestibular system detects angular and linear

acceleration through five end organs of the

membra-nous labyrinth on each side: the saccule, the utricle,

and the anterior, posterior and lateral semicircular

canals (Fig 2) The saccule and utricle, the otolith

organs, transduce linear accelerations, be they from

the pull of gravity or from translation of the head

Each of the semicircular canals has a different spatial

orientation; the summation of signals from the

semi-circular canals allows one to detect rotation of the

head in any direction

2.2 Labyrinth embryogenesis

Vestibular end organs develop from the third week

through the 25th week of gestation At 3–4 weeks,

the otic placode forms from neuroectoderm and

ecto-derm The otic vesicle (otocyst) evolves by the end

of the fourth week, forming the utricular chamber

that later becomes the utricle and semicircularcanals The endolymphatic space is lined withepithelium of ectodermal origin The saccularchamber develops into the saccule and the cochlea,which eventually separate from one another bybirth, with only a small remnant called the ductusreunions The vestibular sensory epithelium origi-nates from ectoderm, resulting in three cristae(one for each semicircular canal) and two maculae(one each for saccule and utricle) The vestibuloco-chlear ganglion eventually divides into superiorand inferior divisions The superior division inner-vates primarily the anterior and lateral semicircularducts and the utricle, whereas the inferior divisioninnervates primarily the saccule and posterior semi-circular canal

2.3 Labyrinthine fluidThe labyrinth has two fluid compartments that areseparated by a membrane The perilymph has anelectrolyte composition similar to extracellularfluid and cerebrospinal fluid ([Kþ] ¼ 10 mEq/l;[Naþ] ¼ 140 mEq/l) and drains into venules andmiddle ear mucosa Endolymph is similar in compo-sition to intracellular fluid ([Kþ] ¼ 144 mEq/l,[Naþ] ¼ 5 mEq/l) and is generated from perilymph

by cells in the stria vascularis of the cochlea lymph is then absorbed by the endolymphatic sacand by dark cells in the cristae and maculae Experi-mentally induced obstruction of the endolymphaticduct results in a condition similar to endolymphatichydrops (Kimura, 1967) The endolymphatic sacuses active transport within dark cells to maintainthe discrepant electrolyte composition of the twofluid compartments The endolymphatic sac alsogenerates and regulates local immunologicalresponses within the labyrinth and the middle ear(Tomiyama and Harris, 1986; Ikeda and Morgen-stern, 1989)

Endo-*

Correspondence to: Terry D Fife, Arizona Balance Center,

Barrow Neurological Institute, 222 W Thomas Road, Suite

110A, Phoenix, AZ 85013, USA

Tel.: +1-602-406-6338; fax: +1-602-406-6339

E-mail:tfife@email.arizona.edu(T.D Fife)

Vertigo and Imbalance: Clinical Neurophysiology of the Vestibular System

Handbook of Clinical Neurophysiology, Vol 9

S.D.Z Eggers and D.S Zee (Vol Eds.)

2.4 Vestibular receptor cells

The vestibular receptor cells, like those of the

cochlea, are referred to as hair cells The “hairs”

are actually stereocilia Each cell possesses 40–200

stereocilia and one kinocilium that arise from the

api-cal region of the cell (Fig 3) Stereocilia are arrayed

so that those closest to the kinocilium are longest

Their actin filament infrastructure makes them fairly

rigid, like stiff rods (Flock and Orman, 1983)

Deflection of the cilia toward the kinocilium leads

to an excitatory nerve potential, and deflection away

from the kinocilium leads to an inhibitory nervepotential The stereocilia act in concert to a largedegree due to tip links that connect the stererocilia(Assad et al., 1991) The kinocilia are long andextend into the gelatinous matrix of the cupula andotolithic membrane Transduction, that is, conversion

of mechanical forces to electrochemical impulses, isproportional to the degree of deflection of the stereo-cilia As little as 3 degrees of displacement of thecilia in the plane of excitation produces a maximumresponse The hair cell resting membrane potential

Fig 1 Overview of the vestibular system showing its influence on ipsilateral muscle tone, cerebellar responses and ocular motility Lateral canal signals synapse in the ipsilateral vestibular nuclear complex and project to the contralateral abducens nucleus innervating the lateral rectus Abducens interneurons cross back and ascend in the ipsilateral medial longitudinal fasciculus to reach the oculomotor nucleus and innervate the medial rectus Vestibular signals from various labyrinthine structures also synapse in the lateral vestibular nucleus and travel down the vestibulospinal pathways in the spinal cord to modulate ispilateral muscle tone Tonic signals from muscle feed back to the vestibular nucleus, interacting with the cerebellum to regulate muscle tone Vestibular signals also relay through the thalamus to the cerebral cortex for cortical perception Also illustrated in simplified form are numerous vesibulocerebellar interconnecting pathways, VPL: ventral posterolateral and VPM: ventral posteromedial nucleus of the thalamus.

is 40 to 60 mV The cell depolarizes with an

excitatory stimulus by 5–20 mV and becomes

hyper-polarized to about64 mV with an inhibitory

stimu-lus Therefore, the responses are skewed to favor an

excitatory over an inhibitory response Furthermore,

hair cells generate spontaneous firing of action

potentials to the afferent nerves that can be

modu-lated by excitatory and inhibitory influences from

the vestibular sensory epithelium The spontaneous

firing rate of hair cells of the semicircular canals

in mammals is 80–90 spikes/s (Goldberg and

Ferna´ndez, 1971)

Two morphologically distinct types of hair cells are

in the vestibular labyrinth as depicted inFig 4 Bothtypes of hair cells are present in the vestibular sensoryepithelium Type I hair cells are flask-shaped andtype II hair cells are cylindrical Type I hair cells have

a large calyceal afferent nerve terminal and are centrated in the crests of cristae and within the striolae

con-of maculae Type II hair cells have simple nerveterminals at their membrane Type I hair cell havemorphologically larger nerve fibers that have irregulardischarge patterns; type II hair cells are innervated

by smaller fibers with regular discharge patterns(Gacek, 1969; Goldberg and Ferna´ndez, 1971)

In the crista ampullaris of the lateral canal, thekinocilium is located closest to the utricle while inthe anterior and posterior canals, the kinocilium isoriented away from the utricular side of the canals

In the maculae of the saccule, kinocilia are orientedaway from the striola, whereas in the utricle theyare oriented toward the striola

Mammalian vestibular hair cells do not regeneratespontaneously; once lost, peripheral vestibular hypo-function is permanent A number of studies havefocused on interventions to induce regeneration ofhair cell function in mammals, but so far none hasbecome clinically applicable (Staecker et al., 2007)

Fig 3 Stereocilia and the single kinocilium of a several hair cell

bundles of the bullfrog saccule by scanning electron micrograph

(courtesy of David Corey, PhD and John A Assad, PhD, Harvard

Medical School).

Fig 2 Orientation and structures of the right membranous

laby-rinth, including the semicircular canals, saccule, utricle and

2.5 Vestibular sensory epithelium

The vestibular apparatus has two types of sensory

epithelium: the macula, which detects linear

acceler-ation and the crista ampullaris, which detects angular

acceleration The maculae represent the specialized

sensory epithelium within the saccule and utricle,

and the crista ampullaris is the sensory structure of

the semicircular canals

2.5.1 Macula

The macula consists of calcium carbonate crystals

embedded in a gelatinous matrix, into which the

stereocilia of hair cells project The calcium

carbon-ate crystals are dense with a specific gravity of about

2.7 g/ml compared to the endolymph, which is about

1 g/ml This makes the macula a bioaccelerometer

that reacts to linear acceleration, e.g., translation fore

and aft or side to side (utricle) and vertical translation

and gravity (saccule) These structures consist of

three key components: a heavy mass load (calcium

carbonate), a sensor (hair cells), and an elastic

con-nection (matrix of the otolithic membrane) between

the two (Fig 5)

The otoconial membrane consists of two layers:

an outer layer of otoconia enmeshed in an organic

matrix, and an underlying gelatinous membrane

con-taining glycoprotein and glycosaminoglycans The

gelatinous layer itself consists of two parts: a dense

outer layer of highly cross-linked fibrils that firmly

supports the otoconia and a columnar layer that is a

loose meshwork with elastic properties (Fermin

et al., 1998) These layers distribute inertial forces

of the many otoconia equally to the underlying sory epithelia The otoconial membrane consists ofotoconia and a gelatinous layer composed of otoge-lin The top heavy mass of calcium carbonate crystals

sen-on top of an elastic intermediary serves to make themacular receptor very sensitive in transmitting linearaccelerations to the stereocilia bundles of the sensoryepithelium (Ross et al., 1987; Lins et al., 2000).The supportive globular substance is non-cellularand unable to generate matrix proteins (Suzuki et al.,

1995) Proteins form a meshwork holding otoconiatogether, forming connections between otoconia thatmay also modulate the size, shape and turnover of oto-conia (Lins et al., 2000) Otoconin 90 accounts formore than 90% of the proteins (otoconins) aroundwhich otoconia appear to develop and mineralize(Thalmann et al., 2001) Otoconia are calcium carbon-ate crystals usually numbering about 200,000 permacula in mammals The process of biomineralization

is only partially understood, however there is a dient of calcium concentration as nascent otoconiamove from the sensory epithelial side to the outerotoconial side in both the utricle and the saccule(Campos et al., 1999) Otoconin 90, along with otherotoconins, appears to orchestrate the formation of cal-cium carbonate crystals but also regulates their size,which typically ranges from about 0.5 to 30mm (Lins

gra-et al., 2000)

The striola is a centrally located curvilinear ing line in the macula that separates hair cells in oneorientation from those in another The end result isthat the macula, by its shape and spatial position,responds to linear motion in all directions The oto-conia near the striola are especially susceptible todegeneration (Thalmann et al., 2001)

divid-2.5.2 Crista ampullarisEach semicircular canal (or duct) has a bulge calledthe ampulla that contains a septum called the crista.The crista consists of a cupula (Fig 6), which is agelatinous mass extending across the ampulla at aright angle and is attached at its base and its apicalend to walls of the ampulla, creating a seal that pre-vents endolymph from freely passing (McLaren andHillman, 1979) Due to its elasticity, the cupulasways or bulges to and fro with movement of endo-lymph Hair cells (type I on the crests and type II

on the slopes) of the crista extend their stereocilia

Striola

Otoconia Globular substance

Hair cells

Fig 5 The otolithic membrane The globular substance is a

gelat-inous matrix with the principal structural protein otoconin 90 upon

which calcium carbonate crystals are formed, maintained and held

in place Due to the “top-heavy” structure, the hair cells are

sensitive to movement of the otoconia The otoconia thin out at

the striola, which can be considered a dividing line separating

the directional orientation of hair cell bundles.

into the cupula and react to mechanical displacement

of the cupula Hence, when the head turns,

endo-lymph movement bends the cupula; the hair cell

stereocilia bend, thereby creating an excitatory or

inhibitory response depending on the canal and the

direction of the endolymph current

The crista is not sensitive to gravity; rather, it

reacts to angular acceleration in the plane of the

canal Following acceleration, the cupula returns to

its prior position based on its elastic properties The

restoration of the cupula to its original position can

be modeled mathematically such that the cupular

time constant, estimated to be about 6–7 s, is the time

it takes for the cupula to return to 63% of its resting

position after acceleration (Ferna´ndez and Goldberg,

1971)

2.6 Membranous labyrinth

2.6.1 Semicircular canals

There are three semicircular canals on each side: the

anterior (superior), the lateral (horizontal) and

poste-rior (infeposte-rior) Each canal has a different spatial

ori-entation such that the anterior canal is parallel to

the contralateral posterior canal The lateral canals

are oriented about 25–30 degrees up in the front

relative to the back (Fig 7) Because of the varied

positions of these angular accelerometers, all turning

movements of the head are detected by some nation of stimulation of these canals

combi-The kinocilia are located closest to the utricle inthe lateral canals Therefore turning the head to theright, for example, causesexcitation of the right lat-eral canal crista and inhibition of its counterpart onthe left The anterior and posterior canals are differ-ent since the kinocilia are on the canal side Putanother way, ampullopetal endolymph flow (towardthe ampulla) in the long arm of the semicircularcanal is excitatory in lateral canals, but inhibitory inanterior and posterior canals

There are three important observations known asEwald’s laws that describe the relationship betweenthe plane of the semicircular canals, the direction ofendolymph flow, and how these factors affect thedirection of eye movements Ewald’s laws are:(1) the axis of nystagmus should be in the same plane

as the semicircular canal that generated it; (2) in thelateral canal, ampullopetal flow produces a stronger

Fig 6 The crista ampullaris consists of a gelatinous dome, the

cupula, whose top is attached within the ampullary duct and at

whose apex are hair cells oriented so that tilting of the cupula

bends the hair cells to produce an excitatory nerve impulse

Cupu-lar deflection in one direction is excitatory and in the opposite

direction is inhibitory.

Lateral canal

response than does ampullofugal flow; (3) in the

anterior and posterior canals, ampullofugal flow of

endolymph produces a stronger response than does

ampullopetal flow (Baloh and Honrubia, 1990)

2.6.2 Saccule

The saccule is considered one of the “otolithic

organs” because its receptor, the macula, contains

individual otoliths or calcium carbonate crystals

Due to the position of the macula in the saccule, it

is the vestibular sensor most associated with

detec-tion of gravity (Fig 8) While the saccule does detect

gravity, some of its sensors also respond to sound

sti-muli This is the basis of the vestibular-evoked

myo-genic potential (VEMP) described in a later chapter

The output of the saccule, like other vestibular sense

organs, regulates not only ocular motility via the

ves-tibulo-ocular reflex (VOR), but also ipsilateral

mus-cle tone (Halmagyi et al., 2005)

2.6.3 Utricle

Like the saccule, the utricle is considered an

“oto-lithic organ”, but due to the orientation of the macula

(Fig 8) it is more suited to detecting horizontal linear

movement of the head The utricle responds to zontal linear acceleration whereas the sacculeresponds to vertical linear accelerations, includinggravity

hori-2.7 Bony labyrinth anatomyThe bony labyrinth represents that part of the petrousportion of the temporal bone that houses the mem-branous labyrinth Anteromedially is the internalauditory canal through which the facial and vestibu-locochlear nerves traverse Laterally is the entrance

to the mastoid antrum (aditus ad antrum) Thecochlea is anterior to the vestibular structures andconnects to the vestibule by the embryologic rem-nant, the ductus reunions The mastoid air cells areposterior and lateral to the vestibular apparatus.Medial to the vestibule is the posterior fossa intowhich the endolymphatic sac and duct project underthe dura mater within the vestibular aqueduct Ros-tral to the anterior semicircular canal is the middlecranial fossa

There are two openings between the middle earand inner ear, each covered by a membrane The ovalwindow is an opening on which the footplate of thestapes attaches Sound transmitted through the mid-dle ear bones to the stapes causes vibration at theoval window, which in turn vibrates endolymph forhearing The round window is the other membranecovered communication between the middle andinner ear spaces and serves as a pressure valve bybulging in or out in response to changes in pressure

A fistula is an abnormal rupture or breach in themembrane of the membranous labyrinth, and thesecommonly occur at either the round or oval window

A similar disturbance can occur when a portion ofthe bony labyrinth overlying the superior semicircu-lar canal becomes patent This is important becausethere are clinical symptoms associated with dehis-cence of the superior semicircular canal (Carey

et al., 2000) as discussed in Chapter 15

2.8 Blood supply to the vestibular labyrinthThe labyrinthine (or internal auditory) artery suppliesthe vestibular end organs This vessel is usually abranch of the anterior inferior cerebellar artery butmay also arise from other vessels including the basi-lar artery and rarely the superior cerebellar artery(Fig 9) Upon entering the inner ear, the labyrinthineartery branches into the anterior vestibular artery and

Fig 8 Orientation of the maculae of the utricle and saccule The

macula of the saccule is oriented to render it most sensitive to

vertical acceleration and gravity, whereas the macula of the

utri-cle is oriented to better detect linear accelerations in the

earth-horizontal plane.

the common cochlear artery, which becomes the

ves-tibulocochlear artery that in turn gives off the

poste-rior vestibular artery The anteposte-rior vestibular artery

supplies the anterior and lateral semicircular canals,

the utricle and a small part of the saccule The

poste-rior vestibular artery runs along the medial aspect of

the vestibule supplying the posterior ampulla and

most of the saccule This arterial distribution is fairly

consistent, but the venous drainage of the labyrinth is

highly variable (Mazzoni, 1990)

2.9 Labyrinthine innervation and the

vestibular nerve

The superior vestibular nerve carries fibers from the

anterior and lateral ampullae and the utricular

mac-ula The inferior vestibular nerve supplies the

poste-rior ampulla and saccular macula In humans, the

utricle and the cristae of each semicircular canal are

represented by an approximately equal number of

nerve fibers while the saccule has slightly fewer

fibers (Rasmussen, 1940) The superior and inferior

divisions form a common bundle that proceeds in

the subarachnoid space entering the lateral medulla.The vestibulocochlear nerve is formed by the union

of the vestibular division and the more anteriorlylocated cochlear division Scarpa’s ganglion containsbipolar ganglion cells of first order vestibular neurons

As the vestibular nerve enters the medulla, fibers forthe semicircular canals occupy the rostral half of thenerve and fibers from the maculae of the saccule andutricle are located in the caudal half of the nerve.2.9.1 Efferent projections to the labyrinthAlthough the vestibulocochlear nerve containsmostly afferent nerve fibers, some efferent projec-tions from the brainstem travel with cochlear effer-ents (olivo-cochlear bundle) in the eighth cranialnerve Most vestibular efferent fibers originate in acluster of cell bodies posterolateral to the abducensnucleus referred to as Group E (Goldberg andFerna´ndez, 1980) The efferents synapse widely tovestibular structures in both labyrinths (Schwarz

et al., 1981; Purcell and Perachio, 1997) The pose of the efferent system is not understood

pur-Fig 9 Arterial supply of the membranous labyrinth The labyinthine artery, often a branch of the anterior inferior cerebellar artery, divides into the anterior vestibular artery and the common cochlear artery The latter further divides to form the main cochlear artery that supplies the cochlea and the vestibulocochlear artery and its branch the posterior vestibular artery The anterior vestibular artery supplies the anterior and lateral semicircular canals, the utricle and a small part of the saccule The posterior vestibular artery supplies the posterior canal ampulla and most of the saccule.

2.9.2 Primary vestibular afferent projections

to the cerebellum

Primary vestibular afferents connect to the vestibular

nuclei and the cerebellum No primary vestibular

afferents cross the midline

The primary afferents that are destined for the

cerebellum bypass the vestibular nuclei and go

directly through the juxtarestiform body through

the inferior cerebellar peduncle ending up

predomi-nantly in the ipsilateral flocculus, nodulus, and

ante-rior uvula of the cerebellum (Shinoda and Yoshida,

1975) The flocculonodular lobe (also called the

archicerebellum or vestibulocerebellum) evolved

closely with the vestibular system Most primary

vestibular afferents are from dimorphic synapses

(i.e., both type I calyceal and type II bouton like

endings together) The semicircular canals project

to the flocculus, nodulus, and uvula, whereas those

of the utricle and saccule only to the nodulus and

uvula (Purcell and Perachio, 2001)

2.9.3 Vestibular nuclei

Table 1 lists the main afferent and efferent

projec-tions of the vestibular nuclei The superior vestibular

nucleus is located in the rostral floor of the fourth

ventricle bordered by the middle cerebellar peduncle

(brachium pontis) above and the restiform body

later-ally (Fig 10) The superior vestibular nucleus is a

major relay nucleus for the vestibulo-ocular reflex

(VOR) from the semicircular canals It receives

incoming fibers mainly from the cristae of the

semi-circular canals, while its efferent fibers go to the medial

longitudinal fasciculus on each side and the ocular

motor nuclei (Fig 11) Efferents also go to the

cerebel-lum and through the vestibular commissure

The medial vestibular nucleus is the largest of thevestibular nuclei and is located just caudal to thesuperior vestibular nucleus, though its morphologicappearance is not distinct The medial vestibularnucleus receives important semicircular canal inputsfor the VOR (Highstein and McCrea, 1988) but alsorelays vestibular signals to the vestibulospinal tract

to regulate muscle tone For example, excitatorystimulation of the crista of the lateral canal results

in increased ipsilateral muscle tone and decreasedcontralateral muscle tone This is important in the

Superior nucleus

Lateral nucleus

Vlll Nerve Inferior nucleus Medial nucleus

Fig 10 Coronal depiction of the vestibular nuclei (superior, medial, inferior and lateral) within the dorsolateral rostral medulla.

Table 1

The main afferent and efferent projections of the vestibular nuclei ( Gacek, 1969; Carleton and Carpenter, 1983 )

SCC, saccule, utricle, fastigial n.,

MLF, abducens nucleus, cerebellum, lateralvestibulospinal tract, other vestibular nuclei

SCC ¼ semicircular canal; MLF ¼ medial longitudinal fasciculus.

postural righting reflexes, particular during rapid or

unanticipated head movements

The inferior vestibular nucleus is caudal to the

lat-eral nucleus and morphologically blends with the

adja-cent medial vestibular nucleus The inferior vestibular

nucleus receives afferents broadly and projects to the

cerebellum, spinal cord, and other vestibular nuclei

The inferior vestibular nucleus, with its wide-ranging

afferents and efferents, can integrate vestibular

infor-mation among many of the vestibular structures

The lateral vestibular nucleus or Deiters’ nucleus

receives utricular inputs on its ventral side and

cere-bellar inputs to its dorsal side The cerecere-bellar fibers

originate from the cerebellar cortex, the ipsilateral

anterior vermis, the fastigial nucleus, flocculus, and

paraflocculus The predominant output of the lateral

nucleus descends to form the ipsilateral lateral

vesti-bulospinal tract

2.10 Vestibulo-ocular reflex (VOR)The vestibulo-ocular reflex (VOR) acts at shortlatency to generate eye movements that compensatefor head rotations in order to preserve clear vision dur-ing motion of the head and body The VOR has beenextensively studied and is the basis of many commonlyemployed vestibular tests as will be discussed in laterchapters The VOR can be subdivided into reflex path-ways associated with the sensory structures within thelabyrinth, i.e., canal- and otolith-ocular reflexes

2.10.1 Canal-ocular reflex (VOR)The neural circuit for the canal-ocular reflex beginswith an excitatory stimulus from the ampulla of thesemicircular canal Fig 12 illustrates the right-sidedexcitatory pathways for each of the semicircular

Fig 11 Primary and secondary vestibular connections, including primary vestibular afferents from the labyrinth, efferents from the tibular nuclei to the cerebellum, vestibulospinal tracts and descending medial longitudinal fasciculus, and the vestibulo-ocular and vestibulothalamic projections.

canals (Ito et al., 1976) Stimulation of each canal

evokes a muscle contraction in the plane of the canal

(Flouren’s law)

Signals from the anterior canal are relayed to the

ipsilateral superior vestibular nucleus, then via

bra-chium conjunctivum (superior cerebellar peduncle)

and the contralateral medial longitudinal fasciculus

to the contralateral oculomotor nucleus This results

in stimulation of the ipsilateral superior rectus

muscle and the contralateral inferior oblique

result-ing in upward and contradirectional torsional eye

movements

Lateral canal signals synapse in the ipsilateral

medial vestibular nucleus and from there project to

the contralateral abducens nucleus and to the

ipsilat-eral oculomotor nucleus by two pathways: (1) from

the contralateral abducens nucleus back to the

ipsilat-eral medial longitudinal fasciculus; and (2) by a more

direct path directly from the ipsilateral medial

vestib-ular nucleus via the ipsilateral ascending tract of

Dei-ters These combined pathways lead to activation of

the ipsilateral medial rectus and the contralateral

lat-eral rectus, resulting in conjugate deviation of the

eyes to the opposite side

Posterior canal excitatory projections synapse in

the medial vestibular nucleus then cross over to the

contralateral medial longitudinal fasciculus These

fibers then project to: (1) the contralateral trochlear

nucleus that leads to stimulation of the ipsilateral

superior oblique; and (2) the contralateral inferior

rectus subnucleus of the oculomotor nucleus

resulting in contraction of the inferior rectus muscle.This results in downward and contradirectional tor-sional eye movements

2.10.2 Otolith-ocular reflex (VOR)The otolith-ocular reflex pathways are not as wellunderstood as are those of the canal-ocular pathways.The otolith organ hair cells respond to linear acceler-ation including gravitational pull The otolith-ocularreflexes are of two types: (1) the translational VOR(tVOR) responds to horizontal (side to side and foreand aft) and vertical translations of the head, and (2)the otolith righting reflex responds to static tilt aboutthe naso-occipital axis in an attempt to realign theeyes with the earth-horizontal plane Stimulation ofthe utricle in cats leads to elevation of the ipsilateraleye, depression of the contralateral eye, and contra-directional cyclotorsion of the eyes This normal pat-tern of response in a lateral eyed animal becomes thepathological ocular tilt reaction (OTR) in humanswith lesions in otolith and vertical canal pathways.The OTR refers to the triad of vertical eye (skew)deviation, head tilt toward the lower eye, and cyclo-torsional eye deviation (counterrolling) toward thelower eye The ocular tilt reaction results fromasymmetrical utricular inputs to the vestibular nucleiand the interstitial nucleus of Cajal and from there tothe oculomotor and trochlear nuclei Lesion studies

in humans and other data suggest that the utricle jects to the ipsilateral lateral vestibular nucleus,

pro-Anterior canal excitatory projections SR

AC

LC ATD

Posterior canal excitatory projections

Fig 12 Excitatory projections from individual semicircular canals on the right side to the extraocular muscles SO: superior oblique; IO: inferior oblique; IR: inferior rectus; LR: lateral rectus; SR: superior rectus; MR: medial rectus; AC: anterior canal; PC: posterior canal; LC: lateral canal; MLF: medial longitudinal fasciculus; ATD: ascending tract of Deiters; BC: brachium conjunctivum; VN: vestibular nuclei (S ¼ superior; I ¼ inferior; L ¼ lateral; M ¼ medial); III: oculomotor nucleus; IV: trochlear nucleus; VI: abducens nucleus.

crosses in the pontine tegmentum, and ascends to

the contralateral interstitial nucleus of Cajal

The saccular projections are believed to synapse in

the lateral vestibular nucleus and y group of the

vestib-ular nuclear complex and appear to play an important

role in vestibulospinal pathways, producing relatively

weak vertical eye movement responses Note however

that stimulation of the sacculus by sound is the basis

for eliciting vestibular-evoked myogenic potential

(VEMPs), which are discussed in a later chapter

2.10.3 Neural integration and velocity storage

Oculomotor neurons encode both the position and the

velocity of the eye The vestibular inputs from the

crista of the semicircular canals only signal head

velocity, and the direction and amplitude can be

adjusted by the vestibular nuclei The eye position

signal must be produced by another mechanism

Since mathematical integration of the velocity signal

yields a position signal, this function has been termed

neural integration This process applies not just to

the VOR but also to other types of eye movements

The neural integrator for the horizontal VOR is likely

represented by the nucleus prepositus hypoglossi and

the medial vestibular nucleus, with an important

con-tribution from the cerebellum (Cannon and Robinson,

1987) The neural integrator for the vertical VOR is

thought involve the interstitial nucleus of Cajal

Horizontal VOR responses to a rotational stimulus

last longer than the driving signals from the lateral

canal This prolongation of vestibular responses is

referred to asvelocity storage and can be

conceptua-lized as a neural integration specific to vestibular

sig-nals In engineering parlance the velocity-storage

mechanism improves the low-frequency response of

the VOR This effect of the velocity-storage

mecha-nism is the basis for many quantitative tests of

ves-tibular function including the changes of the phase

relationships at low frequencies of sinusoidal head

rotation and the duration of responses to

constant-velocity rotations, which determine the time constant

of the VOR, tilt-suppression of post-rotatory

nystag-mus, and the appearance of head-shaking induced

nystagmus and optokinetic afternystagmus

2.10.4 Vestibulocerebellar interactions

The largest contingent of afferents to the vestibular

nuclei comes from the cerebellum, followed by

pri-mary vestibular afferent fibers from the vestibular

nerve and the spinal cord Some descending fibersfrom the interstitial nucleus of Cajal passing via themedial longitudinal fasciculus and reticular forma-tion also synapse in the medial vestibular nucleus(Walberg, 1972)

Numerous secondary vestibular neuronal tions include fibers connecting the cerebellar vermis

interac-to the lateral vestibular nucleus and interneurons necting to the fastigial nucleus and reticular forma-tion The flocculus receives vestibular afferents viamossy fibers, which in turn send inhibitory GABA-ergic signals via Purkinje cell axons that project tovestibular nuclear cells involved in VOR pathways.Several lines of evidence suggest that retinal signalerrors provoke the flocculus to improve VOR perfor-mance in an attempt to reduce retinal errors (Ito,

con-1993) Hence the flocculus appears to be particularlyimportant for adaptive change of the horizontal andthe vertical VOR

The nodulus and uvula exert an inhibitory ence on the velocity-storage mechanism In normalindividuals, post-rotatory nystagmus can be signifi-cantly foreshortened by tilting the head forward atthe onset of post-rotatory nystagmus or so-called “tiltsuppression” This is likely due to a “dumping”effect upon the velocity-storage mechanisms Patientswith uvulonodular lesions lose tilt suppression (Hain

influ-et al., 1988) Excitation of the nodulus results in areduced VOR time constant and reduced velocitystorage (Solomon and Cohen, 1994)

2.10.5 Ewald’s lawsSeveral principles of anatomic and functional impor-tance were noted by Ewald His first law was likeFluoren’s law, namely that eye movements from canalstimulation occur in the plane of the canal and in thedirection of endolymph flow Ewald’s second lawindicates that in the lateral semicircular canal, ampul-lopetal endolymph flow causes a greater responsethan ampullofugal endolymph flow Ewald’s thirdlaw states that for the anterior and posterior canals,ampullofugal flow causes a greater response thanampullopetal flow

2.11 Vestibulospinal reflexesExcitatory inputs to the motor neurons for antigravitymuscles are carried in the lateral vestibulospinal tractthat emanates from Deiters nucleus on the same side

In addition, a medial vestibulospinal tract emanates

from each medial vestibular nucleus Together, these

pathways are important to maintain balance

Unilat-eral vestibular loss results in ipsilatUnilat-erally reduced

muscle tone and a general tendency to fall toward

the side of the lesion Vestibulocollic reflex

path-ways mediate the transient inhibitory signals from

the saccule to ipsilateral musculature in

vestibular-evoked myogenic potentials (see Chapter 15)

2.12 Vestibulothalamic projections

Vestibular fibers from the medial and superior

ves-tibular nuclei project to the central lateral, ventral

posterolateral and ventrolateral thalamic nuclei via

the medial longitudinal fasciculus, tract of Deiters

and superior cerebellar peduncles Fibers from the

inferior vestibular nuclei project to the rostral dorsal

medial geniculate nucleus by way of the medial

lon-gitudinal fasciculus, superior cerebellar peduncle,

and lateral lemniscus (Nagata, 1986)

2.13 Vestibular cortical perception

Cortical representation of vestibular function has

been identified in primates Recordings have shown

that these cortical regions receive inputs from both

the vestibular labyrinth and from converging visual

and somatosensory information The human

homo-logue of the primate parieto-insular vestibular cortex

(PIVC) appears to play a role in perceiving

vertical-ity and self-motion Acute ablative lesions in this

area as may occur with strokes lead to head tilt away

from the side of the lesion and distortion of perceived

verticality (Brandt and Dieterich, 1999)

Positron emission tomography or functional

mag-netic resonance tomography showed that the PIVC

acti-vates during caloric irrigation of the ears and following

galvanic stimulation of the mastoid This is discussed

further by Dieterich in Chapter 24 (this volume)

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CHAPTER 3

Overview of anatomy and physiology

of the ocular motor system

Departments of Neurology and Ophthalmology, Mount Sinai School of Medicine, One Gustave L Levy Place, Box 1052, New York, NY 10029, USA

3.1 Introduction

The shared goal of all components of the ocular motor

system is to maintain clear, single vision by placing

and maintaining an object of visual interest on the fovea,

the retinal region with the highest density of

photorecep-tors and the best visual acuity Several functional classes

of eye movements coexist to meet this shared goal

These include saccades, smooth pursuit, vergence,

optokinetic responses, and vestibular reflexes

Anato-mically and physiologically, separate premotor or

supranuclear command networks exist for initiation

and modulation of each functional class of eye

move-ments These premotor networks converge upon a “final

common pathway” that includes the ocular motoneuron,

neuromuscular junction, and the final effector organ of

eye movements – the extraocular muscle It has long

been held true that all motoneurons and extraocular

muscle fibers participate in all types of eye

move-ments (Scott and Collins, 1973), though some may be

more important for certain types of eye movements

(Bu¨ttner-Ennever et al., 2001; Bu¨ttner-Ennever, 2005)

Modern biologic, anatomic, and physiologic

techni-ques such as gene expression profiling, single cell

recordings to determine cell electrophysiologic

proper-ties, lesional inactivation with observation of

behav-ioral changes, and tracer methodologies to determine

neural networks have greatly advanced understanding

of the ocular motor system – to the point of challenging

some classically held truisms such as the concept of a

definitive “final common pathway” and absolute

con-jugacy of the ocular motor system (Mays et al., 1986;

Zhou and King, 1998; Miller et al., 2002; Miller,2003; Sylvestre et al., 2003) The complexity andvariety of demands that the ocular motor system mustmeet in order to maintain stable vision require complexanatomy and physiology at every level – from extra-ocular muscle to cortical ocular motor regions.3.2 Functional classes of eye movements3.2.1 Saccades

Saccades are rapid, conjugate eye movements withwhich we explore a visual scene or shift gaze to pointthe fovea at pertinent details in the visual world (Robin-son, 1964) Because of the small foveal size, a highdegree of accuracy is required Saccades may be volun-tary or reflexive and generated to actual targets or tomemory for target location They are fast eye move-ments, with most ranging between 300 and 500
/s;and they are brief, most lasting less than 100 ms so asnot to disrupt vision The average saccadic latency is200–250 ms This increases slightly with aging andcan be manipulated by the presence of a fixation stimu-lus prior to presentation of the saccade target (Kalesny-kas and Hallett, 1987; Sharpe and Zackon, 1987).Saccadic peak velocity and duration are a function ofsaccade size (for example, the larger a saccade, the fasterand longer it is)(Fig 1)(Bahill et al., 1975; Baloh et al.,1975; Garbutt et al., 2003; Leigh and Kennard, 2004).Execution of a saccade requires an initial neuronalburst command called the pulse to stimulate the moto-neuron to generate a rapid eye movement of a specificsize and in a specific direction (Robinson, 1970) This

is followed by continued neuronal discharge called thestep to maintain the eyes in the new eccentric gazeposition against the pull of orbital elastic forces (Millerand Robins, 1992) The resultant two-componentmotoneuron discharge pattern is termed “pulse-step”

or “burst-tonic” (Van Gisbergen et al., 1981; Sylvestre

*

Correspondence to: Dr J.C Rucker, Departments of

Neurology and Ophthalmology, Mount Sinai School of

Medicine, One Gustave L Levy Place, Box 1052, New York,

NY 10029, USA

Tel.:þ1 (212) 241-7282; fax: þ1 (212) 987-3301

E-mail:janet.rucker@mssm.edu(J.C Rucker)

Vertigo and Imbalance: Clinical Neurophysiology of the Vestibular System

Handbook of Clinical Neurophysiology, Vol 9 S.D.Z Eggers and D.S Zee (Vol Eds.)

# 2010 Elsevier B.V All rights reserved

18

and Cullen, 1999) Between the two components is an

exponential slide, joining the pulse and the step (Miller

and Robins, 1992) Occasionally, there is a mismatch

between the step and the pulse, and the eye drifts at

the end of the saccade Such post-saccadic drift has

been termed a glissade (Bahill et al., 1978)

3.2.2 Smooth pursuit

Smooth pursuit allows the image of a small, slowly

moving target to be maintained on the fovea In contrast

to saccades, smooth pursuit is a slow eye movement withaverage velocities of 20–50
/s and latencies of approxi-mately 100 ms (Morrow and Sharpe, 1993) While sac-cades may be voluntary or reflexive, smooth pursuit isprimarily voluntary, driven by visual motion, and modu-lated by attention and motivation (Recanzone and Wurtz,

2000) Both retinal cues such as the velocity and position

of target image on the retina and non-retinal cues such ascomparisons of target movement with gaze movementgovern smooth pursuit (Robinson et al., 1986; Lisberger

et al., 1987; Blohm et al., 2005; Thier and Ilg, 2005)

40

500

0 100 200 300 400

Amplitude (deg)B

40

Fig 1 Properties of saccades for normal subjects (small dots), with 5 and 95% prediction intervals for normals also shown on each plot For comparison, an example of saccade properties is illustrated for a patient with late-onset Tay–Sachs disease (LOTS) (large circles), in which saccades are slower, and hence longer duration, than in normal subjects A: Relationship between saccadic amplitude and peak veloc- ity for horizontal saccades Note increasing saccadic velocity for increasing saccadic amplitude in normals In the LOTS patient, saccades are slower than expected for size B: Relationship between saccadic amplitude and duration for horizontal saccades Note increasing sac- cadic duration for increasing saccadic amplitude in normals In the LOTS patient, saccades are much longer than expected for size (Figure courtesy of Patrick Lynch and Yale University School of Medicine.)

3.2.3 Vergence

Vergence is a disconjugate eye movement by which a

single foveal image is maintained with gaze shifts

from near to far (divergence) or from far to near

(con-vergence) The primary stimuli for vergence are retinal

blur and retinal disparity Retinal blur is loss of visual

image sharpness and retinal disparity is image

separa-tion when images fall on non-corresponding areas of

each retina

3.2.4 Vestibular reflexes

The phylogenetically old vestibulo-ocular reflex

gen-erates compensatory eye movements during brief head

movements It is essential to maintain a stable image

during walking and to see an object clearly while the

head is moving The anatomy and physiology of the

vestibular system are discussed in detail in the

preced-ing chapter and are not further discussed here

3.2.5 Optokinetic responses

Optokinetic responses are generated by movement of

a large visual scene and function to hold an image

steady on the fovea during sustained head rotation

Optokinetic nystagmus is elicited upon continuous

stimulation in a single direction and consists of two

components – a slow phase in the direction of the

moving stimulus and a quick phase to reset the eyes

in the opposite direction

3.3 Extraocular muscles

3.3.1 Overview and muscle actions

Six extraocular muscles control the movements of each

eye: medial rectus, lateral rectus, superior rectus, inferior

rectus, superior oblique, and inferior oblique The

medial rectus, superior rectus, inferior rectus, and

infe-rior oblique are innervated by the oculomotor nerve

(cra-nial nerve III) The lateral rectus is innervated by the

abducens nerve (cranial nerve VI) The superior oblique

is innervated by the trochlear nerve (cranial nerve IV)

Coordinated extraocular muscle action facilitates

movement of the eyes in three directional planes:

hori-zontal, vertical, and torsional When the head is in a

fixed position, torsional eye movements are governed

by Donders’ and Listing’s laws which describe

(Don-ders’ law) and quantify (Listing’s law) the single

tor-sional eye position possible for each combination of

horizontal and vertical position (Straumann et al.,

1996) The actions of each muscle depend on the cle’s origin and terminal insertion, the center of rotation

mus-of the eye, and the optical axis mus-of the eye Muscle actionmay vary depending on the position of the globe in theorbit Each extraocular muscle has a primary direction

of action and all but the medial rectus and lateral rectusalso have secondary and tertiary directions of action.Horizontal eye movements are controlled by theantagonistic medial rectus and lateral rectus muscles.The primary and only action of the medial rectus isadduction and the primary and only action of the lat-eral rectus is abduction For any agonist/antagonistmuscle pair, Sherrington’s law dictates that increasedinnervation to the agonist results in an equal amount

of decreased innervation to the antagonist Verticaland torsional eye movements are controlled by twoantagonist pairs; the superior and inferior recti andthe superior and inferior oblique muscles The contri-bution of a given muscle to vertical eye movementdepends upon the horizontal position of the eye.When the eye is in an abducted position, the superiorand inferior rectus muscles are the principal elevatorand depressor muscles, respectively When the eye is

in an adducted position, inferior oblique actioncauses elevation and superior oblique action causesdepression The superior oblique and superior rectusmuscles are intorters of the eye and the inferioroblique and inferior rectus are extorters The primary,secondary, and tertiary actions of each muscle areshown inTable 1

In addition to existing as antagonistic pairs withopposite directions of action, the extraocular musclesexist as “yoked” pairs to generate conjugate eyemovements The three yoked pairs include: (1) themedial rectus in one eye and the contralateral lateralrectus for conjugate horizontal gaze; (2) the inferioroblique in one eye and the contralateral superior rec-tus for gaze up and laterally; and (3) the superioroblique in one eye and the contralateral inferior rec-tus for gaze down and laterally Hering’s law ofequal innervation dictates that “yoked” musclesreceive equal and simultaneous innervation generatedfrom premotor control systems stimulating the cra-nial nerve nuclei to elicit the conjugate eye move-ment However, some studies of disjunctive eyemovements (in which one eye moves more than theother) conflict with Hering’s law and suggest thatpremotor control circuits encode monocular eyemovements (McConville et al., 1994; Zhou and King,1998; King and Zhou, 2002)

3.3.2 Orbital and muscle gross anatomy

The extraocular muscles reside within the bony

con-fines of the pyramid-shaped orbit, the walls of which

are formed by the frontal, lacrimal, ethmoid,

sphe-noid, and zygomatic bones, and the maxilla

(Fig 2) At the apex of the pyramid (the orbital

apex), the four rectus muscles and the superior

oblique arise from a dense fibrous ring of periosteum

called the annulus of Zinn The annulus encircles the

optic foramen through which the optic nerve passes

and divides the superior orbital fissure into two

portions (Fig 3) The oculomotor, abducens, andtrochlear nerves and the first division of the trigemi-nal nerve pass through the superior orbital fissure.The inferior oblique arises from the maxillary perios-teum in the inferior nasal orbit From the orbitalapex, the muscles course anteriorly through theorbital fat and, ultimately, terminate in tendinous tis-sue (see the section “Extraocular muscle layers”below for additional discussion of extraocular muscleterminations)

The portions of the four recti muscles that nate in the sclera of the globe attach to the globe

termi-Table 1

Primary, secondary, and tertiary actions of the extraocular muscles

Levator palpebrae superioris muscle Trochlea of superior oblique muscle Superior oblique muscle Superior rectus muscle

Medial rectus muscle

Superior division Inferior division

Oculomotor nerve

Lateral rectus muscle (cut) Inferior oblique muscle Inferior rectus muscle Ciliary nerves Ciliary ganglion

Fig 2 Orbital contents and positioning of extraocular muscles in a sagittal orbital view (Figure courtesy of Patrick Lynch and Yale versity School of Medicine.)

on its anterior half between 5 and 8 mm from the

limbus (the border between the cornea and the

sclera) The superior and inferior rectus muscles

attach slightly medial to the vertical axis of rotation

of the eye The superior oblique passes through a

rigid ring of connective tissue called the trochlea

that is located in the upper, nasal portion of the

orbital frontal bone (Fig 2) It then terminates in

the sclera in a lateral posterior position After origin

in the inferior nasal orbital wall, the inferior oblique

crosses the orbital floor to ascend along the globe

laterally and insert on the lateral posterior globe

medial to the lateral rectus(Fig 2) The globe itself

is suspended in and supported by Tenon’s capsule, a

layer of connective tissue covering the posterior

two-thirds of the globe and attaching anteriorly to

the sclera and posteriorly to the optic nerve

3.3.3 Extraocular muscle in contrast to skeletal

muscle

The biochemical and structural characteristics of

muscle are in large part determined by the specific

task the muscle is designed to do Skeletal muscles

are primarily classified in terms of fiber type, with

each individual muscle composed of the fiber type

or combination of fiber types appropriate for the task

at hand, such as constant generation of force with

resistance to fatigue for anti-gravity muscles or rapid

generation of unsustained force with rapid fatigue

for muscles activated intermittently for specific

and precise tasks (Porter, 2002) Skeletal muscle

fibers include slow-twitch, fatigue-resistant fibers

(type I – red); fast-twitch, high-fatigue fibers (typeIIB – white); and intermediate fibers (type IIA)

In contrast to the single function of a given etal muscle, each extraocular muscle is highlyspecialized and designed to perform different types

skel-of movement and to contract at high speed for longperiods of time The variety of functional eye move-ment classes including smooth pursuit, saccades,and vergence is likely responsible for the biologiccomplexity of the extraocular muscles Variations

in fiber type alone would be insufficient to meetthe demands of ocular motor control systems Inaddition to differences in fiber type, extraocularmuscles attain functional diversity by and differ sig-nificantly from skeletal muscles in compartmentali-zation of layers, innervation pattern, myosin heavychain isoforms, metabolic properties, and geneexpression (Bu¨ttner-Ennever et al., 2001; Porter

et al., 2001; Porter, 2002) Individual extraocularmuscle fibers are much smaller in diameter thanskeletal muscles Motor units are also smaller, withone motoneuron innervating only 10 extraocularmuscle fibers (Spencer and Porter, 2005) Recentprogress toward understanding the properties ofextraocular muscle has resulted in recognition ofextraocular muscles as a distinct muscle class andgenerated significant interest in differential involve-ment of eye muscles in disease states (Porter et al.,2001; Kaminski et al., 2003)

3.3.3.1 Extraocular muscle layersEach extraocular muscle is compartmentalized intotwo distinct layers: a global layer and an orbital layer

Superior oblique muscle Levator palpebrae superioris muscle

Superior rectus muscle Oculomotor nerve, superior division

Oculomotor nerve, inferior division

Inferior rectus muscle

Inferior oblique muscle Medial rectus muscle

Trochlear nerve Lateral rectus muscle Abducens nerve

Fig 3 Orbital apex and the annulus of Zinn (Figure courtesy of Patrick Lynch and Yale University School of Medicine.)

(Mayr, 1971) A third layer, the marginal zone, has

been more recently described and is likely the same

as the previously described peripheral patch layer in

sheep (Harker, 1972; Wasicky et al., 2000) These

muscle layers have distinct morphologic,

physio-logic, and functional characteristics – many of which

remain incompletely understood The inner global

layer parallels the optic nerve and globe and consists

of large muscle fibers, each innervated by a single

motoneuron (Lam et al., 2002) The c-shaped outer

orbital layer is located along the external bony orbital

surface and consists of small muscle fibers with a

high oxidative capacity and high vascular and

mito-chondrial content(Fig 4)(Carry et al., 1986;

Spen-cer and Porter, 2005) It has been suggested that the

marginal zone covers the outer surface of the orbital

layer with the exception of the proximal and distal

ends of the muscle and is composed of larger musclefibers than the orbital layer (Wasicky et al., 2000).The distal ends of the inner global layer insert onthe sclera of the globe, while the distal ends of theouter orbital layer end before the sclera and insert

at the equator of the globe on fibrous sleeves or rings

of collagenous tissue in Tenon’s capsule calledpulleys (Fig 5) (Demer et al., 1995, 2003; Oh

et al., 2001) Pulleys are suspended by the orbitalwall via collagen, elastin, and smooth muscle (Kono

et al., 2002) The presence of pulleys is supported byMRI, anatomic, and histologic studies (Demer,

2002) Anatomic and functional differences betweenthe global and orbital layers suggest that these mus-cle fibers serve different purposes, and an active pul-ley hypothesis provides for a direct connectionbetween structure and function According to thehypothesis, the global layer is responsible for eyerotation, while the orbital layer alters the direction

of action of global layer fibers This orbital layer roleexists because the pulley defines the functional origin

of the muscle and allows distal inflection of the cle to effect eye movement rather than large scalemovement of the muscle throughout its entire length

mus-in the orbit (Demer et al., 2000) This concept hasrevolutionized the study of ocular motility, as itallows transference of some of the responsibility foradherence to the rules that govern three-dimensionaleye movements to the extraocular muscle from thebrain (Tweed and Vilis, 1987; Quaia and Optican,1998; Porrill et al., 2000) The oxidative metabolicefficiency and fatigue-resistance of the orbital layermuscle fibers make them particularly suited to theirrole and to the sustained contraction required by thesteady elastic tension of the pulleys

3.3.3.2 Innervation patternAll skeletal muscle fibers are singly innervated, withone nerve terminus contacting the muscle end-plate

in the central portion of the muscle and generatingaction potentials to elicit an “all or none” response

In contrast, extraocular muscles contain both singlyinnervated fibers (SIFs) and phylogenetically oldmultiply innervated fibers (MIFs)(Fig 4) The com-position of these innervation types varies between theglobal and orbital muscle layers, with the orbitallayer containing a higher percentage (20%) of MIFsthan the global layer (Porter et al., 1995)

Singly innervated fibers in extraocular muscleshave a similar structure to those in skeletal muscle;

a single neuron terminates as a large en plaque

6

5

4

Fig 4 A: Cross-section of mouse extraocular muscle from the

midportion of the muscle showing a well-developed c-shaped orbital

region and a global region of approximately equal size.

B: Trichrome-stained section of mouse extraocular muscle

empha-sizing the structural contents of the muscle Fibers are labelled:

1, orbital singly innervated fibers (SIF); 2, orbital multiply

innervated fibers (MIF); 3–5, global SIF; 6, global MIF (Figures

courtesy of Dr Henry Kaminski.)

motor end-plate in the central portion of the muscle

fiber that propagates action potentials In multiply

innervated fibers, in contrast, there are numerous,

small en grappe synapses along the muscle fiber,

with the greatest density of synapses distally

(Wasicky et al., 2000) MIFs in global layer fibers

and at the proximal and distal ends of orbital layer

fibers are non-twitch muscle fibers that do not

gener-ate action potentials; rather, they genergener-ate slow, tonic

responses to neural stimulation in a fatigue-resistant

manner resulting in only minor degrees of muscle

movement (Bondi and Chiarandini, 1983; Jacoby

et al., 1989) In contrast, MIFs in the belly of orbital

layer fibers have twitch contraction with generation

of action potentials The functional role of tonic,

non-twitch MIFs is uncertain, but it has been

hypothesized that they may play a role in fine eye

movement control near the central position

Motoneu-rons for the SIFs are located in the center of the ocular

cranial nerve nuclei, whereas motoneurons for the

MIFs are located in the periphery of these nuclei

(Fig 6)(Bu¨ttner-Ennever et al., 2001; Bu¨ttner-Ennever,2005a) The motoneurons differ in histochemical prop-erties, in addition to location (Eberhorn et al., 2005).Premotor inputs for the MIFs originate in neural inte-grator, vergence, and smooth pursuit areas and not insaccadic premotor areas (Bu¨ttner-Ennever et al., 2002).Debate exists regarding whether the brain receivesfeedback about eye position directly from eye muscleproprioceptors (inflow theory) or strictly from a copy

of the central motor command (outflow theory)(Guthrie et al., 1983) Studies of the effect of bilat-eral proprioceptive deafferentation on ocular motorcontrol suggest that efferent commands provide ade-quate and sufficient information for normal ocularmotor control, and the existence of functional propri-oception in extraocular muscles is not definitivelyproven (Lewis et al., 2001) In humans, traditionalproprioceptive muscle spindles are associated withthe orbital layer but not with the global layer

Pulley Ring

Pulley sling

Smooth muscle Collagen Elastin Optic ner

ve MR LR

LPS

Pulley sling

Pulley ring

Fig 5 Orbital connective tissues (including the rectus muscle pulleys) and their relationship to the extraocular muscles Arrows pointing

to the axial section of the orbit show locations of corresponding coronal views Abbreviations: LPS – levator palpebrae superioris, SR – superior rectus, SO – superior oblique, SOT – superior oblique trochlea, LR – lateral rectus, MR – medial rectus, IO – inferior oblique,

IR – inferior rectus, LG – lacrimal gland (Figure courtesy of Dr Joseph Demer.)

(Lukas et al., 1994; Bu¨ttner-Ennever et al., 2003).

Traditional proprioceptive Golgi tendon organs are

associated with the global layer A small cap of nerve

filaments called myotendinous cylinders or palisade

endings is located at the distal end of global layer MIFs

(Richmond et al., 1984) The nerve that terminates in

the palisade ending originates in the muscle, extendsout to the tendon, and then turns back 180
to contact

an individual multiply innervated fiber The function

of these palisade endings is unknown, and controversyexists between whether they have a motor or sensoryrole (Lukas et al., 2000; Blumer et al., 2001; Konakci

et al., 2005), but many lines of evidence suggest a sory role with afferent projections to the ipsilateralsemilunar (gasserian) ganglion and spinal trigeminalnucleus (Porter and Spencer, 1982; Ruskell, 1999;Donaldson, 2000; Bu¨ttner-Ennever et al., 2003, 2005;Eberhorn et al., 2005b) While deafferentation has littleeffect on ocular motor control, such afferent proprio-ceptive information may play a role in development ofocular conjugacy, long-term adaptation to strabismicdisturbances, or visuospatial processing (Steinbachand Smith, 1981; Trotter et al., 1990; Lewis et al.,

sen-1994, 2001)

3.3.3.3 Myosin heavy chain expressionMuscles generate force via interactions between actinand myosin filaments While actin is conservedacross all muscle types, myosin heavy chains(MyHCs) are variable (Porter, 2002) Skeletal mus-cles express only adult isoforms of MyHCs Extrao-cular muscles express developmental (embryonicand neonatal), cardiac, and extraocular muscle-specific MyHC isoforms, in addition to the typicalskeletal muscle isoforms (Wieczorek et al., 1985;Rubinstein and Hoh, 2000) In extraocular muscle,expression of these isoforms varies not only betweenthe global and orbital muscle layers, but betweensingly- and multiply-innervated fibers and along thelength of a single fiber type (Jacoby et al., 1990;Rubinstein et al., 2004) These differences are likelyresponsible for the differing twitch versus tonic con-tractile properties of the SIF and MIF muscle fibers.3.3.3.4 Gene expression and metabolic propertiesExpression profiling techniques such as DNA micro-array and serial analysis of gene expression (SAGE)have been utilized to determine differential geneexpression between extraocular and skeletal musclewith the expectation that the unique anatomic, meta-bolic, and physiologic phenotype of extraocular mus-cle extends to the molecular level Such work hasestablished the “novel molecular signature of extra-ocular muscle” (Porter et al., 2001; Cheng andPorter, 2002) Genes regulating expression of embry-onic and extraocular muscle-specific MyHCs, oxida-tive metabolism, mitochondrial and vascular content

Fig 6 The multiply innervated fiber (MIF) motoneurons (black

dots), mainly supplying the global layer of muscle, lie around

the periphery of the nuclei of cranial nerves III, IV and VI in a

dif-ferent pattern from the singly-innervated fiber (SIF) motoneurons.

The C-group contains medial rectus and inferior rectus MIF

motoneurons The S-group contains inferior oblique and superior

rectus MIF motoneurons The medial rectus SIF motoneurons

(open circles) are located in the dorsal B-group and ventral

A-group (Figure courtesy of Dr Jean Bu¨ttner-Ennever, see

refer-ences Bu¨ttner-Ennever et al., 2001; Bu¨ttner-Ennever, 2005 )

have been found to be up-regulated in extraocular

muscle compared to skeletal muscle (Porter et al.,

2001; Cheng and Porter, 2002; Fischer et al., 2002)

Genes regulating glycogenolysis and

gluconeogene-sis are down-regulated, suggesting that extraocular

muscle obtains glucose directly from its extensive

microvascular network, rather than generating it

internally (Porter et al., 2001; Cheng and Porter,

2002; Fischer et al., 2002) These genetic differences

contribute directly to the fatigue-resistant, efficient

metabolic properties of extraocular muscle

The concept of differential functional tasks for the

orbital and global muscle layers engendered by

the active-pulley hypothesis led to application of

gene expression profiling techniques to these muscle

layers Genetic expression differences were most

prominently identified for sarcomeric contractile

structure, in keeping with the concept of substantial

differences in contractile speed and mechanical loads

for the orbital and global layers (Khanna et al., 2004)

3.3.3.5 Extraocular muscle classification

The unique and diverse properties of extraocular

muscle defy application of standard skeletal muscle

classifications that are based solely on classical fiber

type As a result, the most accepted classification

structure for extraocular muscle is divided into six

extraocular muscle-specific fiber types based on

layer location, mitochondrial content as it relates to

twitch characteristics, and innervation (Table 2)

These fiber types include orbital singly innervated,

orbital multiply innervated, global slow-twitch singly

innervated, global fast-twitch singly innervated,global intermediate-twitch singly innervated, andglobal multiply innervated (Fig 4B) (Porter et al.,1995; Wasicky et al., 2000)

) of nictotinicACh receptors at their crests (Kandel and Siegelbaum,

1991) ACh interaction with the ACh receptor ates an excitatory end-plate potential, and these aresummed to create an action potential with subsequentmuscle contraction Embryologically, formation ofthe NMJ is triggered by signaling pathways initiated

gener-by the motoneuron which induce ACh receptor tering and post-synaptic maturation

clus-Given the unique phenotype and complexity ofextraocular muscle, it is not surprising that NMJs

in extraocular muscle differ from those in skeletalmuscle Differences exist not only between extraocular

Table 2

Extraocular muscle fiber types

twitch SIF

slow-Global mediate-twitchSIF

inter-Globalfast-twitchSIF

Global MIF

Mitochondrial

Non-twitch – distaland proximal ends

Table adapted from Prog Brain Res 2005; 151: 43–80.

Abbreviations: SIF – singly-innervated fiber;

MIF – multiply-innervated fiber.

and skeletal muscle NMJs, but also between various

extraocular fiber types The primary differences

include: (1) NMJ morphology; (2) a non-linear

relation-ship between motor end-plate size and muscle fiber

size; (3) the lack of generation of action potentials by

most multiply innervated fibers (MIFs); and (4)

expres-sion of the neonatal gamma ACh receptor subunit in the

mature state These differences may explain, in part,

why extraocular muscles are susceptible to involvement

in specific disease states, such as myasthenia gravis

(Kaminski et al., 2003)

Extraocular muscle NMJs lack the dense

post-syn-aptic junctional folding found in skeletal muscle but

share the molecular structure of post-synaptic

skele-tal NMJs (Fig 7) (Khanna et al., 2003)

Develop-mental signaling pathways are highly conserved and

identical in extraocular and skeletal muscles (Khanna

and Porter, 2002) However, some of the signaling

molecules are found in novel extracellular locations

in extraocular muscle (Khanna et al., 2003) Four

types of NMJs are identified in extraocular muscle:

singly-innervated fibers have either typical, rounded,

or elongated NMJs and multiply-innervated fibers

have multiple, small, simple NMJs (Oda, 1986;

Khanna et al., 2003) In contrast to the linear

rela-tionship between NMJ size and motor fiber diameter

found in skeletal muscle, extraocular motor

end-plates are relatively large in relationship to muscle

fiber diameter (Oda, 1985; Khanna et al., 2003)

Adult skeletal muscle NMJs contain ACh receptors

composed of four types of subunits: 2a-subunits, one

b-subunit, one d-subunit, and one e-subunit A fetal

g-subunit is replaced by the e-subunit with maturation

of the muscle and concentration of the ACh receptors

at the motor end-plate (Mishina et al., 1986) Inmature extraocular muscle, both the fetal g-subunitand the typical adulte-subunit are expressed There

is general agreement that singly innervated enplaque NMJs express the e-subunit and multiplyinnervated en grappe NMJs express the g-subunit(Kaminski et al., 1996; Fraterman et al., 2006).Multiply innervated en grappe NMJs may or maynot also express the e-subunit (Kaminski et al.,1996; Fraterman et al., 2006) Fetal ACh receptorsstay open longer, have lower conductance, and havegreater calcium conductivity It has been suggestedthat their unusual presence in extraocular musclemay play a role in intracellular signaling via inter-nal calcium release and force generation in theabsence of action potential generation in multiplyinnervated fibers (Kaminski et al., 2003)

3.5 Ocular motoneurons (cranial nervesand nuclei)

The ocular motoneurons for horizontal eye ments are located in the abducens and oculomotornuclei These motoneurons supply the lateral rectusand the medial rectus, respectively For vertical eyemovements, the motoneurons are in the trochlearand oculomotor nuclei The trochlear motoneuronssupply the superior oblique and the oculomotormotoneurons supply the superior and inferior rectusmuscles and the inferior oblique

move-Fig 7 Electron photomicrographs of extraocular muscle neuromuscular junctions (NMJ) A: Orbital singly-innervated fiber (SIF) NMJ B: Global SIF NMJ Terminals (t) are embedded in myofiber surface depressions and capped by a Schwann cell (S) Post-junctional folding

is sparse (arrowheads) and myonuclei (mn) and mitrochondria (m) accumulate post-junctionally Scale: A-B, 1 mm (Figures courtesy of

Dr Henry Kaminski.)

3.5.1 Oculomotor nerve (cranial nerve III)

Paired oculomotor nuclei are located in the dorsal

midbrain ventral to the periaqueductal gray matter

at the level of the superior colliculus (Fig 8) Each

nucleus includes a superior rectus subnucleus that

provides innervation to the contralateral superior

rec-tus; inferior rectus, medial rectus, and inferior

oblique subnuclei providing ipsilateral innervation;

and an Edinger–Westphal nucleus supplying

pre-ganglionic parasympathetic output to the iris spincter

and ciliary muscles (Warwick, 1953; Bienfang, 1975;

Bu¨ttner-Ennever and Akert, 1981) A single midline

caudal central subnucleus provides innervation to

both levator palpebrae superioris muscles

A third nerve fascicle originates from the ventral

surface of each nucleus and traverses the midbrain,

passing through the red nucleus and in close

proxim-ity to the cerebral peduncles before emerging as

ven-tral rootlets in the interpeduncular fossa In the

interpeduncular fossa, the rootlets converge into a

third nerve trunk that continues ventrally through

the subarachnoid space toward the cavernous sinus,

passing between the superior cerebellar artery and

the posterior cerebral artery It travels near the

ante-rior portion of the posteante-rior communicating artery

(PCOM) at its junction with the intracranial internal

carotid In the cavernous sinus, the third nerve is

located in the dural sinus wall, just lateral to the

pitu-itary gland From the cavernous sinus, the third nerve

enters the superior orbital fissure(Figs 2 and 3) Just

prior to entry, the nerve anatomically divides intosuperior and inferior divisions in the anterior cavern-ous sinus, although careful evaluation of brainstemlesions and their corresponding patterns of pupiland muscle involvement suggests that functionaldivision occurs in the midbrain (Ksiazek et al.,1989; Eggenberger et al., 1993; Saeki et al., 2000).The superior division innervates the superior rectusand the levator palpebrae superioris, and the inferiordivision innervates the inferior and medial recti, theinferior oblique, and the iris sphincter and ciliarymuscles Prior to innervating the ciliary and sphinctermuscles, parasympathetic third nerve fibers synapse

in the ciliary ganglion within the orbit See Fig 9

for an example of a radiographic lesion causing lomotor nerve dysfunction

ocu-3.5.2 Trochlear nerve (cranial nerve IV)Paired trochlear nuclei lie very close the dorsal sur-face of the midbrain just inferior to the inferior colli-culus(Fig 10) The fascicles emerge from the nucleiand course dorsally only 3–9 mm before exiting thebrainstem The trochlear nerves are the only cranialnerves to emerge from the dorsal brainstem surface.After emerging, the nerves decussate within the ante-rior medullary velum and wrap around the surface ofthe midbrain to travel ventrally within the subarach-noid space toward the cavernous sinus(Fig 11) Inthe cavernous sinus, the trochlear nerve is located

in the lateral dural wall, inferior to the oculomotor

SNc

lll RN

nerve From the cavernous sinus, the nerve passes

into the superior orbital fissure (Fig 3) and

ulti-mately innervates the superior oblique muscle

con-tralateral to the nucleus of origin

3.5.3 Abducens nerve (cranial nerve VI)

Paired abducens nuclei are located in the dorsal pons

in the floor of the fourth ventricle, in close proximity

to the fascicle of the facial nerve (Fig 12) Each

nucleus contains abducens motoneurons that formthe abducens nerve (2/3 of nuclear neurons) andinterneurons (1/3 of nuclear neurons) that decussate

at the nuclear level and ascend in the medial dinal fasciculus (MLF) to the contralateral oculomo-tor medial rectus subnucleus to facilitate conjugatehorizontal gaze in the direction ipsilateral to theabducens nuclear origin of the interneurons Theabducens fascicle arises from the ventral surface ofthe nucleus, traverses the brainstem, emerges fromthe ventral pontomedullary sulcus or caudal pontinesurface, and travels in the subarachnoid space where

longitu-it ascends near the clivus It pierces the dura andpasses under the petroclinoid (Gruber’s) ligament

in Dorello’s canal, then travels through the body

of the cavernous sinus lateral to the internal carotidartery (unlike the oculomotor, trochlear, and trigem-inal nerves housed in the lateral dural wall) and,ultimately into the superior orbital fissure to inner-vate the ipsilateral lateral rectus muscle (Fig 3).See Fig 13 for examples of abducens nerve dys-function

3.6 InternuclearThe medial longitudinal fasciculus (MLF) carriessignals from the abducens nucleus to the contralat-eral medial rectus portion of the oculomotor nucleus

(Fig 12) These signals allow conjugate horizontaleye movements with co-contraction of the ipsilat-eral lateral rectus and contralateral medial rectusmuscles The MLF also carries signals for verticalgaze from the medullary vestibular nuclei to themidbrain vertical gaze control centers These sig-nals are most important for vertical smooth pursuit

DBC

DR IV

ML

Inferior colliculus

Fig 10 Histologic brainstem cross-section of the midbrain at

the level of the inferior colliculus Note the trochlear nuclei (IV).

Abbreviations: DR – dorsal raphe, DBC – decussation brachium

con-junctivum, ML – medial lemniscus (Figure courtesy of University of

Chicago Neuroanatomy Collection.)

Fig 9 T1-weighted coronal MRI with gadolinium with a large left

intracavernous carotid aneurysm in a patient with an isolated left

third nerve palsy.

Fig 11 Axial T1-weighted MRI with gadolinium at the level of the fourth nerve and inferior colliculus Note the enhancement

of the left fourth nerve fascicle as it wraps around the midbrain within the subarachnoid space (arrow) The lesion is a presumptive fourth nerve schwannoma.

and vestibular eye movements (Tomlinson and

Robinson, 1984) Unilateral inactivation of the

MLF results in ipsilateral impaired adduction and

abducting nystagmus in the contralateral eye in

combination with a skew deviation with ipsilateral

hypertropia Bilateral MLF inactivation results in

bilateral impairment of adduction, bilateral

disso-ciated abducting nystagmus, impaired vertical

smooth pursuit, and reduced vertical VOR gain

(Ranalli and Sharpe, 1988)

3.7 Supranuclear3.7.1 Subcortical – brainstem3.7.1.1 Burst and pause neurons

A combination of factors including the initial force toovercome the elastic inertia of the extraocular orbitaltissues, high saccadic velocity, long saccadic duration,and the requirement for a high degree of accuracy toplace the small fovea on target make saccades a verydemanding task for the brain Many of these demands

Facial nerve

Abducens nucleus nerve

Medial superior olive

Lateral superior olive

Medial longitudinal fasciculus

Genu of facial nerve

Superior vestibular nucleus

Brachium pontis

Brachium conjunctivum

Fig 12 Histologic brainstem cross-section of the pons at the level of the abducens and facial nuclei (Figure courtesy of University of Chicago Neuroanatomy Collection.)

Fig 13 A: Right abducens palsy secondary to microvascular ischemia Note the prominent esotropia B: T1-weighted axial MRI with gadolinium through the pons at the level of the abducens nerve in an elderly patient with a painless left abducens palsy secondary to a pre-pontine en plaque meningioma (arrow).

are met directly by brainstem burst neurons that carry

the immediate premotor or supranuclear saccadic

com-mand and that project monosynaptically to ocular

motoneurons (Horn et al., 1995) The discharge

characteristics of burst neurons are tightly correlated

with saccade properties when the head is immobilized

For example, the number of spikes in the burst

dis-charge is correlated with the size of the saccade; the

duration of the burst discharge is correlated with the

duration of the saccade; and the peak frequency of

the burst discharge is correlated with the peak velocity

of the saccade (Strassman et al., 1986a; Scudder et al.,

1988; Cullen and Guitton, 1997a) These relationships

between neuronal discharge and saccade properties

may be uncoupled when the head is moving during the

saccade since small head movements also contribute

to gaze changes and stabilization (Cullen and Guitton,

1997b; Ling et al., 1999) Uncoupling also occurs

dur-ing monocular saccades – such as when the target is

aligned with one eye (Zhou and King, 1998), thereby

challenging the long held belief that burst discharge

pat-terns are always conjugate and tightly correlated with

saccade dynamics

The burst neurons for horizontal saccades are

located in the paramedian pontine reticular formation

(PPRF) in the pons just rostral to the abducens nucleus

and, for vertical and torsional saccades, in the rostral

interstitial medial longitudinal fasciculus (riMLF) tral to the oculomotor nucleus and ventral to the peria-queductal gray in the mesencephalic reticularformation (Fig 14) (Bu¨ttner-Ennever and Bu¨ttner,1978; Bu¨ttner-Ennever et al., 1982; Horn et al., 1995;Horn and Bu¨ttner-Ennever, 1998) A few vertical burstneurons lie outside of the riMLF boundaries in the cen-tral mesencephalic reticular formation (cMRF)(Waitzman et al., 2000a, b) For horizontal saccades,premotor burst signals project to ipsilateral motoneur-ons to generate an ipsilateral saccade (for example, for

ros-a rightwros-ard sros-accros-ade, the premotor signros-al originros-ates inthe right PPRF burst neurons and projects to the rightabducens nucleus) (Strassman et al., 1986a) For verti-cal saccades, single burst neurons project to classicyoked muscle pairs (for example, superior rectus andinferior oblique for upward saccades and inferior rec-tus and superior oblique for downward saccades)(Moschovakis et al., 1990) These neurons burst foreither upward or downward saccades and in a singledirection for torsional quick phases (for example, apopulation of burst neurons may burst only forcounterclockwise quick phases) (Villis et al., 1989;Henn et al., 1991; Moschovakis et al., 1991a, b;Bhidayasiri et al., 2000) Burst neurons projecting tomotoneurons for the elevator muscles project bilater-ally In contrast, burst neurons to motoneurons for

Fig 14 Monkey brainstem sagittal view demonstrating the locations of the ocular motor nuclei and premotor structures Abbreviations:

TR – tractus retroflexus, ND – nucleus of Darkschewitsch, RIMLF – rostral interstitial medial longitudinal fasciculus, MT – lamic tract, MB – mamillary body, SC – superior colliculus, PC – posterior commissure, INC – interstitial nucleus of Cajal, MLF – medial longitudinal fasciculus, PPRF – paramedian pontine reticular formation, NRPO – nucleus reticularis pontis oralis, NRPC – nucleus reticularis pontis caudalis, NRTP – nucleus reticularis tegmenti pontis, RIP – nucleus raphe interpositus, NVI – sixth nerve fascicle, PGD – nucleus paragigantocellularis dorsalis, PH – prepositus hypoglossus nucleus, SG – nucleus supragenualis, IO – inferior olive (Figure courtesy of Dr Jean Bu¨ttner-Ennever.)

depressor muscles project unilaterally (Moschovakis

et al., 1990; Bhidayasiri et al., 2000) This anatomic

difference predisposes unilateral riMLF lesions to

preferentially impair downward saccades Bilateral

riMLF lesions abolish all vertical saccades and

torsional quick phases (Suzuki et al., 1995)

The immediate premotor burst neurons are the

excitatory medium-lead burst neurons (EBNs), which

begin firing 8–12 ms before a saccade and fire

throughout the duration of the saccade The firing

rate of these neurons is tightly linked with eye

veloc-ity during the saccade They are silent during fixation

and slow eye movements It has been classically held

as true that burst neurons encode only conjugate

sac-cadic command signals, but some recent evidence

has raised the possibility that some of these neurons

may encode monocularly (Zhou and King, 1998) In

addition to the EBNs described above, there are

inhibitory medium-lead burst neurons (IBNs) that

project monosynaptically to contralateral

motoneur-ons The IBNs are located in the medullary reticular

formation for horizontal eye movements and are

intermingled with EBNs in the riMLF and interstitial

nucleus of Cajal (INC) for vertical eye movements

(Moschovakis et al., 1991a, b) For horizontal eye

movements, IBNs project to contralateral horizontal

motoneurons to inhibit them during ipsilateral

sac-cades (Strassman et al., 1986b)

Burst neurons require constant inhibition at all

times other than when a saccade is taking place

This inhibition is mediated by tonically discharging

omnipause neurons (OPNs) located in the nucleus

raphe interpositus (RIP) in the PPRF (Fig 14)

(Strassman et al., 1987; Bu¨ttner-Ennever et al.,

1988; Horn et al., 1994) OPN firing ceases just

prior to burst neurons firing and resumes

immedi-ately at saccade end Microstimulation of OPNs in

the middle of a saccade will stall the saccade

mid-flight (Keller et al., 1996) It has been suggested

that OPNs also cease firing for vergence and for

high-velocity smooth pursuit, indicating a broader

role for OPNs in fast eye movements other than

sac-cades (Zee et al., 1992; Missal and Keller, 2002)

The mechanism by which omnipause neurons are

inhibited to allow a saccade to occur is unclear

The initial inactivation of the OPNs may result from

activity in trigger-latch long-lead burst neurons

(LLBNs – described below) or in fixation neurons

in the superior colliculus (SC – also described

below) (Pare and Guitton, 1994; Gandhi and Keller,

1999; Yoshida et al., 2001; Scudder et al., 2002)

Long-lead burst neurons (LLBNs) exhibit activity

up to 100 ms prior to saccade onset These LLBNsare located throughout brainstem nuclei and reticularformations and likely consist of several types: relayLLBNs, trigger-latch LLBNs, and pre-cerebellarLLBNs (Scudder et al., 2002) Relay LLBNs may form

a connection between the superior colliculus and atory burst neurons (Scudder et al., 1996a; Izawa et al.,1999; Keller et al., 2000) The role of trigger-latchLLBNs is unclear but they may function to inhibitomnipause neurons and to hold omnipause neuronsoff for the duration of the saccade (Kamogawa et al.,

excit-1996) Pre-cerebellar LLBNs receive input from thesuperior colliculus and project to the nucleus reticu-laris tegmenti pontis (NRTP) which, in turn, projectsprimarily to the cerebellar saccadic areas (the oculo-motor vermis and the fastigial oculomotor region)

(Fig 14) (Scudder et al., 1996b) However, the role

of NRTP seems to be broader than a simple conduitbetween the superior colliculus and the cerebellum,

as chemical inactivation of NRTP actually results inimpaired saccadic velocity and amplitude rather thanjust saccadic accuracy (Kaneko and Fuchs, 2006)

3.7.1.2 Superior colliculusThe primary source of commands to the brainstemimmediate premotor structures is the superior colli-culus (SC), which projects both directly to the EBNsand indirectly to the EBNs via LLBNs It receivesretinal input both directly and indirectly via corticaleye fields and contains retinotopically coded infor-mation regarding target location (Klier et al., 2001;Bergeron et al., 2003) Pharmacologic inactivation ofthe rostral SC results in decreased saccadic latency(express saccades), whereas inactivation of the caudal

SC impairs saccade initiation (Schiller et al., 1987;Pierrot-Deseilligny et al., 1991) There are three types

of saccade-related cells in the ventral colliculus: tion neurons, build-up neurons, and collicular burstneurons (Munoz and Wurtz, 1995) Fixation neuronsare located at the rostral pole, discharge tonically at asteady rate, project directly to the OPNs, and likelysuppress saccades (Munoz and Wurtz, 1993a, b; Everl-ing et al., 1998) Inhibition of fixation neurons wouldalso inactivate the OPNs, thereby allowing activation

fixa-of burst neurons and saccade initiation Build-up, orprelude, neurons in the intermediate and deep SClayers exhibit a low-level, tonic discharge when avisual stimulus becomes the target of a saccade, indi-cating the importance of their role in target selectionand saccade amplitude and direction preparation

(Wurtz and Goldberg, 1972; Sparks, 1975; Glimcher

and Sparks, 1992; Munoz and Wurtz, 1995; Carello

and Krauzlis, 2004; McPeek and Keller, 2004; Muller

et al., 2005) The discharge ascends, and when the

dis-charge reaches the rostral pole, the saccade ends

Col-licular burst neurons have a lead time of 20–40 ms

prior to saccade initiation (Keller et al., 2000) They

burst for saccades of a certain vector and are

instru-mental in determining saccadic size and direction

(Sparks, 1978; Moschovakis et al., 1988)

In addition to direct and indirect projections to

burst neurons, the SC also projects to the brainstem

central mesencephalic reticular formation (cMRF)

(Cohen and Bu¨ttner-Ennever, 1984) This connection

may play a role in transformation of the spatial

sac-cadic target selection signal into the temporal signal

required for motor output via cMRF connections

with OPNs and burst neurons (Langer and Kaneko,

1990; Cromer and Waitzman, 2006; Pathmanathan

et al., 2006) The cMRF may also play a role in

feedback of information about the saccade to the

SC (Waitzman et al., 1996; Chen and May, 2000;

Soetedjo et al., 2002)

3.7.2 Subcortical – cerebellum

The cerebellar role in eye movements is related to

fine refinement to improve accuracy In order to

per-form this role, the cerebellum receives both sensory

and motor information regarding the eye movement

and must compare the predicted eye movement based

on the command with the desired eye movement and

generate a signal to decrease the error between

pre-dicted and desired and to get the eyes accurately on

target (Darlot, 1993; Robinson and Fuchs, 2001)

No region of the cerebellum is absolutely necessary

for eye movement execution, nor is any region of

the cerebellum devoted solely to ocular motility

(Voogd and Barmack, 2005)

There are three primary regions of the cerebellum

involved with ocular motility: (1) the posterior

ver-mis (oculomotor verver-mis) consisting primarily of

lobules VI and VII and the caudal fastigial nucleus;

(2) the uvula and nodulus; and (3) the flocculus and

paraflocculus (Noda et al., 1990; Voogd and

Bar-mack, 2005) The primary inputs into these regions

consist of olivocerebellar climbing fibers originating

in the inferior olive and mossy fibers originating in

the nucleus reticularis tegmenti pontis (NRTP) and

other brainstem nuclei (Brodal, 1980; Noda et al.,

1990; Thielert and Thier, 1993; Bu¨ttner-Ennever and

Horn, 1996) Lobule VII of the vermis projects to thefastigial nucleus which, in turn, projects to the mesen-cephalon (SC, cMRF, riMLF), NRTP, paramedianpontine and medullary reticular formations, the medialvestibular nuclei (MVN), and to cortical areas like thefrontal eye fields via the thalamus (Batton et al., 1977;Gonzalo-Ruiz and Leichnetz, 1987; Noda et al., 1990;Homma et al., 1995) Lobule VII and fastigial nucleusPurkinje cells discharge for both saccades and smoothpursuit, participate in the mechanisms for saccadeadaptation and learning, and temporally encode theprecise time when the eyes must stop moving to landaccurately on target (Fuchs et al., 1993; Barash et al.,1999; Thier et al., 2002; Soetedjo and Fuchs, 2006).Lesions result primarily in saccadic dysmetria; specif-ically, muscimol inactivation of one fastigial nucleusresults in hypermetria of saccades toward the lesionedside and hypometria of saccades away from thelesioned side (Robinson et al., 1993; Bu¨ttner et al.,1994; Takagi et al., 1998; Iwamoto and Yoshida,

2002) The uvula and nodulus have extensive lar connections and lesions primarily affect VORgains The flocculus and paraflocculus may play a role

vestibu-in calibration of the VOR based on visual feedback.Unilateral lesions result in asymmetries of theVOR, whereas bilateral lesions impair smooth pursuittracking and gaze-holding (Zee et al., 1981)

3.7.3 CorticalMany cortical areas are involved in saccadic control,including both anterior frontal regions and posteriorparietal regions The evidence supporting a role insaccadic control for these regions is derived fromstudies evaluating the effects of inactivation or stim-ulation of these areas and by modern neuroimagingtechniques such as PET and functional MRI Thesecortical structures are integral to proper target selec-tion, attention, motivation, and programming of theeye movement The most current view of corticalcontrol of saccades is that these regions constitute avast network with multiple reciprocal connectionsrather than a strictly serial or hierarchical plan(Lynch and Tian, 2005) Involved frontal regionsinclude the frontal eye fields (FEF), supplementaryeye fields (SEF), and the dorsolateral prefrontal cor-tex (or prefrontal eye field) (Pierrot-Deseilligny

et al., 2003) The primary parietal region is the etal eye field (PEF) within the posterior parietal cor-tex which corresponds to the monkey lateralintraparietal sulcus See Table 3 for the specific

oculomotor roles of these cortical regions (Corbetta,

1998; Luna et al., 1998; Perry and Zeki, 2000; Lobel

et al., 2001; Gaymard et al., 2003; Milea et al.,

2005) Several lines of evidence suggest that the

frontal saccadic regions are more involved with

intentional saccades, while the parietal regions have

a more active role in reflexive saccades (Sweeney

et al., 1996; Milea et al., 2005) All cortical saccade

areas receive input from the striate and extrastriate

visual cortices

Similar but separate and parallel systems exist for

control of smooth pursuit and optokinetic nystagmus

(OKN) (Tanaka and Lisberger, 2002; Lynch and

Tian, 2005; Bense et al., 2006a, b) For example, in

the FEF, the pursuit-related area has been localized

to the deep anterior region and the saccade-related

area to the upper anterior region (Rosano et al.,

2002) Although temporal cortical regions have

clas-sically been considered to be the most important

cor-tical regions for control of smooth pursuit, the FEF

has now been shown to play a significant role (

Krau-zlis, 2004) In fact, lesions of the FEF result in more

severe and persistent pursuit deficits than lesions of

the temporal lobe (Lynch, 1987) Temporal lobe

regions important in smooth pursuit include the

mid-dle temporal (MT) and medial superior temporal

(MST) regions (Newsome et al., 1985; Durstelerand Wurtz, 1988) MT is important for pursuit initia-tion and MST for pursuit maintenance (Newsome

et al., 1985; Dursteler and Wurtz, 1988; Ilg andThier, 2003) FEF, MT, and MST project via pontinenuclei (mainly the dorsolateral pontine nucleus) tothe cerebellar flocculus and ventral paraflocculus(Zee et al., 1981; Krauzlis, 2004) Some projections

to the NRTP and subsequently to the cerebellarvermis to lobules VI and VII also exist The long-recognized cortico-ponto-cerebellar pathways havegenerally been considered to be the primary path-ways for smooth pursuit control However, directcortico-bulbar connections have been identifiedbetween the FEF smooth pursuit region and thebrainstem burst neurons, suggesting that direct path-ways may also play a role in pursuit control and thatthe neural control of smooth pursuit is, in manyways, similar to the neural control of saccades (Mis-sal et al., 2000; Yan et al., 2001; Missal and Keller,2002; Keller and Missal, 2003; Krauzlis, 2004).The visual cortex, including cortical eye fields and

MT, are also activated during OKN The direct nections responsible for OKN are less well establishedthan for saccades, but the cerebellar hemispheres andoculomotor vermis and a transition zone between theposterior thalamus and mesencephalon which incorpo-rates the nucleus of the optic tract (NOT) are known toplay a premotor role and likely receive cortical projec-tions (Mustari and Fuchs, 1990; Galati et al., 1999;Dieterich et al., 2003; Bense et al., 2006a, b)

con-3.7.4 Gaze holdingHolding the eye eccentrically and steady fixation inbetween eye movements are active processes requir-ing continuous extraocular muscle contraction This

is modulated by a neural ocular motor integrator thatuses head-velocity vestibular signals and eye-velocitysaccadic commands to generate eye position com-mands (Robinson, 1968; Fukushima and Kaneko,1995; Moschovakis, 1997) It is unclear if there is asingle common ocular motor integrator for all func-tional classes of eye movements (Robinson, 1989;Kaneko, 1999; Goldman et al., 2002) The nucleusprepositus hypoglossi (NPH) and medial vestibularnucleus (MVN) in the rostral medulla play a key role

in integration of horizontal eye movements (Langer

et al., 1986; Cannon and Robinson, 1987; Mettens

et al., 1994; Kaneko, 1999; McCrea and Horn,

2005) During conjugate fixation, most NPH neurons

Table 3

Cortical areas involved in ocular motor control

Frontal eye field

(FEF)

Generation of accurate and rapidcontralateral saccades,triggering of intentionalsaccades (Corbetta, 1998; Luna

et al., 1998; Lobel et al., 2001)Supplemental eye

field (SEF)

All voluntary saccades,potential role in motorlearning (Gaymard, 2003)Dorsolateral

prefrontal cortex

(DLPC)

Decision-making regardingsaccades in terms of goals anddesires, inhibition of

unwanted saccades, triggering

of predictive saccades, term spatial and temporalmemory (Pierrot-Deseilligny

short-et al., 2003)Parietal eye field

(PEF)

Triggering of reflexive saccades,visuospatial integration(Perry and Zeki, 2000)