Craniofacial Muscles

Craniofacial Muscles

Linda K. McLoon • Francisco H. Andrade

Editors

Craniofacial Muscles

A New Framework for Understanding

the Effector Side of Craniofacial

Muscle Control

Editors

Linda K. McLoon

Department of Ophthalmology

University of Minnesota

Minneapolis , MN, USA

Francisco H. Andrade

Department of Physiology

University of Kentucky

Lexington , KY, USA

ISBN 978-1-4614-4465-7 ISBN 978-1-4614-4466-4 (eBook)

DOI 10.1007/978-1-4614-4466-4

Springer New York Heidelberg Dordrecht London

Library of Congress Control Number: 2012945590

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Contents

Part I Overview

1 The Craniofacial Muscles: Arguments for Uniqueness ....................... 3

Francisco H. Andrade and Linda K. McLoon

Part II Development

2 Head Muscle Development ..................................................................... 11

Itamar Harel and Eldad Tzahor

Part III Extraocular Muscles

3 Extraocular Muscle Structure and Function ........................................ 31

Linda K. McLoon, Christy L. Willoughby,

and Francisco H. Andrade

4 Motor Control of Extraocular Muscle .................................................. 51

Vallabh E. Das

5 Extraocular Muscles Response to Neuromuscular Diseases

and Specific Pathologies ......................................................................... 75

Fatima Pedrosa Domellöf

Part IV Masticatory Muscles

6 Masticatory Muscle Structure and Function........................................ 91

Mark Lewis, Nigel Hunt, and Rishma Shah

7 Motor Control of Masticatory Muscles ................................................. 111

Barry J. Sessle, Limor Avivi-Arber, and Gregory M. Murray

v

vi

Contents

8 Masticatory Muscle Response to Neuromuscular Diseases


Sadie L. Hebert, Christy L. Willoughby, Francisco H. Andrade,

and Linda K. McLoon

Part V Laryngeal and Pharyngeal Muscles

9 Structure and Function of the Laryngeal and Pharyngeal

Muscles ..................................................................................................... 141

Lisa A. Vinney and Nadine P. Connor

10 Motor Control and Biomechanics of Laryngeal

and Pharyngeal Muscles ......................................................................... 167

Christy L. Ludlow

11 Laryngeal Muscle Response to Neuromuscular Diseases


J.C. Stemple, L. Fry, and R.D. Andreatta

Part VI Tongue Musculature

12 Tongue Structure and Function ............................................................. 207

Alan Sokoloff and Thomas Burkholder

13 Tongue Biomechanics and Motor Control ............................................ 229

Mary Snyder Shall

14 Tongue Muscle Response to Neuromuscular Diseases


Zi-Jun Liu

Part VII

Facial Muscles

15 Facial Nerve Innervation and Facial Palsies ........................................ 265

Adriaan O. Grobbelaar and Alex C.S. Woollard

16 Spastic Facial Muscle Disorders ............................................................ 287

Juwan Park, Andrew R. Harrison, and Michael S. Lee

Part VIII Summary and Conclusions

17 Comparison of the Craniofacial Muscles: A Unifying

Hypothesis ................................................................................................ 325

Linda K. McLoon and Francisco H. Andrade

Index ................................................................................................................. 337

Contributors

Francisco H. Andrade Department of Physiology, University of Kentucky ,

Lexington , KY , USA

R. D. Andreatta Division of Communication Sciences and Disorders, University

of Kentucky , Lexington , KY , USA

Limor Avivi-Arber University of Toronto , Toronto , ON , Canada

Thomas Burkholder School of Applied Physiology, Georgia Institute of

Technology , Altanta , GA , USA

Nadine P. Connor Departments of Communicative Disorders and Surgery,

University of Wisconsin-Madison , Madison , WI , USA

Vallabh E. Das College of Optometry, University of Houston , Houston , TX , USA

L. Fry Division of Communication Sciences and Disorders, University of

Kentucky , Lexington , KY , USA

Adriaan O. Grobbelaar Institute for Plastic Surgery Research and Education ,

Royal Free Hospital, London , UK

Itamar Harel Department of Biological Regulation, Weizmann Institute of

Science , Rehovot , Israel

Andrew R. Harrison Department of Ophthalmology, University of Minnesota ,

Minneapolis , MN , USA

Sadie L. Hebert Departments of Ophthalmology and Neuroscience, University of

Minnesota , Minneapolis , MN , USA

Nigel Hunt UCL Eastman Dental Institute , London , UK

Michael S. Lee Department of Ophthalmology, University of Minnesota ,


vii

viii

Contributors

Mark Lewis School of Sport, Exercise and Health, Loughborough University,

Loughborough, Leicestershire, UK and UCL Eastman Dental Institute, London,

UK

Zi-Jun Liu Department of Orthodontics, University of Washington , Seattle ,

WA , USA

Christy L. Ludlow Department of Communication Sciences and Disorders, James

Madison University , Harrisonburg , VA , USA

Linda K. McLoon Department of Ophthalmology, University of Minnesota ,


Gregory M. Murray University of Sydney , Sydney , Australia

Juwan Park Department of Ophthalmology, University of Minnesota ,


Fatima Pedrosa Domellöf Department of Ophthalmology, Umeå University ,

Umeå , Sweden

Barry J. Sessle University of Toronto , Toronto , ON , Canada

Rishma Shah UCL Eastman Dental Institute , London , UK

Mary Snyder Shall Department of Physical Therapy, Virginia Commonwealth

University , Richmond , VA , USA

Alan Sokoloff Department of Physiology, Emory University , Atlanta , GA , USA

J.C. Stemple Division of Communication Sciences and Disorders, University of

Kentucky , Lexington , KY , USA

Eldad Tzahor Department of Biological Regulation, Weizmann Institute

of Science , Rehovot , Israel

Lisa A. Vinney Departments of Communicative Disorders and Surgery, University

of Wisconsin-Madison , Madison , WI , USA

Christy L. Willoughby Departments of Ophthalmology and Neuroscience,

University of Minnesota , Minneapolis , MN , USA

Alex C.S. Woollard Institute for Plastic Surgery Research and Education ,

Royal Free Hospital, London , UK

Part I

Overview

Chapter 1

The Craniofacial Muscles: Arguments

for Uniqueness

Francisco H. Andrade and Linda K. McLoon

1.1 Introduction

The craniofacial muscles are small skeletal muscles associated with head and neck

structures and involved in a wide array of non-locomotor activities such as mastication,

swallowing, breathing, vocalization, facial expression, and even vision and

other special senses. These muscles are the new kids on the block, starting with their

relatively recent appearance with the evolution of the head and neck in vertebrates

and to our growing understanding of their distinctive development programs, functions,

and pathologies. For convenience, we can group the craniofacial muscles

according to their developmental origin: extraocular muscles, branchiomeric muscles

(facial, masticatory, pharyngeal, and laryngeal muscles), and tongue muscles

(Noden and Francis-West 2006 ) . There is growing recognition of clinical relevance

of the craniofacial muscles in terms of diseases that are speci fi c to them (strabismus,

laryngeal dystonias, facial paralysis, and many others), but also their characteristic

divergent response to certain systemic neuromuscular disorders (sparing by some

muscular dystrophies, targeting by myasthenia gravis, to name a few). These are the

basic arguments for the uniqueness of the craniofacial muscles that serve as the

central theme for the following chapters.

F. H. Andrade , Ph.D. (*)

Department of Physiology , University of Kentucky ,

800 Rose Street , Lexington , KY 40536-0298 , USA

e-mail: paco.andrade@uky.edu

L. K. McLoon , Ph.D.

Department of Ophthalmology , University of Minnesota, 2001 6th Street SE ,

Minneapolis , MN 55455 , USA

L.K. McLoon and F.H. Andrade (eds.), Craniofacial Muscles: A New Framework

for Understanding the Effector Side of Craniofacial Muscle Control,

DOI 10.1007/978-1-4614-4466-4_1, © Springer Science+Business Media New York 2013

3

4 F.H. Andrade and L.K. McLoon

1.2 Origin of Head and Neck Musculature

Craniofacial evolution is one of the key steps in the origin and diversi fi cation of

vertebrates (Trainor et al. 2003 ) . The Craniata, a clade within the phylum Chordata

(animals with notochords at one point in their lives), arose during the Cambrian

explosion (~525 million years ago). In contrast to other chordates, the craniates

have heads with complex (vesicular) brains encased in a rigid cranium and specialized

sensory organs, including laterally placed eyes. Properly speaking, a skull is

composed of the cranium and the jaw. The latter is an even more recent evolutionary

feature: its presence separates the “jawed vertebrates” (Gnathostomata, the great

majority of vertebrates, including mammals) from the older members of the Craniata

clade, the jawless fi shes (lampreys and hag fi shes). The appearance of the head and

neck is one of the factors that allowed vertebrates to shift from fi lter feeding to

active predation, greater motility, and a faster metabolic rate. At least partly due to

these characteristics, vertebrates have a presence in a broad range of terrestrial and

aquatic environments. Among many other distinguishing features, vertebrates have

a complex muscular digestive system, and the cardiovascular system has a heart

with two or more chambers, all additions required to cope with greater metabolic

demands imposed by their larger size and active lifestyle.

The craniofacial muscles allow for a broad motor repertoire in the head and neck.

It will become apparent in the next chapters that these muscles build on the striated

muscle stereotype to serve the unique motor needs of craniofacial structures. In

other words, the craniofacial muscles do not have quite the same developmental

origin as other striated muscles, skeletal or cardiac. To start, craniofacial muscles

are non-somitic; they do not follow the progression from mesoderm to segmented

somites, which characterizes the development of trunk and limb muscles. Instead,

the cranial mesoderm that originates craniofacial muscles differentiates along limits

set by molecular rather than anatomical boundaries (Sambasivan et al. 2011 ) .

Craniofacial muscles can trace their most primitive origins to trunk musculature, as

evidenced by shared steps in their respective myogenic programs. However, the

developmental programs for craniofacial muscles show a level of complexity that

be fi ts both their relatively recent appearance and the allocation of craniofacial

mesoderm for multiple fates. For example, some craniofacial muscles follow a

developmental program very similar to that of the heart, hinting at a common evolutionary

origin (Kelly 2010 ) . Neural crest plasticity and independent gene regulation

(from other muscle groups) are needed for greater adaptability to environmental

pressures (Trainor et al. 2003 ) . This inherent plasticity in the craniofacial developmental

program gives rise to the diverse cranial phenotypes we see around us today:

wide range of beaks in birds, the repurposing of mandibular bones for hearing (all

the way to four middle ear bones in mammals), the sensory and motor function of

the elephant’s trunk, the muscles of facial expression in humans, and the enhanced

sensory role of the nose of the star-nosed mole.

1 The Craniofacial Muscles: Arguments for Uniqueness

5

1.3 Craniofacial Muscle Function

The structures of the head and neck protect the brain, provide support for delicate

sensory organs, and are needed for feeding and exploratory behaviors. The craniofacial

muscles, which include the extraocular, facial, masticatory, pharyngeal, laryngeal,

and tongue muscles, are required for all motor activities of the head and neck.

The extraocular muscles are responsible for the coordinated voluntary and re fl exive

movement of the vision organs, the eyes. Their anatomical arrangement and innervation

are highly conserved, suggesting that the ocular motor system is fairly

ancient, maybe predating some trunk and limb muscles. With rare exceptions, even

the most primitive vertebrates have at least six extraocular muscles for each eye

(Noden and Francis-West 2006 ) . As is the case in other underused motor systems,

these muscles are poorly developed in a non-vision-dependent species, the naked

mole-rat (McMullen et al. 2010 ) . An even more extreme example of functional

extraocular muscle adaptation occurs in the bill fi sh, whose enlarged dorsal (superior)

extraocular muscles serve as heat-generating organs to maintain the brain

warmer than the environment (Block and Franzini-Armstrong 1988 ) .

The branchiomeric muscles control jaw movement, facial expression, and laryngeal

and pharyngeal function. Jaw (masticatory) muscles are important for feeding

and sound production; together with some neck muscles, they arise from the fi rst

and second branchial arches (Kuratani 2004 ) . These are versatile muscles that are

adapted to diverse jaw articulation plans and feeding behaviors. Mammals are

unique in having muscles of facial expression and external ear movement. The pharyngeal

and laryngeal muscles in mammals are mostly responsible for coordinated

swallowing and breathing (i.e., normally, we do not swallow and breathe at the

same time). The laryngeal muscles are also involved in airway protective re fl exes

and sound production (Lang et al. 2002 ) .

A tongue containing voluntary muscles is present in most amphibians, and all

reptiles, birds, and mammals, pointing to an association with the terrestrial lifestyle,

and adapted for feeding and a sensory role (Iwasaki 2002 ) .

1.4 Craniofacial Muscles and Neuromuscular Disease

The non-locomotor activities of feeding, sound production, breathing, facial expression,

and vision are performed by the craniofacial muscles, and are altered by diseases

affecting these muscles. For example, strabismus impairs vision secondary to

the loss of coordinated eye movements, laryngeal muscle dysfunction alters phonation

and airway protective re fl exes, facial muscle paralysis affects facial expression

and mastication. In addition, structural factors such as craniofacial shape and the

position of its muscles predispose to conditions such as obstructive sleep apnea,

which affect humans almost exclusively, apparently because of the morphological

adaptations required for speech (Davidson 2003 ) .

6 F.H. Andrade and L.K. McLoon

The aforementioned examples are commonly the speci fi c craniofacial consequences

of systemic neuromuscular diseases. Of greater interest and perhaps more

signi fi cant is the divergent response of at least some craniofacial muscles to major

neuromuscular disorders. The most extensively studied example are the extraocular

muscles, which are spared by Duchenne muscular dystrophy and other dystrophies

affecting the dystrophin–glycoprotein complex, yet targeted by myasthenia

gravis and certain mitochondrial myopathies (Kaminski and Ruff 1997 ; Porter and

Baker 1996 ; Rowland et al. 1997 ) . The extraocular muscles, and more appropriately

their motor neurons, are also spared by amyotrophic lateral sclerosis (ALS);

at most, patients on long-term ventilator support may eventually have ocular motor

involvement (Hayashi et al. 1987 ) . The laryngeal muscles are also insensitive to

dystrophin de fi ciency, the primary defect in Duchenne muscular dystrophy (Fry

et al. 2010 ; Thomas et al. 2008 ) . Oculopharyngeal muscular dystrophy, a trinucleotide

repeat disease, affects many craniofacial muscles. Ptosis and dysphagia are

the most common signs, and include gaze limitations, tongue weakness and atrophy,

dysphonia, and facial weakness. There are also dystonias that target speci fi c

subgroups of craniofacial muscles, blepharospasm and laryngeal dystonia being

the frequent examples.

It is unquestionably important to elucidate the pathogenesis of each neuromuscular

disease in order to cure it or at least minimize its consequences. The contrasting

response of craniofacial muscles to major generalized neuromuscular disorders

gives us a window into disease-modifying strategies.

1.5 A Preamble

The purpose of this chapter is to set the stage for this book, presenting a brief argument

for the uniqueness of the craniofacial muscles. The biology of these small

muscles is relatively unexplored. We are just beginning to understand their developmental

programs and the features that make them extreme examples of the skeletal

muscle stereotype. The following chapters present an extensive survey of our knowledge

of the craniofacial muscles by addressing their development, structure, function,

and pathology.

References

Block BA, Franzini-Armstrong C (1988) The structure of the membrane systems in a novel muscle

cell modi fi ed for heat production. J Cell Biol 107:1099–1112

Davidson TM (2003) The Great Leap Forward: the anatomic basis for the acquisition of speech

and obstructive sleep apnea. Sleep Med 4:185–194

Fry LT, Stemple JC, Andreatta RD, Harrison AL, Andrade FH (2010) Effect of dystrophin

de fi ciency on selected intrinsic laryngeal muscles of the mdx mouse. J Speech Lang Hear Res

53:633–647

1 The Craniofacial Muscles: Arguments for Uniqueness

7

Hayashi H, Kato S, Kawada T, Tsubaki T (1987) Amyotrophic lateral sclerosis: oculomotor function

in patients on respirators. Neurology 37:1431–1432

Iwasaki S (2002) Evolution of the structure and function of the vertebrate tongue. J Anat

201:1–13

Kaminski H, Ruff R (1997) Ocular muscle involvement by myasthenia gravis. Ann Neurol

41:419–420

Kelly RG (2010) Core issues in craniofacial myogenesis. Exp Cell Res 316:3034–3041

Kuratani S (2004) Evolution of the vertebrate jaw: comparative embryology and molecular developmental

biology reveals the factors behind evolutionary novelty. J Anat 205:335–347

Lang IM, Dana N, Medda BK, Shaker R (2002) Mechanisms of airway protection during retching,

vomiting, and swallowing. Am J Physiol Gastrointest Liver Physiol 283:G529–G536

McMullen CA, Andrade FH, Crish SD (2010) Underdeveloped extraocular muscles in the naked

mole-rat ( Heterocephalus glaber ). Anat Rec 293:918–923

Noden DM, Francis-West P (2006) The differentiation and morphogenesis of craniofacial muscles.

Dev Dyn 235:1194–1218

Porter JD, Baker RS (1996) Muscles of a different “color”: the unusual properties or the extraocular

muscles may predispose or protect them in neurogenic and myogenic disease. Neurology

46:30–37

Rowland LP, Hirano M, DiMauro S, Schon EA (1997) Oculopharyngeal muscular dystrophy,

other ocular myopathies, and progressive external ophthalmoplegia. Neuromuscul Disord

7(suppl 1):S15–S21

Sambasivan R, Kuratani S, Tajbakhsh S (2011) An eye on the head: the development and evolution

of craniofacial muscles. Development 138:2401–2415

Thomas LB, Joseph GL, Adkins TD, Andrade FH, Stemple JC (2008) Laryngeal muscles are

spared in the dystrophin de fi cient mdx mouse. J Speech Lang Hear Res 51:586–595

Trainor PA, Melton KR, Manzanares M (2003) Origins and plasticity of neural crest cells and their

roles in jaw and craniofacial evolution. Int J Dev Biol 47:541–553

Part II

Development

Chapter 2

Head Muscle Development

Itamar Harel and Eldad Tzahor

2.1 Skeletal Muscle Formation

Vertebrate movement depends on trunk skeletal muscles, which are derived from

the segmented paraxial mesoderm known as somites (Christ and Ordahl 1995 ) .

During embryogenesis, muscle precursor cells proliferate extensively prior to their

differentiation and fusion into muscle fi bers containing multiple nuclei. Skeletal

muscle was the fi rst tissue in which a determination gene for cell fate, MyoD , was

identi fi ed in vertebrates (Weintraub et al. 1991 ) . Molecular and technical advances

in the last two decades have resulted in a detailed understanding of the embryology

of this tissue and its genetic regulation by key transcription factors, including the

paired/homeobox genes Pax3 and Pax7 , and the myogenic regulatory genes Myf5 ,

MyoD , Mrf4 , and Myogenin (MRFs: myogenic regulatory factors (Kassar-Duchossoy

et al. 2004 ) ). These genes are crucial for regulating muscle cell fate, as shown by

genetic loss-of-function analyses. Because many transcription factors that regulate

the fate of muscle progenitors have been identi fi ed, skeletal muscle tissue constitutes

an ideal model for the study of organogenesis and regeneration (Tajbakhsh 2005 ) .

Questions related to the inductive processes and the molecular events underpinning

embryonic myogenesis are currently under intensive study worldwide. Answers to

these questions may provide basic insights into developmental biology, as well as to

the growing fi eld of regenerative medicine as myogenesis in adult muscle stem cells

recapitulates that of the embryo.

I. Harel • E. Tzahor (*)

Department of Biological Regulation , Weizmann Institute of Science , Rehovot 76100, Israel

e-mail: eldad.tzahor@weizmann.ac.il




11

12 I. Harel and E. Tzahor

2.2 Head Muscles

In contrast to our understanding of how skeletal muscle is formed in the trunk, much

less is known about the tissues and molecules that induce the formation of the head

musculature. This chapter summarizes studies of the origins, composition, signaling,

genetics, and evolution of distinct craniofacial muscles. Cellular and molecular

parallels are drawn between cardiac and pharyngeal arch muscle developmental

programs, and argue for the tissues’ common evolutionary origins. It is clear that the

developmental paths that lead to the formation of skeletal muscles in the head

appear to be distinct from those operating in the trunk. Considerable cellular and

genetic variations also exist among the different craniofacial muscle groups.

Approximately 60 muscles are present in the vertebrate head, which, rather than

serving for locomotion, move the eyes, control the cranial openings and facial

expression, facilitate food uptake and, in humans, speech (Noden 1983a ; Noden and

Francis-West 2006 ; Wachtler and Jacob 1986 ) (Fig. 2.1a, b ). These head muscles

encompass the extraocular muscles (EOM), the muscles of mastication that open

and close the jaw apparatus (derived from pharyngeal arch 1; PA1) and the muscles

of facial expression (derived from pharyngeal arch 2; PA2). The muscles of the third

pharyngeal arch (also known as branchial arches) operate the pharynx and larynx.

A number of these head muscles, including the hypobranchial muscles, the tongue

muscles, and the muscles of the posterior PAs, develop from the somites (Fig. 2.1a, b ).

While head muscles exhibit the same tissue architecture as muscles in the trunk,

their development is remarkably distinct.

Fig. 2.1 The anatomy and mesodermal origins of craniofacial muscles in the mouse. ( a ) A transverse

section of an E16.5 embryonic head stained for the muscle marker MyHC ( red ). DAPI staining

( gray ) is seen in the background. Distinct marked muscles are detailed in ( b ) with respect to their

muscle subgroups and their origins. ( b ) An anatomical cartoon of adult mouse head highlighting

the craniofacial muscles shown also in ( a )

2 Head Muscle Development

13

2.3 Head Muscles Are Heterogeneous in Terms of Their

Mesodermal Origins

Head muscles are highly heterogeneous in their structure, function, anatomical

position, and developmental origins. In contrast to the segmented paraxial mesoderm

(the somites) in the trunk, the head mesoderm lacks any sign of segmentation

(Noden and Trainor 2005 ) . Myoblasts that form head muscles arise within several

precursor populations, including prechordal, paraxial, and splanchnic (lateral)

mesoderm, and migrate into regions where the connective tissue progenitors may be

either ectodermal (neural crest) or mesodermal in origin (Noden and Trainor 2005 ) .

In the past, craniofacial development was widely viewed within the context of the

neural crest cells, leading to the misconception (often seen in textbooks) that the

head musculature originates from neural crest cells. In fact, all head muscles derive

from mesodermal cells (Couly et al. 1992 ; Harel et al. 2009 ; Noden 1983a ) .

Head mesoderm precursors undergo gastrulation in the primitive streak, prior to

those of trunk mesoderm (Kinder et al. 1999 ; Psychoyos and Stern 1996 ) . Pharyngeal

muscles are derived from the pharyngeal arch mesodermal core, which constitutes a

subset of head mesoderm surrounding the pharynx. The pharyngeal mesoderm (PM)

is divided into two subdomains: the loosely connected mesenchymal paraxial mesoderm,

located on both sides of the neural tube and notochord (Fig. 2.2a , b), and the

medial splanchnic mesoderm, which is maintained as epithelial tissue, although

there seems to be no clear division between these two mesodermal populations

(Fig. 2.2 , Tzahor and Evans 2011 ) .

During embryonic ventral folding, the lateral splanchnic mesoderm is located on

the ventral side, beneath the fl oor of the pharynx (Fig. 2.2b ). Both paraxial and

splanchnic mesodermal cells converge to form the mesodermal core within the pharyngeal

arches (Nathan et al. 2008 ) (Fig. 2.2c , d). Hence, the PM includes both

paraxial and lateral splanchnic mesoderm cells that surround the pharynx (Fig. 2.2 ,

green). Taken together, PM cells contribute to the cores of the PAs (Fig. 2.2d ) and

give rise to signi fi cant areas of the heart and pharyngeal muscles. Moreover, PM

cells are found in close proximity to the pharyngeal endoderm, ectoderm, and neural

crest cells, all of which tightly in fl uence pharyngeal muscle development

(Fig. 2.2d ) (summarized below).

In addition to their contribution to the pharyngeal muscles, PM cells give rise to

cardiac progenitors (Grifone and Kelly 2007 ; Tzahor 2009 ; Tzahor and Evans 2011 ) .

Studies in both chick and mouse embryos have shown that cardiac progenitor cells

populating the cardiac out fl ow tract and right ventricle, collectively referred to as

the anterior heart fi eld (Kelly et al. 2001 ; Mjaatvedt et al. 2001 ; Waldo et al. 2001 ) ,

are progressively added by PM cells during heart looping stages. In the mouse, the

anterior heart fi eld is a subset of the second heart fi eld, which contributes to the outflow

tract and right ventricle, and will later contribute a majority of cells to the atria.

Thus, a subset of PM cells constitutes the second heart fi eld, in contrast to the

more lateral splanchnic mesoderm, known as the fi rst heart fi eld (Fig. 2.2a, d, red),


Fig. 2.2 Pharyngeal mesoderm cells give rise to parts of the heart and the pharyngeal muscles.

( a – d ) Schematic illustration of the anatomy of the pharyngeal mesoderm in a 1.5–3-day-old chick

embryo is shown. Pharyngeal mesoderm cells ( green ) in the anterior part of the embryo surround

the pharynx. Later, these cells fi ll the mesoderm core of the pharyngeal arches, and are incorporated

into the arterial pole of the heart (e.g., out fl ow tract). The fi rst heart fi eld ( red ) is restricted to

the lateral splanchnic mesoderm that later contributes to the linear heart tube. Second heart fi eld

cells ( green ) are PM cells that contribute to the arterial pole of the heart. PM cells interact and

migrate together with cranial neural crest cells. Cardiac neural crest cells are part of the cranial

neural crest population, migrating into the out fl ow tract via the posterior arches (arches 3–6)

which is contiguous with the PM, differentiates earlier, and eventually populates the

left ventricle (reviewed in Buckingham et al. 2005 ; Dyer and Kirby 2009 ; Evans

et al. 2010 ; Tzahor and Evans 2011 ; Tzahor and Lassar 2001 ; Vincent and

Buckingham 2010 ) .

2.4 Head Muscle Satellite Cells

Recent studies have begun to uncover an unexpected heterogeneity in head muscles

with respect to their origins, genetic lineages, and transcriptional programs, as well

as their proliferative, differentiative, and regenerative properties (Harel et al. 2009 ;


15

Fig. 2.3 Distinct mesoderm populations contribute to skeletal muscles and satellite cells in the

head and trunk. ( a ) Satellite cells, located on the surface of the myo fi ber, beneath its basement

membrane (basal lamina), serve as a source of myogenic cells for growth and repair of skeletal

muscles after birth. ( b ) Skeletal muscles and satellite cells in trunk and limb derive from somites

(paraxial mesoderm). Pharyngeal arch muscles and their associated satellite cells derive from both

cranial paraxial mesoderm and splanchnic mesoderm sources. Extraocular muscles derive from

prechordal and paraxial mesoderm

Ono et al. 2010 ; Sambasivan et al. 2009 ) . Adult skeletal muscle possesses a

remarkable ability to regenerate following injury. The cells that are responsible for

this capacity are the satellite cells, adult stem cells positioned under the basal lamina

of muscle fi bers (Fig. 2.3a ) that can give rise to both differentiated myogenic cells,

and also maintain their “stemness” by means of a self-renewal mechanism.

Satellite cells play a key role in the routine maintenance, hypertrophy, and repair

of damaged adult skeletal muscles (Buckingham 2006 ; Kuang and Rudnicki 2008 ;

Zammit et al. 2006 ) . Until recently, however, the embryonic origins of satellite

cells in the head musculature had been enigmatic. Previous studies addressing the

origins of satellite cells in trunk and limb muscles (Gros et al. 2005 ; Kassar-

Duchossoy et al. 2005 ; Relaix et al. 2005 ; Schienda et al. 2006 ) fi rmly established

that somites give rise to muscle progenitors (Fig. 2.3b ), including proliferative

Pax3/Pax7 cells; some satellite cells later spatially localize under the basal lamina

and become quiescent.

Lineage tracing techniques in both avian and mouse models demonstrated that

PM cells contribute to distinct pharyngeal arch-derived muscles and their associated


satellite cells (Fig. 2.3b , Harel et al. 2009 ) . In contrast, trunk muscle-associated satellite

cells (including tongue muscles) derive from the Pax3 + lineage; Pax3 + cells and

Pax3 expression are not seen in any other head muscles. In contrast, all head muscles

and their satellite cells derive from the MesP1 + lineage (including the tongue

and EOM), whereas the Isl1 lineage solely marks the pharyngeal arch-derived muscles

and their satellite cells (Harel et al. 2009 ) . In addition to lineage distinction,

differences in gene expression and differentiation potentials were observed between

satellite cells in head vs. trunk-derived muscles (Harel et al. 2009 ; Ono et al. 2010 ;

Sambasivan et al. 2009 ) . Transplantation of myo fi ber-associated head satellite cells

into damaged limb muscle contributed toward ef fi cient muscle regeneration (Harel

et al. 2009 ; Sambasivan et al. 2009 ) . Furthermore, in vitro experiments demonstrated

the cardiogenic nature of head-, but not trunk-derived satellite cells (Harel

et al. 2009 ) . Fewer head satellite cells from the masseter (see Fig. 2.1 ) are seen;

also, these cells are more proliferative, and display delayed differentiation relative

to the timing of differentiation of satellite cells derived from trunk muscles (Ono

et al. 2010 ) . Taken together, these fi ndings highlight a link between myogenesis in

the early embryo and the generation of adult muscle progenitor pools required for

muscle maintenance and regeneration (Fig. 2.3 ).

Heterogeneity in skeletal muscles can also be seen during adulthood, as re fl ected

in distinct genetic signatures and susceptibilities to myopathies in both head and

trunk skeletal muscles (Emery 2002 ; Porter et al. 2006 ) . In humans, several diseases

are characteristic of skeletal muscle tissue, and one of the longstanding mysteries in

the fi eld is why some muscles, but not others, are affected, even though they are

often located in close anatomical proximity. For example, Duchenne Muscular

Dystrophy (DMD), seen in 1/3,500 male births, results in lethality by the time these

individuals reach their mid-twenties, even with extensive intervention and health

care support in the later stages of the disease. Strikingly, in DMD patients, most

muscles are affected; yet EOM and laryngeal muscles are largely spared. This

fi nding re fl ects an underlying theme in muscle diseases: understanding why virtually

all myopathies affect only a subset of muscles is of great scienti fi c interest, with

potential clinical relevance. Hence the phenotypic outcome observed in diverse

myopathies maybe rooted in developmental underpinnings.

2.5 Distinct Genetic Programs in Trunk and Head Muscles

It appears that different intrinsic and extrinsic regulatory pathways control skeletal

muscle formation in the trunk and in the head, as indicated by genetic loss of myogenic

transcription factors in mice (Kelly et al. 2004 ; Lu et al. 2002 ; Rudnicki et al.

1993 ; Tajbakhsh et al. 1997 ) as well as by manipulations of tissues and signaling

molecules in chick embryos (Hacker and Guthrie 1998 ; Mootoosamy and Dietrich

2002 ; Noden et al. 1999 ; Tzahor et al. 2003 ) . While skeletal muscle formation in

both regions of the embryo requires either MyoD or Myf5 (Rudnicki et al. 1993 ) ,

mice lacking both Myf5 and Pax3 are completely devoid of trunk muscles, yet retain


17

normal head muscles (Tajbakhsh et al. 1997 ) . Thus, in the absence of Myf5 , Pax3 is

necessary for the expression of MyoD in the trunk, but not in the head, a fi nding

consistent with the fact that Pax3 is not expressed in head muscle progenitors (Harel

et al. 2009 ) .

The bHLH transcription factors, Capsulin and MyoR, were shown to act as

upstream regulators (presumably repressors) of pharyngeal arch-derived muscle

development. In Capsulin/MyoR double mutants, the masseter, pterygoid, and temporalis

muscles were missing, while distal lower jaw muscles (e.g., anterior digastric

and mylohyoid) were not affected (Lu et al. 2002 ) . In T-box transcription factor

Tbx1 mutants, pharyngeal arch-derived muscles were frequently hypoplastic and

asymmetric, whereas the EOM and tongue muscles were not affected (Kelly et al.

2004 ) . Hence, pharyngeal arch-derived muscles require Tbx1 for robust bilateral

speci fi cation. Head muscle defects in Tbx1 mutants are likely due to an intrinsic

defect in the mesoderm (Dastjerdi et al. 2007 ) , as well as to Tbx1’s indirect function

in the endoderm and ectoderm (Arnold et al. 2006 ) . Indeed, analyses of various

Tbx1 mutant embryos indicated that several fi broblast growth factor (FGF) family

members expressed in these adjacent tissues were down-regulated, demonstrating a

role for Tbx1 and FGF signaling during head muscle development (Hu et al. 2004 ;

Kelly et al. 2004 ; Knight et al. 2008 ; Vitelli et al. 2002 ; von Scheven et al. 2006 ) .

Tbx1 and the bicoid-related homeodomain transcription factor Pitx2 are thought

to be linked to the same genetic pathway in many developmental processes, including

cardiac and craniofacial muscle development (reviewed in Grifone and Kelly

2007 ) . In both mouse and chick, Pitx2 is expressed in the head mesoderm and, subsequently,

in the mesodermal core of PA1 (Dong et al. 2006 ; Shih et al. 2007 ) . In

Pitx2 mutants, the EOM and PA1 muscles of mastication are affected. Pitx2 is

essential for EOM formation. Reducing Pitx2 gene dose results in small rectus muscles,

while eliminating Pitx2 expression completely prevents the formation of all

the EOM (Diehl et al. 2006 ) .

A recent study in mice that addressed the genetic programs promoting myogenesis

in the head muscles revealed distinct requirements for Myf5 and Mrf4 in EOM

and in pharyngeal arch-derived muscles (Sambasivan et al. 2009 ) . Furthermore, this

study suggests that Tbx1 in PM progenitors plays a similar role to that of Pax3 during

somitogenesis. In zebra fi sh, the functions of Myf5 and MyoD during head muscle

formation are non-redundant: in this organism, the homeodomain transcription

factor Six1 seems to play a role in the genetic program regulating development of

subsets of muscles during head myogenesis (Lin et al. 2006, 2009 ) .

In summary, embryological and genetic studies indicate that distinct regulatory

circuits control the formation of head and trunk skeletal muscles. These loss-offunction

studies, combined with fi ndings from lineage tracing studies, highlight the

heterogeneity in head muscle development, such that distinct genetic programs regulate

different groups of muscles within the head. An important open question in the

fi eld is how the aforementioned set of transcription factors expressed in head muscle

progenitors interacts in a hierarchical regulatory network to activate myogenesis in

the head.


2.6 Extrinsic Regulation of Head Muscle Development

The tissues and signaling molecules that promote skeletal muscle formation

(myogenesis) from muscle progenitors in the somites have been intensively studied

(Buckingham 2006 ; Pourquie 2001 ; Tajbakhsh 2005 ) . Somitic myogenesis in the

trunk is affected by signals emanating from the axial tissues, the surface ectoderm,

and the lateral plate mesoderm. Wnt family members expressed in the dorsal neural

tube work together with Sonic hedgehog (Shh) expressed in the notochord to activate

Myf 5 and MyoD in the somite (Borycki et al. 2000 ; Gustafsson et al. 2002 ;

Munsterberg et al. 1995 ; Stern et al. 1995 ; Tajbakhsh et al. 1998 ) . Bone morphogenic

protein (BMP) signals from the lateral plate have been shown to delay the

activation of myogenic bHLH gene expression in the somites (Pourquie et al. 1996 ;

Reshef et al. 1998 ) .

The differences between head and trunk myogenic programs re fl ect the in fl uence

of both intrinsic (e.g., tissue-speci fi c transcription factors) and extrinsic regulatory

pathways (e.g., signaling molecules). Although signals from the dorsal neural tube

promote myogenesis in the trunk (Munsterberg et al. 1995 ) , such signals block myogenesis

in PM explants (Tzahor et al. 2003 ) . Accordingly, overexpression of Wnt

family members expressed in either the dorsal neural tube ( Wnt3a ) or surface ectoderm

( Wnt13 ), or forced expression of stabilized b -catenin , which stimulates the

canonical Wnt-signaling pathway, block myogenesis in PM explants and in vivo

(Tzahor et al. 2003 ) . In striking contrast, Wnt family members expressed in either the

dorsal neural tube or in surface ectoderm overlying the somites were shown to promote

skeletal myogenesis in this tissue (Capdevila et al. 1998 ; Ikeya and Takada 1998 ;

Munsterberg et al. 1995 ; Stern et al. 1995 ; Tajbakhsh et al. 1998 ; Takada et al. 1994 ) .

In contrast to the differential effects of Wnt signaling on head vs. trunk

mesoderm, BMP signals were found to repress myogenesis in both head (Tirosh-

Finkel et al. 2006 ; Tzahor et al. 2003 ) and trunk regions (Amthor et al. 1999 ;

Hirsinger et al. 1997 ; McMahon et al. 1998 ; Pourquie et al. 1996 ; Reshef et al.

1998 ) . Accordingly, myogenesis in the head is induced by a combination of BMP

inhibitors such as Noggin and Gremlin, and a Wnt inhibitor (e.g., Frzb). These molecules

were shown to be secreted by both CNC cells, and by other tissues surrounding

the cranial muscle anlagen (Tzahor et al. 2003 ) .

The expression of certain FGF family members in the mouse is Tbx1-dependent,

suggesting that FGF signaling may act downstream of Tbx1 function, although the

precise role of FGF signaling on head myogenesis is not entirely clear (Knight et al.

2008 ; von Scheven et al. 2006 ) .

Taken together, in the trunk, signals from the neural tube and notochord

speci fi cally stimulate the development of the epaxial muscle anlagen, which remain

in the vicinity of the axial midline tissues to give rise to the deep muscles of the back

(Burke and Nowicki 2003 ) . In contrast, head muscles develop at a distance from the

neural tube (the developing brain) in either the core of the PAs (pharyngeal muscles)

or around the eye (EOM). Hence, Wnt and BMP (and likely FGF) signals block

premature head muscle differentiation in the vicinity of the axial tissues. It is tempting


19

to speculate that these signals play a role in the delayed differentiation of head

muscle progenitors within regulatory circuits involving transcription factors such as

Tbx1 , Pitx2 , MyoR , Capsulin , and Isl1 . Overexpression studies in chick PM explants

and in vivo have demonstrated that this is, indeed, the case (Harel et al. 2009 and

data not shown). Thus, Wnt, BMP, and FGF signaling pathways are thought to control

the balance between myogenic precursor proliferation and differentiation in the

head. Whether some of these extrinsic signals play roles in the speci fi cation of head

muscle progenitors is a plausible assumption that remains to be validated.

2.7 Cranial Neural Crest Cells Affect Head Muscle

Patterning and Differentiation

Cranial neural crest cells surround the muscle anlagen in a highly organized fashion,

separating the myoblasts from the overlying surface ectoderm (Noden 1983b ;

Trainor et al. 1994 ) . Cranial neural crest cells give rise to most of the skeletal

elements of the head, and also serve as precursors for connective tissues and tendons

(Couly et al. 1993 ; Le Douarin et al. 1993 ) . Neural crest cells affect the patterning

of muscle, placodes, and connective tissue in the head. Both PM and cranial

neural crest cells migrate into the PAs, which form the templates of adult craniofacial

structures (Hacker and Guthrie 1998 ; Noden 1983b ; Noden and Trainor

2005 ; Trainor and Tam 1995 ; Trainor et al. 1994 ) . In a similar fashion cranial neural

crest cells affect the patterning of EOM formation within the orbit (Bohnsack

et al. 2011 ) . Mesoderm-derived muscle progenitors fuse together to form myo fi bers

within cranial neural crest-derived connective tissue in a precisely coordinated

manner.

Craniofacial shapes are amazingly diverse in vertebrates (Helms et al. 2005 ) .

This diversity apparently re fl ects the tight linkage between skeletal elements and

connective tissue, derived from the cranial neural crest, and the muscles, which are

mesoderm-derived. The relationship between muscle and skeletal elements within

the jaw region strongly affects feeding mechanics. This may re fl ect on the ability of

vertebrates to rapidly modify the jaw complex, a critical evolutionary advantage

enabling the organism to accommodate to new ecological conditions (Herrel et al.

2005 ) . In keeping with this view, the emergence of vertebrate predators is also associated

with the increased muscularization of PA muscles, along with an increase in

size of the jaw skeleton (Takio et al. 2004 ) .

The molecular mechanisms underlying head muscle patterning—myoblast guidance,

positioning, and connection to speci fi c attachment sites—have in the past

been poorly understood. Furthermore, the degree to which skeletal muscle

speci fi cation, differentiation, and patterning is intrinsic to muscle (mesoderm) progenitors,

or controlled by extrinsic environmental signals (e.g., cranial neural crest

cells), is a fundamental embryological question. It has long been suggested that, in

addition to contributing to the formation of skeletal elements and connective tissue


in the head, cranial neural crest cells may also be involved in producing the signals

necessary for the patterning of the head musculature (Couly et al. 1992 ; Ericsson

et al. 2004 ; Grammatopoulos et al. 2000 ; Grenier et al. 2009 ; Heude et al. 2010 ;

Kontges and Lumsden 1996 ; Noden 1983a, b ; Olsson et al. 2001 ; Rinon et al. 2007 ;

Schilling and Kimmel 1997 ; Tokita and Schneider 2009 ; Tzahor et al. 2003 ) .

Because skeletal muscles in the head, except for EOM, still form (albeit in a

distorted fashion), following in vivo ablation of the cranial neural crest cells in

amphibian and chick embryos (Ericsson et al. 2004 ; Olsson et al. 2001 ; Tzahor et al.

2003 ; von Scheven et al. 2006 , reviewed in Noden and Trainor 2005 ) , the precise

impact of cranial neural crest cells on head muscle formation remains unclear. Thus,

while it is generally accepted that the cranial neural crest cells in fl uence cranial

muscle formation, exactly how cranial neural crest cells participate in this process

has yet to be elucidated. The current view in the fi eld is that cranial neural crestderived

connective tissue progressively imposes the characteristic anatomical musculoskeletal

architecture upon PM muscle progenitors (Heude et al. 2010 ; Rinon

et al. 2007 ; Tokita and Schneider 2009 ) .

PM progenitors are exposed to signals from pharyngeal arch endoderm, ectoderm,

and neural crest cells that together create a complex regulatory system

(reviewed in Rochais et al. 2009 ; Vincent and Buckingham 2010 ) . Perturbation of

the balance of signals within this system can lead to abnormal cardiac and craniofacial

development (see below). Neural crest ablation in the chick, for example, results

in increased FGF signaling and elevated proliferation in the PM (Hutson et al. 2006 ;

Rinon et al. 2007 ; Waldo et al. 2005 ) . These fi ndings suggest that both cardiac neural

crest (affecting caudal PM progenitors) and cranial neural crest cells (affecting

cranial PM) buffer proliferative signals (presumably FGFs) secreted from the endoderm

and ectoderm, to promote PM migration and differentiation.

2.8 The Link Between Heart and Pharyngeal-Arch Derived

Muscle Development

The skeletal myogenic potential of PM cells and their contribution to pharyngeal

arch-derived muscles have long been documented (Noden and Francis-West 2006 ;

Wachtler and Jacob 1986 ) . In contrast, the cardiogenic potential of these cells has

only been revealed over the last decade (reviewed in Black 2007 ; Buckingham

et al. 2005 ; Dyer and Kirby 2009 ; Evans et al. 2010 ; Tzahor and Evans 2011 ;

Vincent and Buckingham 2010 ) . For example, PM explants dissected from early

chick embryos undergo cardiogenesis (Nathan et al. 2008 ; Tirosh-Finkel et al.

2006 ; Tzahor and Lassar 2001 ) . The in vivo cardiogenic potential of PM was further

revealed in chick embryos (Nathan et al. 2008 ; Rana et al. 2007 ; Tirosh-Finkel

et al. 2006 ) . It has been shown that Wnt signaling (e.g., Wnt1 and Wnt3a from the

dorsal neural tube) inhibit PM-derived cardiogenesis (Nathan et al. 2008 ; Tzahor

and Lassar 2001 ) . Considerable overlap in the expression of head muscle markers

(e.g., Myf5 , Tcf21 ( capsulin ), Msc ( MyoR ), Tbx1 , Pitx2 ) and cardiac markers such


21

as Islet1 and Nkx2.5 has been documented in the PM, suggesting that these cells

play a dual role in myogenesis and cardiogenesis (Bothe and Dietrich 2006 ; Nathan

et al. 2008 ; Tirosh-Finkel et al. 2006 ) . Likewise, lineage studies in the mouse demonstrated

an overlap in progenitor populations contributing to pharyngeal muscles

and second heart fi eld derivatives (Dong et al. 2006 ; Harel et al. 2009 ; Nathan et al.

2008 ; Verzi et al. 2005 ) . Thus, the genetic program controlling development of

pharyngeal arch-derived muscles overlaps with that controlling the PM-derived

heart progenitors.

The LIM-homeodomain protein Islet1 (Isl1) is required for a broad subset of

cardiac progenitors in the mouse (Cai et al. 2003 ; Laugwitz et al. 2008 ; Lin et al.

2007 ; Sun et al. 2007 ) . Gene expression and lineage experiments in the chick have

revealed that the core of the pharyngeal arch is divided along the proximal–distal

axis, such that paraxial mesoderm cells mainly contribute to the proximal region of

the core, while the splanchnic mesoderm contributes to its distal region (Nathan

et al. 2008 ) . Isl1 is expressed in the distal part of the PM, and its expression is correlated

with delayed differentiation of lower jaw muscles (Nathan et al. 2008 ) .

Over-expression of Isl1 in the chick represses pharyngeal muscle differentiation

(Harel et al. 2009 ) .

Lineage tracing experiments in the mouse, using an Isl1 Cre line revealed the

signi fi cant contribution of Isl1 + cells to the mesodermal core of the pharyngeal

arches (Harel et al. 2009 ; Nathan et al. 2008 ) , as well as to the heart (Moretti et al.

2006 ) . Isl1 + PM cells were shown to contribute to a subset of pharyngeal arch-derived

muscles (mylohyoid, stylohyoid, and digastric) at the base of the mandible, facilitating

its opening. Isl1 + cells give rise to PA2 muscles controlling facial expression

(Harel et al. 2009 ; Nathan et al. 2008 ) and, to a lesser extent, the masseter, pterygoid,

and temporalis, the jaw closing muscles, indicating that this gene is not expressed

in all PM progenitors. In both species, tongue and EOM are not derived from the

Isl1 lineage (Harel et al. 2009 ; Nathan et al. 2008 ) . Taken together, Isl1 marks a

subset of PM cells, and plays an important role in the development of distinct

PM-derived cardiovascular and skeletal muscle progenitors (Tzahor and Lassar

2001 ) . The direct role of Isl1 in pharyngeal arch-derived muscle development has

yet to be resolved, as Isl1 knockout embryos die at around E10 (Cai et al. 2003 ) .

A retrospective clonal analysis in the mouse, developed in the Buckingham lab,

demonstrated recently that head muscles and second heart fi eld derivatives originate

from multipotent PM progenitors (Lescroart et al. 2010 ) . Two myogenic lineages

that link groups of head muscles to different parts of the heart were identi fi ed. The

fi rst muscle lineage gives rise to the temporalis and masseter as well as to the EOM.

Strikingly, this single cell clone also contributes to myocardial cells in the right

ventricle. The second lineage gives rise to a broad range of muscles controlling

facial expression, which derive from PA2 mesoderm, and also contributes myocardial

cells at the arterial pole of the heart (Lescroart et al. 2010 ) . In conclusion, this

study and others provide cellular and molecular insights into how pharyngeal

mesoderm cells form distinct pharyngeal arch-derived muscles and certain parts of

the heart.


2.9 Evolution of Pharyngeal Mesoderm: From Pharyngeal

Arch-Derived Muscles to the Heart

The architecture and function of muscle cells have been remarkably conserved

throughout evolution, suggesting that all muscle cells likely evolved from an ancestral

developmental program involving a single contractile myogenic cell type (Baugh

and Hunter 2006 ; Fukushige et al. 2006 ) . The fact that the developmental programs

of the heart and pharyngeal arch-derived muscles are tightly linked suggests that

these tissues share common evolutionary origins (Grifone and Kelly 2007 ; Tzahor

2009 ; Tzahor and Evans 2011 ) . For example, nematodes are invertebrates that do

not possess a heart or de fi ned circulatory system. Instead, their pharyngeal archderived

muscle functions like a heart, and exhibits electrical activity similar to that

of mammalian cardiomyocytes. Furthermore, it has been shown that pharyngeal

arch-derived muscle development in nematodes is regulated by the homeobox gene

Nkx2.5 (ceh-22) (Harfe and Fire 1998 ) and may be functionally replaced by the

zebra fi sh nkx2.5 (Haun et al. 1998 , reviewed in Grifone and Kelly 2007 ; Olson

2006 ; Tzahor 2009 ; Tzahor and Evans 2011 ) .

Tunicates belong to the Chordata phylum, and are considered as the “sister

group” of vertebrates (Davidson 2007 ) . The tunicate Ciona intestinalis is a sessile

marine invertebrate. As in vertebrates, the Ciona heart is located ventrally and posterior

to the pharynx, and anterior to the stomach; in the gastrulating embryo, its

heart arises from a pair of blastomeres expressing the MesP gene. Several studies

suggest signi fi cant similarities in the gene regulatory networks controlling cardiogenesis

in vertebrates and tunicates (Davidson 2007 ; Davidson et al. 2006 ; Satou

et al. 2004 ) . The heart and pharyngeal arch-derived muscle cells in Ciona are seemingly

distinct, based on the expression of different myosin heavy chain isoforms

(Ogasawara et al. 2002 ) ; yet both are derived from MesP + cells.

Strikingly, Isl1 + PM cells in both Ciona (Stol fi et al. 2010 ) and vertebrates (Harel

et al. 2009 ; Nathan et al. 2008 ) give rise to pharyngeal arch-derived muscles (termed

siphon muscles in Ciona). These fi ndings suggest that the last common ancestor of

tunicates and vertebrates contained PM cells derived from MesP + lineages that

expressed Isl1, FoxF, and Nkx2.5, and had the potential to give rise to both heart

tissue and pharyngeal arch-derived muscles (Stol fi et al. 2010 , reviewed in Tzahor

and Evans 2011 ) . With the increasing complexity of the vertebrate heart and, in

particular, during the heart tube elongation that occurs in vertebrates, Isl1 + PM cells

were recruited into the looping heart to give rise to cardiomyocytes. Hence, this

study implies that reallocation of PM cells into the looping heart represents the

emergence of the second heart fi eld in vertebrates. In addition, these fi ndings suggest

a distinct evolutionary separation in the origins of the two heart fi elds.


23

2.10 Summary

Skeletal muscles throughout the body facilitate locomotion and movement due to

their contractile functionality. Two decades ago our view on skeletal muscle development

argued for a common developmental program for this tissue that is governed

by a set of MRFs. Our current view is gradually changing with the realization

that skeletal muscles are highly heterogeneous in terms of their developmental origins,

the molecular networks that activate myogenesis, their function, and their malfunction

under disease conditions. In particular, head muscle differs in these aspects

from the muscles in our body. Recent studies focusing on head muscle development

provide novel insights on the origins of these muscles and their molecular signatures.

These insights are relevant to an understanding of head myogenesis, the link

between cardiac and craniofacial muscle development, as well as to the etiology of

craniofacial muscle myopathies.

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Part III

Extraocular Muscles

Chapter 3

Extraocular Muscle Structure and Function

Linda K. McLoon , Christy L. Willoughby , and Francisco H. Andrade

3.1 Introduction

It has become increasingly clear that skeletal muscles are not all the same, but have

signi fi cant differences in terms of embryological development, fi ber type, physiological

properties, metabolic properties, and disease pro fi le. If one thinks about

skeletal muscle as a continuum from the least to most complex, with the leg muscle

soleus at one end, the extraocular muscles (EOMs) would be at the other end. The

combination of its unusual properties compared to other skeletal muscles has

resulted in the suggestion that the EOM represent a distinct allotype (Hoh and

Hughes 1988 ) . The goal of this chapter is to summarize the characteristics of the

EOM that make them so unique amongst skeletal muscles.

3.2 Anatomy

The EOM are traditionally described as including 7 muscles in each orbit. Six muscles

move each eye in the orbit, 4 rectus muscles and 2 oblique muscles, and the location

of each determines its role in controlling eye position and movement. A seventh

L.K. McLoon, Ph.D. (*)

Department of Ophthalmology, University of Minnesota, 2001 6th Street SE,

Minneapolis, MN 55455, USA

e-mail: mcloo001@umn.edu

C.L. Willoughby

Departments of Ophthalmology and Neuroscience ,

University of Minnesota , Minneapolis , MN , USA

F.H. Andrade , Ph.D.






31

32 L.K. McLoon et al.

Fig. 3.1 Diagram of the anatomical locations of the extraocular muscles (EOM) within the orbit

from the superior view. The inferior rectus would be parallel to the superior rectus but cannot be

seen from this view. The inferior oblique takes its origin from the medial side of the inferior orbital

wall, and would run parallel to the direction of the SO from the trochlea (T) to the sclera. Superior

rectus (SR), medial rectus (MR), lateral rectus (LR), superior oblique (SO)

Fig. 3.2 The medial and lateral rectus muscles move the eye in the horizontal plane. To look to the

right, the lateral rectus of the right eye abducts the right eye, moving it away from the nose, and the

medial rectus adducts the left eye, moving it towards the nose

muscle, the levator palpebrae superioris muscle, acts to raise the eyelid. While an

interesting muscle, it will not be discussed further. The pathways of the EOM from the

orbit to the sclera determine eye position and direction of eye movements. The medial

and lateral rectus muscles both take their origin at the apex of the orbit from a common

tendinous ring and insert onto the sclera on the medial and lateral sides of the globe

anterior to the equator of the globe (Fig. 3.1 ). These muscles have the simplest action

of the six EOM, in that they control horizontal eye movements. The medial rectus

adducts the eye (moving it towards the nose) and the lateral rectus abducts the eye

(moving it away from the nose) (Fig. 3.2 ). Because the eyes move in a conjugate manner

in most directions of gaze at distance, the medial and lateral rectus muscles within

3 Extraocular Muscle Structure and Function

33

Fig. 3.3 The medial orbital walls are parallel to each other, and the lateral wall forms a 45° angle

with the medial wall. If there was no tension on the EOMs the natural direction of gaze would be

at 22.5°, rather than parallel to the medial wall. Thus, tone must be maintained in the medial rectus

muscles bilaterally in primary gaze (see Fig. 3.4d )

the same orbit (and attaching to the same globe) are referred to as agonist/antagonist

pairs. When a person looks to the right in the horizontal plane, the right lateral rectus

and the left medial rectus muscle act in a coordinated fashion; these muscle pairs are

referred to as yoked muscles. The superior and inferior rectus muscles also take their

origin from the same common tendinous ring at the apex of the orbit and insert into the

superior and inferior sides of the globe, anterior to the equator, and play a role in vertical

eye movements. Due to the pyramidal shape of the bony orbit (Fig. 3.3 ), if you draw

a line parallel to the direction of these vertical muscles, it is clear that if one or the other

contracts, the eye would not move directly superiorly or inferiorly. Both also have a

rotational component, the net effect of which is to adduct the eye (move towards the

nose). This secondary action is actually torsional; thus the superior rectus elevates and

intorts the eye, while the inferior rectus depresses and extorts the eye.

The fi nal two EOM in the orbit are the superior and inferior oblique muscles. The

superior oblique muscle takes its origin from the apex of the bony orbit and runs in

the superior part of the orbit along the medial wall. It passes through a cartilaginous

pulley called the trochlea and makes an acute turn posteriorly to insert deep to

the superior rectus muscle on the superior surface of the globe, but posterior to the

equator of the globe. The passage through the trochlea places the effective origin at

the anteromedial orbital wall, and the insertion posterior to the equator results in the

primary action of the superior oblique to be intorsion, which results in abduction of

the eye (rotating away from the nose), and its secondary action is depression. The

inferior oblique takes its origin from the anteromedial inferior orbital wall and

courses posteriorly to insert on the globe posterior to the equator. The direction of

pull of this muscle is parallel to the superior oblique; its primary action is to extort

the eye, which results in abduction of the eye (rotating away from the nose), and its

secondary action is elevation. If you examine the shape of the orbit and the position


Fig. 3.4 Speci fi cally with reference to the right eye, the photographs demonstrate ( a ) elevation

and extortion, ( b ) elevation, ( c ) abduction, and ( d ) primary position of gaze. ( a ) To direct the gaze

to look right, up and out, that is elevate and extort, the inferior oblique muscle of the right eye must

contract. As the eyes move conjugately, the left eye must intort and elevate which is performed

by the superior rectus muscle of the left eye. ( b ) To look directly overhead, without bending the

neck, the superior rectus and inferior oblique muscles must co-contract. Both elevate, and their

co-contraction will essentially “cancel out” the extorsion and intorsion components of each of

these muscles seen when they contract alone

of the eyes needed to fi xate on a distant object in primary gaze (Fig. 3.4d ), it is clear

that a certain amount of muscle tension must be maintained on the medial rectus

muscles bilaterally. In addition, due to the complex vectors of each muscle, for the

eyes to look up at the ceiling (without bending your neck), bilaterally the superior

rectus muscle must contract—which elevates and intorts the eye—and the inferior

oblique must contract—which extorts the eye and elevates. The combination of

contraction of these muscles results in elevation directly superiorly (Fig. 3.4b ).

What this means is that the EOM are continuously active, even in the primary direction

of gaze (Fig. 3.4d ).

The EOM are innervated by three pairs of cranial nerves: the oculomotor nerve

(CNIII) innervates the superior rectus, medial rectus, inferior rectus, and the inferior

oblique muscles, the trochlear nerve (CNIV) innervates the superior oblique muscle,

and the abducens nerve (CNVI) innervates the lateral rectus muscle. The EOM are

densely innervated, resulting in very small motor units, with typical fi ring rates an

order of magnitude higher than seen in spinal motor neurons (Fuchs et al. 1988 ) .

3.3 Embryological Origins

The EOM arise from non-segmented cranial mesoderm in contrast to the body and

limb skeletal muscles, which are derived from somites. While all of the craniofacial

muscles except tongue develop from non-segmented cranial mesoderm, the EOM

have a distinct genetic program that controls their initial formation in development.

These genes essentially have little overlap with the embryological development of

other craniofacial muscles (see Chap. 2 , Harel and Tzahor 2012 ) . Limb and body

skeletal muscle somite formation is dependent on the transcription factor Pax3


35

Fig. 3.5 Mesoderm-speci fi c knockout of Pitx2 results in the absence of EOMs. Sagittal sections

behind the globe of the eye allow for visualization of all seven EOMs at later developmental time

points, such as e14.5. ( a ) Immunohistochemistry for developmental myosin heavy chain

(MyHCdev) shows T-Cre+;Pitx2 fl ox/null mutant embryos have little ( c ) to no ( d ) differentiated EOM

at e14.5, as compared to T-Cre+;Pitx2 +/+ ( a ) or T-Cre+;Pitx

+/null

( b ) controls. SO superior oblique;

SR superior rectus; MR medial rectus; RB retractor bulbus; LR lateral rectus; IR inferior rectus; IO

inferior oblique. Used with permission from Elsevier: Zacharias et al. ( 2011 )

(Tajbakhsh et al. 1997 ) . However, eye muscle formation is completely unaffected in

mutants lacking Pax3 expression. In contrast, EOM formation in early development

is dependent on the gene dose of the transcription factor Pitx2; with reduced Pitx2

expression, the oblique muscles do not form, and several of the rectus muscles are

smaller. If the Pitx2 gene is knocked out, the EOM do not develop (Diehl et al.

2006 ; Zacharias et al. 2011 ) (Fig. 3.5 ). Formation of the EOM is also dependent on

optic vesicle and eye development as well as periocular neural crest cells (Bohnsack

et al. 2011 ) . This relationship has a temporal component during development, as

shown in an elegant series of experiments using zebra fi sh embryos (Bohnsack et al.

2011 ) . If the eye does not form before neural crest cell migration into the periocular

mesenchyme, no EOM form; if eye development is halted after neural crest cell

migration, EOM develop. These observations are important for understanding the

anophthalmic orbits of human patients relative to the search for genetic mutations

known to correlate temporally with these developmental processes.


3.4 Unusual Characteristics of EOM Muscle Fibers

Muscles are composed of thousands of individual myo fi bers, which are responsible

for the shortening velocity and overall force produced during contractions. The

EOM have arguably the fastest contractile properties of mammalian skeletal muscles

(Close and Luff 1974 ) , normally generate low force, and are very fatigue resistant

(Asmussen and Gaunitz 1981 ; Fuchs and Binder 1983 ; Prsa et al. 2010 ) . These

properties are due to a number of constitutive differences between EOM myo fi bers

and those in other skeletal muscles. This discussion will include studies in both

human EOM as well as in a variety of animal species; while differences exist, the

general overall pattern of anatomy, metabolism, and physiology are similar.

The microscopic anatomy of the EOM is quite complex. First, cross-sections

through the EOM show that the muscles are not homogeneous, but rather are composed

of two distinct layers (Fig. 3.6a ). There is an outer orbital layer composed of

myo fi bers of extremely small cross-sectional areas, averaging 260 ± 160 m m 2 in

human EOM (Kjellgren et al. 2003a, b ) . The inner global layer myo fi bers are larger

in cross-sectional area, averaging 440 ± 200 m m 2 in human EOM, but still are

signi fi cantly smaller than myo fi bers from limb skeletal muscles, averaging from

6294 ± 2,159 m m 2 (SD) for the fastest fi ber types (myosin heavy chain isoform

(MyHC) type IIB) to 9,278 ± 3496 m m 2 for the slowest fi ber types (MyHC type I)

(Bottinelli et al. 1996 ) . In contrast to limb skeletal muscles, these myo fi bers do not

course from tendon to tendon, as fi rst shown in the 1970s (Mayr 1971 ; Alvarado-

Mallart and Pincon-Raymond 1976 ) , and con fi rmed by serial reconstruction of individual

myo fi bers (Harrison et al. 2007 ) . In addition, there are signi fi cant numbers of

branched fi bers within the EOM (Mayr 1971 ; Alvarado-Mallart and Pincon-

Raymond 1976 ) . This complexity plays a role in the non-linear force summation of

electrically stimulated motor units in the ocular motor system (Shall et al. 2003 ) .

3.5 Innervation

EOM motor control (Das 2012 ) and disease sparing and propensity (Pedrosa-Domellöf

2012 ) in EOM will be discussed in the following two chapters. However, there are

some critical differences between the patterns of motor innervation of the EOM that

should be noted. Early studies demonstrated that there were two morphologically different

endplates on EOM myo fi bers (Kupfer 1960 ) , larger endplates similar to those

seen in limb skeletal muscle, so-called en plaque endings, and smaller nerve terminals

that form multiple endings along individual myo fi bers, the so-called en grappe endings

(Fig. 3.7 ). Many EOM myo fi bers have both en plaque and en grappe endings on

them, and this innervation pattern manifests by signi fi cantly different contractile protein

expression patterns and different contractile properties in different regions of

single myo fi bers (Jacoby et al. 1989a, b ) . Serial reconstructions demonstrate that

there are singly and multiply innervated myo fi bers in both the orbital and global


37

Fig. 3.6 The microscopic

anatomy of the EOM is quite

complex. Cross-sections

through the EOM show that

the muscles are not

homogeneous, but rather are

composed of two distinct

layers, the orbital (ORB) and

global (GLOB) layers. These

vary by muscle fi ber size,

which is much smaller in the

orbital layers, and by patterns

of expression of various

molecules. ( a ), ( c ), and ( e )

are serial cross-sections from

the middle of the medial

rectus muscle of a macaque

monkey. ( b ), ( d ), and ( f ) are

serial cross-sections from a

region midway between the

midregion of the muscle and

the tendon end. ( a ) and ( b )

are immunostained for fast

myosin heavy chain (MyHC)

isoform, ( c ) and ( d ) are

immunostained for

embryonic MyHC isoform,

and ( e ) and ( f ) are

immunostained for neonatal

MyHC isoform. Note the

reduction in numbers of

fi bers positive for both the

fast and neonatal MyHC

isoforms as sections move

anteriorly and away from the

muscle midregion. Note the

small increase in the numbers

of fi bers in the orbital layer

positive for embryonic

MyHC as sections move

anteriorly and away from the

midregion


Fig. 3.7 Longitudinal sections through an EOM immunostained to visualize neuromuscular junctions

with antibodies to the postsynaptic nicotinic acetylcholine receptor ( nAChR, green ) and presynaptic

synaptophysin ( red ). En plaque neuromuscular junctions ( horizontal arrow ) and the

smaller en grappe neuromuscular junctions ( vertically oriented arrows ) that form multiple endings

along individual myo fi bers are present

layers, as well as single fi bers with a central en plaque ending with en grappe endings

along the fi ber length (Pachter et al. 1976 ) . These are found in the orbital layer. The

cause of this heterogeneity of nerve endings, which arise from the innervating motor

nerve, is unclear. However, it is well known that the nerve controls many of the properties

of the myo fi bers it innervates, and is, at least in part, responsible for the complex

properties of the myo fi bers themselves.

In addition to containing multiply innervated myo fi bers, neuromuscular junction

endplates in adult EOM also contain the “embryonic” gamma subunit of the nicotinic

acetylcholine receptor (Horton et al. 1993 ) . Histological evidence suggests

that the majority of en grappe endings include the gamma subunit; however, it is

also present in some en plaque nerve endings (Kaminski et al. 1996 ) . This neuromuscular

junctional complexity is presumed to be critical for the maintenance of at

least some of the unique properties of adult EOM. This was con fi rmed by the use

of a mouse with a conditional knock-out of the transcription factor Pitx2, which is

inactivated at birth (Zhou et al. 2009 , 2011). By 3 months, expression of several

myosin heavy chain (MyHC) isoforms were reduced, speci fi cally type IIX

(MYHC1), alpha-cardiac (MYH6), type I (MYH7), and the EOM-speci fi c isoform

(MYH13), resulting in muscles that were stronger, faster, and more fatigable. In

addition, the conditional loss of Pitx2 resulted in a decrease in multiply innervated

myo fi bers. These studies beautifully illustrate that Pitx2 is one of the factors that

maintain the complex properties of EOM. Future research will focus on additional

factors that de fi ne and control the EOM allotype.


39

3.6 Myosin Heavy Chain Isoforms

Early descriptions of EOM fi ber types used mitochondrial content and patterns of

innervation to divide the myo fi bers into discrete populations (Mayr 1971 ) . Three

fi ber types were described in the orbital layer: two were singly innervated with

either high or low mitochondrial density, and one was multiply innervated with low

mitochondrial density (Pachter 1983 ; Pachter and Colbjornsen 1983 ) . Four fi ber

types were described in the global layer: three were singly innervated with high,

intermediate, or low mitochondrial density, and one was multiply innervated with

low mitochondrial density. If the original fi ber typing scheme is re-examined, it is

noted that in fact there is a continuum of mitochondrial density in EOM myo fi bers

(Mayr 1971 ) . In addition, when myosin heavy chain isoform patterns are overlaid

on this early fi ber typing system, it begins to break down.

Probably the most studied characteristic of the EOM is their complex co-expression

patterns of at least nine MyHC isoforms (Wieczorek et al. 1985 ) . Limb and body

skeletal muscle is composed of four MyHC isoforms; from slowest to fastest in

terms of shortening velocity, they are: MyHC type1 (slow, b -cardiac, MYH7),

MyHC type 2A (fast MYH2), MyHC type 2X (2D, fast MYH1), and MyHC 2B

(fast MYH4). In addition to these isoforms, EOM also contain developmental (or

embryonic) MyHC (MyHCdev or MyHCemb, MYH3), neonatal (or perinatal)

MyHC (MyHCneo or MyHCperi, MYH8), alpha-cardiac MyHC (MyHC a -card,

MYH6) (Pedrosa-Domellöf et al. 1992 ) , and an EOM-speci fi c MyHC (MyHCeom,

MYH13) (Asmussen et al. 1993 ; Rubinstein and Hoh 2000 ; Stirn Kranjc et al. 2009,

2000 ; Wasicky et al. 2000 ; Kjellgren et al. 2003a, b ; Toniolo et al. 2007 ; Bicer and

Reiser 2009 ) . Mammalian EOM also include myo fi bers with slow-tonic contractile

characteristics (Hess and Pilar 1963), one of two mammalian muscles known to

contain fi bers with tonic contractile properties (tensor tympani is also reported to

express the slow tonic MyHC (Mascarello et al. 1982 ) ). Recently two “ancient

myosins,” MYH14/7b and MYH15, were found in mammalian EOM (Rossi et al.

2010 ) . MYH14 is found at low levels in developing skeletal muscles, heart, and all

EOM myo fi bers, but disappears in adult muscle except for the slow-tonic EOM

myo fi bers. MYH15 protein is found only in orbital layer slow-tonic myo fi bers of

adult EOM. In fact, these slow-tonic myo fi bers in EOM and tensor tympani are

unique in mammalian skeletal muscle (Bormioli et al. 1979). A recent study showed

that in addition to the traditional muscle MyHCs, approximately 20% of the global

layer “slow” fi bers also express non-muscle myosin IIB (nmMyHCIIB, MYH10),

as is also seen in cardiac muscle (Moncman and Andrade 2010 ) . As both EOM and

cardiac muscle have a common lineage relationship (Lescroart et al. 2010), it is not

surprising that many of the “unusual” myosins and other proteins expressed in the

EOM, but not limb skeletal muscle, are expressed also in cardiac muscle.

Not only are multiple MyHC isoforms expressed in the muscles as a whole, but

the pattern of expression of these isoforms varies dramatically between orbital and

global layers and even along the length of EOM fi bers (Fig. 3.6b ) (McLoon et al.

1999 ; Rubinstein and Hoh 2000 ; Kjellgren et al. 2003a, b ; Stirn Kranjc et al. 2009 ;


Fig. 3.8 Co-expression of multiple myosin heavy chain isoforms in single “hybrid” fi bers in serially

sectioned cross-sections of rabbit inferior rectus muscle immunostained for the following six

MyHC isoforms: EOM speci fi c, fast type IIA (IIA), embryonic (developmental, EMB), slow tonic,

slow type I (I), neonatal (perinatal, NEO). Green arrow indicates a myo fi ber that is positive for

IIA, EMB, NEO and slightly positive for slow tonic MyHC isoforms. The red arrow indicates a

myo fi ber positive for EMB, slow tonic, I and NEO MyHC isoforms

Zhou et al. 2010 ) . To make this picture even more complex, it is clear that not all

myo fi bers within the EOM course from tendon to tendon (Davidowitz et al. 1977 ;

McLoon et al. 1999 ; Shall et al. 2003 ; Harrison et al. 2007 ) . This has physiological

implications, and may explain the loss of predicted force that occurs in EOM under

experimental conditions (Goldberg et al. 1997 ; Milller et al. 2002 ) .

One of the most distinctive aspects of MyHC expression patterns in EOM is the

presence of multiple isoforms within single myo fi bers, referred to in the limb skeletal

muscle literature as “hybrid” fi bers (Fig. 3.8 ). Limb skeletal muscles also contain

hybrid fi bers, which tend to increase when the muscle is subjected to stress or injury,


41

where they can represent a pool of up to 60% of total myo fi bers (Caiozzo et al. 2000 ) .

Diaphragm muscle shows a very high degree of polymorphism, up to 78%, including

myo fi bers expressing both MyHC slow1 and MyHCIIX (Caiozzo et al. 2003 ) . The

potential for hybrid fi bers increases in EOM simply by the numbers of MyHC isoforms

that are expressed. Many studies in multiple species have demonstrated multiple

isoforms within single fi bers (Pachter 1984 ; Jacoby et al. 1989a, b ; Briggs and

Schachat 2002 ; Kjellgren et al. 2003a, b ; Zhou et al. 2010 ; McLoon et al. 2011 ) . In

an elegant study, individually dissected multiply innervated orbital layer myo fi bers

were shown to express fast MyHC in the middle of the myo fi ber in the location of

the en plaque endplates but expressed slow-tonic MyHC in the fi ber ends where the

en grappe endplates were located (Jacoby et al. 1989a ) . Electrophysiological measurements

con fi rmed that the central region of these fi bers displayed a spiking

response and twitch-like characteristics, while the tendon ends did not show a spiking

response and instead displayed tonic characteristics (Jacoby et al. 1989b ) .

Examination of co-expression patterns in rabbit EOM demonstrated that the majority

of myo fi bers expressed more than one myosin, with up to six MyHC isoforms in

single fi ber segments (McLoon et al. 2011 ) . Shortening velocity and force measurements

were performed on single-skinned fi bers, and again a continuum of velocity

and forces were seen. What is particularly interesting is that while myo fi bers containing

MyHCIIB tended to have faster shortening velocities and fi bers with MyHC1

tended to be slower, there was no clear correlation between co-expression patterns of

MyHC isoforms and shortening velocity (McLoon et al. 2011 ) , and a continuous

range for both force and shortening velocities was seen. In addition, there were a

number of the myo fi bers that expressed both slow and fast MyHC isoforms, referred

to as “mismatched” fi bers in the limb skeletal muscle literature (Fig. 3.9 ). The role this

complex con fi guration of MyHC isoforms plays in controlling eye position and eye

movements is unknown. However, a previous study of fi ber polymorphism in plantaris

muscle after overload or as a result of hypothyroidism showed that global alterations

in numbers of hybrid fi bers resulted in a 15% decrease in maximal shortening

velocity (Caiozzo et al. 2000 ) . Thus it is hypothesized that this complexity of MyHC

co-expression patterns must represent an important means for producing a wider spectrum

of contractile properties than would be possible with myo fi bers that contain a

single MyHC isoform.

3.7 Other Differentially Expressed Molecules in EOM

Additional molecules that control the contractile properties in EOM are also different

than those seen in limb skeletal muscles. For example, while no unique troponin

T molecule appears to be expressed in EOM, the EOM up-regulate troponin isoforms

that are only minor components in limb skeletal muscle (Briggs et al. 1988 ) .

EOM myo fi bers contain myosin-binding protein C-slow (MyBP-Cslow) in all

myo fi bers and lack MyBP-Cfast (Kjellgren et al. 2006 ) . In combination, these data

suggest that individual myo fi bers within EOM contain unique mixtures of molecules

that modulate contractility.


Fig. 3.9 An example of a “mismatched fi ber” ( red arrow ) in serially sectioned rabbit inferior rectus

muscle which is positive for ( a ) fast MyHC (IIA), ( b ) slow MyHC (I), and ( c ) slow tonic MyHC

In limb skeletal muscle fi bers, fast myo fi bers (MyHCII) contain the fast isoform

of the sarco/endoplasmic reticulum Ca 2+ ATPase (SERCA1) and slow myo fi bers

(MyHC1) contain SERCA2. In contrast, 99% of the “fast” EOM myo fi bers contain

SERCA1, and 86% of these also contain SERCA2 (Kjellgren et al. 2003a, b ) . On

the other hand, 100% of the “slow” EOM myo fi bers contain SERCA2, but 54% also


43

contain SERCA1. Overall, calcium handling is also signi fi cantly different in EOM

than in limb and body skeletal muscles. The EOM are more resistant to necrosis

induced by elevated cytosolic calcium levels (Khurana et al. 1995 ; Zeiger et al.

2010 ) . This increased calcium buffering capacity in EOM is due to a combination

of factors: abundant sarcoplasmic reticulum (which increases SERCA content),

high concentrations of parvalbumin, a small cytosolic Ca 2+ -binding protein, and

mitochondria serving as fast Ca 2+ sinks (Andrade et al. 2005 ; Celio and Heizmann

1982 ) . This enhanced ability to regulate cytosolic Ca 2+ concentration plays a role in

controlling contractile amplitude in the EOM.

The EOM are constantly active, have some of the fastest contractile properties

(Close and Luff 1974 ) , are very fatigue-resistant (Fuchs and Binder 1983 ) , and

while they normally need to produce only enough force to move the eye, they are

not intrinsically weaker than limb skeletal muscles (Frueh et al. 2001 ) . The bases

for these properties as well as the maintenance of these properties during eye movements

are an area of continued investigation. It has long been known that the EOM

have an extremely high density of mitochondria compared to non-cranial skeletal

muscles (Mayr 1971 ; Davidowitz et al. 1980 ) . In addition, the EOM mitochondria

have a different mitochondrial biogenesis program than the one used by limb skeletal

muscle (Andrade et al. 2005 ) . Despite their large mitochondrial volume density,

paradoxically the EOM mitochondria have lower respiratory capacity (Patel et al.

2009 ) . In addition, key enzymes controlling glycogen synthesis and breakdown are

repressed in the EOM, and glycogen content is correspondingly reduced (Porter

et al. 2001 ; Fischer et al. 2002 ) , suggesting that the EOM are probably less dependent

on glycogen as a metabolic fuel than other skeletal muscles. It is also possible

that the EOM rely on constant transport of blood-borne glucose and fatty acids

through their extensive microvascular network (Kjellgren et al. 2004 ). Overall, the

pattern is consistent with the EOM relying to a large extent on mitochondria as the

main source of energy under all conditions. One example is the use of lactate as a

substrate for its aerobic metabolism (Andrade and McMullen 2006 ) . In limb skeletal

muscles lactate is usually the end product of glycolysis and is associated with

muscle fatigue. In the EOM, the presence of lactate dehydrogenase B allows the

oxidation of lactate back to pyruvate for entry to the Krebs cycle; therefore, lactate

can sustain EOM activity and slow the progression of fatigue (Fig. 3.10 ).

The EOM contain high levels of both oxidative and glycolytic enzymes. An analysis

of serially sectioned and histochemically stained EOM myo fi bers demonstrated

that, except for the myo fi bers expressing MyHC-slow tonic, all fi bers express both

succinic dehydrogenase and a -glycerophosphate dehydrogenase (Asmussen et al.

2008 ) . This demonstrates that single EOM myo fi bers combine high levels of both

oxidative and glycolytic pathways, in stark contrast to limb skeletal muscle. When

each enzyme was plotted against myo fi ber area or whether the fi ber was fast or

slow, a continuum of fi bers emerged, with only the slow tonic-positive myo fi bers in

a group by themselves. Again it appears that the fi ber type system used in limb and

body skeletal muscles does not fi t the picture in EOM.


Fig. 3.10 Use of lactate in

EOM. ( a ) Proposed fl ow of

substrates in an EOM fi ber.

Blood glucose enters

glycolysis as glucose-6-

phosphate (glucose-6-P).

Glycogen content is low and

glycogenolysis is greatly

down-regulated. The lactate

dehydrogenase (LDH)

reaction fl ows in the direction

of lactate oxidation to

pyruvate, which enters the

mitochondrial Krebs cycle.

( b ) Electron micrograph

illustrating the high

mitochondrial content of an

EOM fi ber

A

Glucose

Lactate

Extraocular muscle fiber

Glycogen

Glucose-6-P

Glycolysis

LDH

Pyruvate

Krebs cycle

OxPhos

Mitochondria

B

3.8 Myonuclear Turnover and Regeneration

Another unusual property of adult EOM is its ability to remodel portions of its

myo fi bers throughout life. Using bromodeoxyuridine labeling and immunohistochemical

techniques, it was shown that the EOM retain a population of activated

satellite cells (McLoon and Wirtschafter 2003 ) , and these cells replicate and appear


45

to fuse into existing myo fi bers (McLoon and Wirtschafter 2002 ; McLoon et al.

2004 ) . This same process occurs in laryngeal muscles (Goding et al. 2005 ) , suggesting

that this may be a general feature of craniofacial muscles.

The rami fi cations of the continual turnover of myonuclei in single EOM myo fi bers

are unclear. It is has been known for a long time that the EOM are resistant to injury

and often react differently to various intramuscular drug treatments when compared

to limb skeletal muscle. Botulinum toxin A, which in limb skeletal muscles causes

muscle atrophy, results in no long-term changes in EOM myo fi ber cross-sectional

area (Spencer and McNeer 1987 ; Croes et al. 2007 ) . While some MyHC isoform

shifting has been described (Stirn Kranjc et al. 2001 ) , basically there are few changes

in EOM compared to limb skeletal muscle after botulinum toxin injections.

Conversely, the EOM also exhibit robust and rapid regenerative responses after

various perturbations. Acutely after botulinum toxin A injections the EOM exhibit a

rapid and signi fi cant increase in myogenic precursor cells for weeks after injection,

while there is only an abortive regenerative response in similarly treated leg muscle

(Ugalde et al. 2005 ) . The same rapid regenerative response occurs after experimental

EOM surgical recession (Christiansen et al. 2010 ) or resection (Christiansen and

McLoon 2006 ) . A similarly robust response to denervation occurs in other craniofacial

muscles, for example the lateral and posterior cricoarytenoid laryngeal muscles,

after experimental section of the recurrent laryngeal nerve (Shinners et al. 2006 ) .

In some way this process must be important for the maintenance of normal function

in the EOM, as examination of surgically resected muscles from patients with strabismus

have shown signi fi cant alterations in the numbers of activated satellite cells

within these muscles compared to normal control EOM (Antunes-Foschini et al.

2006, 2008 ) . Current studies suggest that there is a population of myogenic precursor

cells in the EOM that may be responsible for this elevated ability to adapt and

remodel (Kallestad et al. 2011 ) . Future work will focus on de fi ning these regenerative

cell populations, and the potential role they play in EOM muscle adaptability

and the relative sparing of the EOM in aging and skeletal muscle pathology.

There are several hypotheses for what controls this on-going process of myo fi ber

remodeling in normal adult EOM. In an in vitro experiment, it was shown that the

EOM precursor cells depend on their speci fi c cranial motor neurons for survival;

they do not survive in the presence of spinal motor neurons (Porter and Hauser

1993 ) . This suggests that speci fi c trophic factors are critical for the maintenance of

mature EOM. Analysis of gene expression differences between EOM and leg muscle

reveals that neurotrophic factors such as insulin-like growth factor (IGF-1) as well

as neurotrophic factor receptors such fi broblast growth factor-receptor I are upregulated

in EOM (Fischer et al. 2002 ) . The up-regulation of IGF-1 receptor compared

to leg skeletal muscle has been demonstrated immunohistochemically

(Anderson et al. 2006 ), and western blot demonstration of the up-regulation of IGF-1

protein in EOM compared to leg skeletal muscle con fi rmed and extended the earlier

gene expression pro fi ling studies (Feng and von Bartheld 2011 ) . Much more work

needs to be done in this area, but from the studies thus far, it appears that, compared

to non-cranial skeletal muscles, the EOM and their corresponding motor neurons

maintain up-regulated levels of neurotrophic molecules.


3.9 Summary

In summary, many unique characteristics set the EOM apart from non-cranial skeletal

muscles. These differences start with the early genetic signaling that controls EOM

formation from the non-segmented cranial mesoderm and continue with the maintenance

of EOM-speci fi c characteristics by up-regulated expression of speci fi c

groups of neurotrophic factors compared to limb muscles. The EOM are continuously

active, even in primary gaze. This constancy in the maintenance of contractile

force must play a role in the molecular and anatomical individuality of the EOM.

The suggestion that the EOM may indeed be a distinct allotype is supported by the

myriad differences between the EOM and non-cranial skeletal muscle, including

the complexity of co-expression patterns of myosin heavy chain isoforms and other

contractile elements, the differences in metabolic pathways used by the EOM, and

their ability to remodel throughout life. These properties play a critical role in determining

the unique functional capabilities of these muscles physiologically (see Das

2012 , Chap. 4 ) as well as their propensity for and sparing from various skeletal

muscle diseases (see Pedrosa-Domellöf 2012 , Chap. 5 ). The ability to control the

direction of gaze, coordinate eye movements with position of the head and body in

space, and follow and track moving objects is critical to being able to navigate in the

world. This complexity must be needed to ensure that we maintain exquisite control

over eye position and eye movements in three-dimensional space.

Acknowledgements Supported by NIH grant EY015313, the Minnesota Lions and Lionessess,

and an unrestricted grant to the Department of Ophthalmology from Research to Prevent

Blindness Inc.

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Chapter 4

Motor Control of Extraocular Muscle

Vallabh E. Das

4.1 Introduction

Six pairs of extraocular muscles (EOMs) are innervated by three pairs of cranial

nerves whose cell bodies lie in three cranial nerve nuclei on each side of the brain,

namely the oculomotor, trochlear, and abducens nuclei. Early studies of the oculomotor

system examined neuronal responses of extraocular motoneurons within

these motor nuclei and developed a framework for understanding the motor control

of EOM (Fuchs and Luschei 1970 ; Keller and Robinson 1971 ) . Perhaps one of the

most signi fi cant and elegant outcomes of some of these studies was the proposal for

a “ fi nal common pathway” for eye movements (Robinson 1968, 1981 ) . Thus,

according to the oculomotor fi nal common pathway theory, motoneuron innervation

of EOM was independent of the type of eye movement that was being executed.

While this framework still has validity in understanding the neural control of eye

movements, there have been new developments in the last couple of decades that

has brought about renewed interest in the oculomotor periphery and cast doubt on

the so-called “ fi nal common pathway.” The goals of this chapter are to review ocular

biomechanics and motor control of EOM while highlighting new developments and

identifying issues that are yet unresolved. We have con fi ned our discussion to the

motor neurons and their effector organ, the eye. Central control of eye movements

is outside the scope of this chapter.

V. E. Das , Ph.D. (*)

College of Optometry , University of Houston , Houston , TX 77204, USA

e-mail: vdas@optometry.uh.edu




51

52 V.E. Das

Fig. 4.1 Initial studies modeled the oculomotor plant as multiple Voigt elements in series. The left

panel shows two such Voigt elements hooked up in series. Each Voigt is made up of an elastic element

( K ) and a viscous element ( R ). Each Voigt element contributes a single time-constant exponential

decay response following release from displacement. The actual response then is a sum of

exponential decay curves due to each Voigt element. The right panel shows a simulation of the

decay of eye position following eye-pull as sum of two exponential decay curves of time-constant

20 and 200 ms

4.2 Biomechanical Characteristics of the Eye

The globe, connective tissue, and EOM together form the oculomotor plant. 1 In a

seminal “eye-pull” study to examine mechanical properties of the plant, Robinson

held the eye at an eccentric horizontal location and then suddenly released the eye

while monitoring the trajectory of the movement back to central gaze (Robinson

1964 ) . A fi rst important outcome of this study was that the inertia due to the globe

was of little importance in constructing a mathematical model of the plant. Following

the experimental observation that the eye took a path that could be approximated as

an exponential decay function, Robinson suggested that the passive properties of

the oculomotor plant could be modeled as a series of viscoelastic elements (Voigt

elements—Fig. 4.1 ). The elasticity was primarily due to the spring-like properties of

the EOM itself and the viscosity was due to the orbital connective tissue. There has

been some controversy on the number of Voigt elements and the values of the decay

time constants due to these elements. Initial studies, all based on similar eye-pull

1

The term “plant” comes from engineering terminology for something that is controlled.

4 Motor Control of Extraocular Muscle

53

methodology, suggested that the decay following eye-pull could be approximated

by 1–2 time constants (i.e., 1–2 Voigt elements), although the values of the time

constants were variable (Robinson 1964 ; Collins 1971 ; Pola and Robinson 1978 ;

Seidman et al. 1995 ; Stahl and Simpson 1995 ) . More recent studies have determined

that the number of time constants is at least 4 and perhaps more (Sklavos et al. 2005,

2006 ; Anderson et al. 2009 ) .

Most of the studies described above have primarily examined behavior when

muscle activation is constant (release after sustained eye-pull). Clearly this is not a

normal situation. It has been determined that activation of the muscle produces

additional nonlinearities in plant behavior (Anderson et al. 2009 ) . Another approximation

made by the eye-pull studies is to lump the EOM and the orbital connective

tissue into one element. It turns out that the passive properties of the muscle itself

are quite complicated and nonlinear and could be represented by connecting in parallel

an elastic element, a viscous element, and seven other Maxwell elements where

each Maxwell element is a series combination of an elastic and viscous element

(Quaia et al. 2009a, b, 2010 ) .

Clearly, the examination of the oculomotor plant such as that described in this

section only scratches the surface of the potential complexity of the system. There

are several questions that beg to be answered including: (1) How do the different

muscle fi ber types (see Chap. 3 for details on structure and function of EOM) fi t into

this framework? Do the different fi ber types have similar passive properties or could

the complexity of plant models be a function of different passive properties of each

fi ber type? (2) Are passive properties different during development? In other words

might the mechanical structure of the system be especially susceptible to disruption

during development potentially leading to strabismus? (3) To a large extent, the

neural drive to the plant appears to compensate for the inherent nonlinearities in the

plant as evidenced by the stereotypical nature of eye movements such as saccades.

However, it is not clear if this issue is adequately investigated because the nonlinearities

might play a signi fi cant role in secondary and tertiary position of the eye

and perhaps more importantly in disease conditions such as strabismus. (4) What

happens to passive properties after intervention such as strabismus correction surgery?

(5) If passive properties change due to development, disease, aging, etc., does

the motor innervation adapt to compensate for the change?

4.2.1 Implications of Extraocular Muscle Pulleys

on Ocular Biomechanics

EOMs were once conceptualized as strings that originated at the orbital apex and

terminated at the tendinous insertion onto the globe. However, Miller made the critical

observation that muscle paths of rectus EOMs were remarkably stable despite

large eccentric fi xation (Miller and Robins 1987 ; Miller 1989 ) . This suggested that

the origin of the EOM was not at the orbital apex, but at a more anterior location

closer to the globe. Later studies by Demer and colleagues have shown that the

54 V.E. Das

Fig. 4.2 Schematic view of a

cross-section through the eye

showing the extraocular

muscle pulleys of the lateral

and medial recti.

(Reproduced from Demer

2006 )

EOM passes through connective tissue sleeves coupled to the orbit that functions as

pulleys (Demer et al. 1995, 2000 ; Clark et al. 1997, 2000 ) . Thus, it appears that the

EOM pulley is the actual functional origin of the muscle path and is primarily

responsible for preventing sideslip of the EOM (Miller et al. 1993 ) . It is important

to note that the pulley is not a single identi fi able structure in the orbit. Rather it is a

distributed structure made up of a dense network of collagen, elastin, and smooth

muscle (Miller et al. 2003 ) that interconnects with a complex network of connective

tissue within the orbit (Koornneef 1977 ) . Studies suggest that the orbital layer fi bers

of the EOM terminate at the pulleys and it is only the EOM global layer fi bers that

pass through and insert onto the globe (Oh et al. 2001 ; Kono et al. 2002 ) (Fig. 4.2 )

Here we concern ourselves on the possible in fl uence of pulleys on ocular motility

and their implications for neural control of eye movements. The primary bene fi t

of the pulley system as far as ocular motor control is concerned appears to be implementation

of Listing’s Law (Demer 2004 ) . Brie fl y, eye movements have three

degrees of freedom—horizontal, vertical, and torsional. However, Donder’s law and

Listing’s law mandate that the torsional position of the eye is constrained for any

combination of horizontal and vertical orientations, thus effectively reducing the

number of degrees of freedom to two (Haustein 1989 ; Quaia and Optican 1998 ) .

Prior to the discovery of the existence of EOM pulleys, implementation of Listing’s

law was presumed to be neural (Crawford and Vilis 1992 ; Tweed et al. 1999 ;

Angelaki and Hess 2004 ) . This led to predictions of rather complicated patterns of

neural innervation of EOMs during eye movements to secondary and tertiary positions.

Following the discovery of EOM pulleys, Demer put forth an elegant hypothesis

of how proper positioning of the rectus pulleys could effectively provide a mechanical


55

implementation of Listing’s law (Demer 2004 ) . Subsequent neurophysiological and

electrical stimulation studies in the abducens nerve by Angelaki and colleagues

showed that there was indeed no neural implementation of Listing’s law in the brain

and therefore Listing’s Law must be implemented mechanically (Ghasia and

Angelaki 2005 ; Klier et al. 2006, 2011 ) . Although it appears that the pulleys can

obviate the necessity for central control of torsion required by Listing’s law, the

brain needs to provide control signals for torsion that deviates from Listing’s law

such as during convergence, the vestibulo-ocular re fl ex, and head-free gaze shifts

(Crawford et al. 1999 ; Demer et al. 2003 ) .

The initial studies by Miller and colleagues suggested that the pulley structures

stabilized muscle paths in the posterior orbit (Miller et al. 1993 ) . The functional

signi fi cance of preventing muscle sideslip is that the EOM force vector remains

constrained. In the event of rectus muscle sideslip, perhaps due to pulley malposition,

the rectus EOM force vector could be misdirected into the orthogonal plane

resulting in problems of binocular coordination such as A or V patterns of strabismus

(Oh et al. 2002 ) . Demer suggests that many of the cases of strabismus could in

fact be of biomechanical origin due to pulley problems (Demer 2001, 2004 ) .

However, other studies in monkeys with a developmental strabismus induced by

sensory methods have clearly demonstrated a neural origin for strabismus and a

pivotal neural role in maintaining the state of strabismus including the A and V patterns

(Das and Mustari 2007 ; Das 2011 ; Joshi and Das 2011 ) . An example is provided

in Fig. 4.3 . Corroborating these reports have been studies that examined

muscle anatomy of monkeys with sensory strabismus that determined that the pulley

structure is in fact normal (Narasimhan et al. 2007 ) . Thus, it appears that the

etiology could be important in understanding the role that EOM pulleys and

motoneuron control of EOM might play in determining eye alignment or eye movement

properties in disease states.

4.2.2 Modern Approaches to Modeling of the Plant

The nonlinear properties of the oculomotor plant tissue make it dif fi cult to formulate

models using conventional linear control systems theory and lumped elements (see

Fig. 4.1 ). Lumped element models tend to oversimplify the complexity of the EOM

and other plant tissue. A few laboratories have attempted to create plant models

using modern approaches. The fi rst such attempt was that by Miller (Orbit 1.8 software,

Eidactics Inc.). The Orbit software is a sophisticated biomechanical model of

the eye plant that allows the user to modify many parameters including strength of

innervation of each muscle, muscle stiffness and contractility, pulley stiffness, pulley

locations, etc. The primary use proposed for this software is to simulate expected

outcomes from strabismus surgeries (Demer et al. 1996 ; Clark et al. 1998a, b ) .

Although more sophisticated than control systems models, one disadvantage of this

model is that it only simulates static eye positions, not dynamic eye movements. An

alternative to Orbit 1.8 is the SEE++ software developed by Haslwanter, Buchberger,

56 V.E. Das

Fig. 4.3 Top panel —comparative cross-section MRIs of a normal subject and a patient with

incomitant pattern strabismus. The lateral rectus of the patient is shifted inferiorly in supraduction

(adapted from Oh et al. 2002 ) . This sideslip of the rectus muscle could be the source for pattern

strabismus in this patient. Bottom panels —Recording from a medial rectus motoneuron in a monkey

with sensory-induced strabismus. As expected, during horizontal smooth-pursuit, this rightburst-tonic

(BT) neuron is modulated in correlation with movement of the left eye. During vertical

pursuit with the right eye viewing (right column), there is an inappropriate horizontal component

in the left eye that is the dynamic equivalent to an A-pattern strabismus. The motoneuron shows

activity that is correlated with this horizontal component suggesting that A patterns in sensoryinduced

monkeys are due to central innervation (adapted from Joshi and Das 2011 ) . Right eye—

red ; left eye— blue . Positive values indicate rightward or upward eye positions and negative values

indicate leftward or downward eye positions


57

Fig. 4.4 Advanced model of oculomotor plant that can simulate dynamic eye movements (adapted

from Wei et al. 2010 ) . Previous generations of similar software such as Orbit 1.8 can only simulate

static eye position. Panel ( a ) shows the structure used to develop the model and the gaze trajectory

of the eye for a simulated saccade. Each muscle is modeled as a strand with unique properties as

described by Wei and colleagues. In addition, dynamic pulleys are incorporated in the model. Panel

( b ) shows the model simulating a 20 deg saccade based on neural input derived from actual data

and colleagues that is primarily for use on PC computers (Orbit works only on a

Macintosh) (Haslwanter et al. 2005 ; Hoerantner et al. 2007 ; Brandner et al. 2011 ) .

Another attempt at developing a sophisticated model using a slightly different

approach was by Schutte et al. ( 2006 ) . This fi nite element analysis (FEA) model has

the advantage of being able to model nonlinear tissue interactions. However, currently,

the FEA model also only simulates static eye positions and may be limited by

some computational limitations inherent to FEA. The most recent attempt at using

advanced methods for modeling the plant is by Pai and colleagues at the University

of British Columbia (Wei and Pai 2008 ; Wei et al. 2010 ) . An innovation in this

model is that the individual muscle elements are programmed as “strands” which

can represent even a single fi ber, if required. Because these strands can be strung

together, different levels of sophistication can be achieved. In addition, these investigators

have also incorporated simulation of dynamic eye movements (Fig. 4.4 ).

In addition to being useful to predict outcomes of strabismus surgeries, these

advanced models can help to improve our understanding of ocular biomechanics.

For example, it is often hard to predict the biomechanical contributions of the cyclovertical

muscles when the eye is in tertiary positions and using a fully structured

distributed model (rather than lumped elements) can provide a much better understanding

of how the different elements of the complex system work together. Of

course, predictions of mathematical models are only as good as the data that are

used to develop these models in the fi rst place. As new information about the complex

properties of the oculomotor plant tissue come to light (Schoemaker et al.

2006 ; Yoo et al. 2011 ) , the models are likely to be more accurate and thus develop

more predictive power when used to study disease states.

58 V.E. Das

4.3 Motor Control of Conjugate Horizontal Eye Movements

Coordinated and conjugate eye movements in the horizontal plane require simultaneous

contraction of the ipsilateral eye lateral rectus and the contralateral eye medial rectus

and simultaneous relaxation of the contralateral eye lateral rectus and the ipsilateral

eye medial rectus muscles. The coordinated contraction and relaxation of the

four horizontal recti is mediated by innervation from the abducens and oculomotor

nerves and is facilitated by the hard-wired interconnections between the abducens

and oculomotor nuclei. Most of our understanding of motoneuron control of eye

movements comes from studies of the horizontal system. Although principles of

operation are the same, the cyclo-vertical system is necessarily more complicated

because the brain must control four pairs of EOM.

4.3.1 Neurons in the Abducens Nucleus

4.3.1.1 Neuroanatomy

Excellent reviews of the neuroanatomy of the cranial motor nerves and the extraocular

nuclei can be found elsewhere (Sharpe and Wong 2005 ; Buttner-Ennever 2006 ) .

Here we give a brief summary to provide a suitable context for the discussion of the

response properties of extraocular motoneurons during different kinds of eye movements.

Due to its critical role in binocular coordination, the abducens nucleus is

sometimes called the center of horizontal gaze (Leigh and Zee 2006 ) . The abducens

nucleus is a spherical-shaped structure that is located just below the fl oor of the

fourth ventricle and at the junction of the pons and medulla. Based on neuroanatomical

tracing, the abducens nucleus is now recognized to have four principal

populations of motoneurons—twitch and non-twitch abducens motoneurons,

abducens internuclear neurons, and fl occulus-targeting neurons. The fl occulustargeting

neurons belong to the cell groups of the paramedian tracts and probably

supply the cerebellum with a copy of the command signal (Langer et al. 1985 ) . They

are not directly responsible for generating an eye movement. The abducens motoneurons

(lateral rectus motoneurons) may be of the “twitch” or “non-twitch” sub-type

depending on the type of muscle fi ber that they innervate. Thus, the twitch abducens

motoneurons mostly innervate the singly-innervated fi bers or twitch fi bers in the lateral

rectus muscle and the non-twitch motoneurons mostly innervate the multiplyinnervated

fi bers in the lateral rectus (Buttner-Ennever et al. 2001 ) . Although such a

categorization is potentially interesting, there is yet no neurophysiological evidence

that differentiates twitch and non-twitch motoneurons. The abducens motoneurons

innervate the ipsilateral lateral rectus via the abducens nerve (CNVI). Thus, these

neurons are directly responsible for abduction of the ipsilateral eye. The other population

of neurons in the abducens nucleus that are critical for control of horizontal

gaze are the abducens internuclear neurons. The axons of the abducens internuclear

neurons cross the midline at the level of the abducens nucleus and then ascend via


59

Fig. 4.5 Schematic showing

anatomical connections

between abducens and

oculomotor nuclei that result

in the generation of

coordinated movements of

the right and left eyes. Note

that the abducens nucleus

contains abducens

motoneurons ( green ) and

abducens internuclear

neurons ( black ). CN VI

cranial nerve VI, abducens

nerve; CN III cranial nerve

III, oculomotor nerve; MLF

medial longitudinal

fasciculus; LR lateral rectus;

MR medial rectus

the medial longitudinal fasciculus to synapse onto medial rectus motoneurons in the

contralateral oculomotor nucleus which in turn innervates the medial rectus muscle

ipsilateral to the oculomotor nucleus via the oculomotor nerve (CNIII) (Buttner-

Ennever and Akert 1981 ) . This pattern of interconnection between the abducens and

oculomotor nucleus is illustrated in Fig. 4.5 . Therefore, excitation of one abducens

nucleus and inhibition of the contralateral abducens nucleus due to pre-motor signals

results in the almost simultaneous contraction of the ipsilateral eye lateral rectus

muscle and contralateral eye medial rectus muscle and relaxation of the

contralateral eye lateral rectus muscle and ipsilateral eye medial rectus muscle,

thereby producing a coordinated and conjugate eye movement. This, in its essence,

is the anatomical basis for generating conjugate eye movements wherein the two

eyes are controlled as one by a single pre-motor conjugate command. From a neuroanatomical

standpoint, there are no major differences between the abducens

motoneurons and the abducens internuclear neurons (McCrea et al. 1986 ) . It may be

that the internuclear neurons are slightly smaller than the motoneurons and that they

have axon collaterals while the motoneurons do not. Comparison of the neural

response characteristics of motoneurons and internuclear neurons is provided later.

4.3.1.2 Implication of Anatomical Connection Between Abducens

and Oculomotor Nuclei

The anatomical connection between the abducens and oculomotor nucleus is clearly

critical for binocular coordination of eye movements in the horizontal plane.

Although perhaps not as easily perceived, these neural interconnections also play

60 V.E. Das

Fig. 4.6 Schematic showing how the anatomical connections between the abducens and oculomotor

nuclei can result in a comitant strabismus with either eye viewing. Legend is same as in Fig. 4.5 .

Figure on left shows esotropic misalignment due to a weak lateral rectus of the right eye. Figure on

right shows an esotropic misalignment due to an increased innervation of the medial rectus of the

left eye. During right eye viewing, increased activity in the right abducens is necessary to increase

innervation to the weak right eye lateral rectus

an important role in setting the state of eye misalignment in strabismus and in

understanding outcomes following strabismus correction surgery. Thus, this anatomical

arrangement is the reason a single “weak” muscle can result in an apparent

eye misalignment (strabismus) with either eye viewing. Consider the situation in

Fig. 4.6 (left panel) where the lateral rectus of the right eye is weak. When the normal

left eye is viewing the target (right eye is covered), the contraction of the right

eye lateral rectus is less than that of the right eye medial rectus resulting in adduction

of the covered right eye and an appearance of a right esotropia. Now consider

the situation when the “weak” right eye is forced to fi xate (Fig. 4.6 , right panel). In

order to balance forces in the right eye medial and lateral rectus muscles, the brain

must increase the innervation to the weak lateral rectus muscle in the right eye. This

can be achieved by increasing fi ring rates of neurons in the right abducens nucleus.

By the anatomical scheme shown in Fig. 4.6 , an increase in activity in the right

abducens nucleus will not only increase activity in the right abducens motoneurons,

but will also increase activity of the right abducens internuclear neurons. Therefore,

it follows that there is an increased activity (excitation) of the contralateral (left)

medial rectus motoneurons and therefore an increased innervation of the left eye

medial rectus relative to the left eye lateral rectus, resulting in adduction of the left

eye. Thus, there is appearance of esotropia with either eye viewing, although the

underlying de fi cit is inherent to one muscle. It is worth pointing out that an equivalent

argument can be constructed wherein there is a decreased innervation applied

to an intact antagonist muscle to compensate for the “weak” muscle when the weak


61

eye is forced to fi xate. The predictions would be exactly equivalent, and an eye

misalignment would be expected with either eye viewing. In reality, the situation

shown in Fig. 4.6 is probably only hypothetical in congenital forms of strabismus,

especially if the etiology is sensory. In these cases, it is rather unlikely that “underaction”

or “overaction” of a single muscle results in eye misalignment (Das 2008 ) .

It is likely that more than one or perhaps all muscles are affected in strabismus.

Alternately, it may be that the patterns of innervation are themselves disrupted

resulting in unbalanced forces in the medial and lateral recti of an eye (Das and

Mustari 2007 ; Joshi and Das 2011 ) . Whatever the underlying cause, the anatomical

pathways interconnecting the abducens and oculomotor nuclei will assure that there

is symmetry in behavior.

This anatomical scheme also explains how strabismus angle can be reduced by

resection/recession surgery on a single muscle. Consider the situation when an

esotropia is observed in a patient without apparent weakness of any particular muscle.

When the right eye is fi xating on a target, the left eye is adducted and vice-versa.

One possible surgical intervention is to strengthen the lateral rectus muscle of the

left eye (resection surgery). Thus, when the right eye is viewing a target, the treated

left eye is not as adducted as in the pre-surgical condition. Now when the treated left

eye is forced to fi xate, the brain could decrease innervation to the surgically strengthened

left eye lateral muscle (by decreasing fi ring rates in the left abducens nucleus)

in order to balance the force exerted by the antagonist left eye medial rectus. It follows

that the decrease in activity in the left abducens nucleus also causes a decrease

in activity of the right oculomotor nucleus by the internuclear pathway. Therefore,

when the left eye is forced to fi xate, there is an equivalent decrease in contraction of

the right eye medial rectus and an apparent decrease in the esotropia observed in the

right eye. In reality, surgeons may opt to perform strabismus correction surgery on

more than one muscle since there are physical limits to how much a muscle can be

either recessed or resected.

4.3.1.3 Abducens Neuron Neurophysiology

Several studies have examined fi ring rate properties of neurons in the abducens

nucleus. Abducens neurons (and also oculomotor neurons) are generally described

as showing burst-tonic responses during eye movements. Thus, they show a burst or

a pulse of activity, proportional to eye velocity, which is necessary to compensate

for the viscous properties of orbital tissue. They also show tonic or a step of activity,

proportional to eye position, thereby preventing elastic restoring forces due to EOM

from bringing the eye back to the center of the orbit following an eye movement.

Therefore, the simplest model that relates neural response of abducens nucleus neurons

to eye movements takes the following form

FR( t−Δ t) = K* E( t) + R* E′

( t)

+ B (4.1)

62 V.E. Das

FR: fi ring rate

D t : neural latency

E : Eye position at time t

E ¢ : Eye velocity at time t

K : conjugate position sensitivity

R : conjugate velocity sensitivity

B : constant term that signi fi es neuronal response when fi xating straight ahead

Across the various studies, the estimate for average position sensitivity of

abducens neurons is approximately 4–5 spikes/second/degree (spks/s/deg), the estimate

for average velocity sensitivity is approximately 0.4–1.0 spks/s/deg, and the

estimate for constant term B is approximately 100–150 spks/s. Neural latency is

around 10 ms. The threshold, which is the eye position at which the neuronal fi ring

goes to zero, can be estimated to be – B / K .

While the pulse-step model of ( 4.1 ) remains a popular representation of motoneuron

responses, it is not the most precise. Biomechanical models suggest that the eye

plant is modeled with 2–4 time constants. If the neural drive to the plant is to compensate

for plant dynamics (viscoelastic properties) and generate rapid and precise

saccadic movements (as we know that it can), then we expect that the response

characteristics of abducens neurons to be more complex, i.e., include higher order

terms (Robinson 1964 ) . Keller fi rst suggested that adding an acceleration term to

( 4.1 ) ( U * E ″) would provide a better representation of neuronal discharge (Keller

1973 ) . Later Goldstein examined neuronal discharge during the post-saccadic interval

and suggested adding a new term (post-saccadic slide— C *FR ¢ ) that would

account for the gradual transition from the saccadic pulse to the post-saccadic step

(Goldstein 1983 ) . In a relatively recent study, Sylvestre and Cullen re-examined

abducens neuron discharge during saccadic and slow eye movements (Sylvestre and

Cullen 1999 ) . They attempted to fi t motoneuron responses to several different models

(variations of equation ( 4.1 )) that included higher order and nonlinear terms.

They found that using a fi rst-order pulse-step model ( 4.1 ) was suf fi cient to explain

most of the motoneuron discharge. They also con fi rmed that addition of an acceleration

term and a slide term signi fi cantly improved model fi ts, especially during

saccadic eye movements. Equation ( 4.2 ) shows the model representation that these

authors suggested best represented motoneuron discharge

FR() t = K* E() t + R* E′ () t + U* E′′ () t − C*FR()

′ t + B (4.2)

Figure 4.7 shows an example of motoneuron discharge during a saccadic eye movement

(top panel) and the contribution of the individual terms of ( 4.2 ) (bottom panel)

towards the fi nal response. While the pulse (velocity) and step (position) terms are the

most important components of the response, the slide term is critical for the slow postsaccadic

decay of the neural response. One point of interest that Sylvestre and Cullen

identi fi ed in their study was that model coef fi cients estimated during rapid eye movements

such as saccades were different from model coef fi cients estimated from slow

eye movements such as smooth-pursuit or the vestibulo-ocular re fl ex. Further, the

estimated coef fi cients showed some variability depending on the peak velocity of

sinusoidal smooth-pursuit. Other studies have also shown a similar nonlinearity in the

Fig. 4.7 The top two panels show a sample saccadic eye movement and the eye velocity associated

with the saccade. The third panel shows burst-tonic activity of a motoneuron that drives the rightward

saccade. Included are model fi ts with only position and velocity terms ( 4.1 ) and with position,

velocity, acceleration, and slide terms ( 4.2 ). Although the fi rst-order pulse-step model fi t of

( 4.1 ) results in quite a good representation of motoneuron response, the pulse-slide-step model is

a better representation of motoneuron response. Bottom panel —Contributions of individual terms

of the pulse-slide-step model towards the fi nal motoneuron response

64 V.E. Das

responses of abducens neurons (Fuchs et al. 1988 ) . A straightforward explanation

may be that we have not yet arrived at the correct combination of higher order and

nonlinear eye-terms (variations of ( 4.1 ) and ( 4.2 ) for example) that would provide

a single uni fi ed model representation of motoneuron discharge (Sklavos et al. 2005 ) .

Another possibility, promoted by Sylvestre and Cullen ( 1999 ) , is that the dynamics of

the antagonist muscle may be different during fast and slow eye movements. Thus,

during a fast eye movement, motoneurons innervating the antagonist muscle are completely

shut-off and so the movement is determined by the active agonist muscle

only working against the passive properties of the antagonist muscle. On the other

hand, during slow eye movements, the system works in push-pull manner with both

muscles actively innervated.

A few studies have tried to examine whether the response properties of the abducens

internuclear neurons differed from that of the lateral rectus motoneurons (abducens

motoneurons) in the abducens nucleus (Delgado-Garcia et al. 1986a, b ; Fuchs et al.

1988 ) . Using antidromic activation methods, Fuchs and colleagues unequivocally

identi fi ed internuclear neurons in the abducens nucleus of the monkey. Although both

abducens internuclear neurons and lateral rectus motoneurons showed burst-tonic

responses that are qualitatively similar, there were some important quantitative differences

in their response characteristics. While motoneurons appear to show a recruitment

order (the eye position sensitivity, K , increased with increasing threshold),

internuclear neurons were mostly already recruited even for thresholds of 20 deg in

the off-direction, and there was no apparent relationship between threshold and position

sensitivity. Further, if the velocity sensitivity is plotted as a function of eye

position threshold, then motoneurons and internuclear neurons appear to form two

distinct clusters. The abducens internuclear neurons tend to be clustered with higher

sensitivities at lower thresholds (see Fig. 4.8 in Fuchs et al. 1988 ) . Some studies have

used this indirect strategy to classify abducens neurons into lateral rectus motoneurons

and abducens internuclear neurons (Sylvestre and Cullen 1999, 2002 ) .

4.3.2 Neurons in the Oculomotor Nucleus

4.3.2.1 Neuroanatomy

The oculomotor nucleus is a midline nucleus that extends rostrally to the posterior

commissure and caudally to the trochlear nucleus at the ponto-mesencephalic junction.

Dorso-ventrally, it is just ventral to the peri-aqueductal gray matter. Neurons

from each oculomotor nucleus innervate one of four EOMs as summarized in

Table 4.1 . The topographic organization of neuronal subdivisions was fi rst established

by Warwick ( 1953 ) , and later revised by Buttner-Ennever and colleagues

(Warwick 1953 ; Buttner-Ennever et al. 2001 ) . In this revised scheme, the innervation

of EOM is organized in a rostro-caudal manner with the inferior rectus subdivision

being the most rostral followed caudally by the MR, IO, and SR divisions

(Buttner-Ennever et al. 2001 ) .


65

Fig. 4.8 Distribution of

A-group, B-group, and

C-group cells of the medial

rectus (MR) subdivision in

the oculomotor nucleus of the

monkey. The S-group is the

equivalent of the C-group

cells for the superior rectus

and inferior oblique

subgroups. Adapted from

Buttner-Ennever ( 2006 )

Table 4.1 Patterns of innervation of EOM and their primary and secondary actions

Muscle Innervation Primary action Secondary action

Medial rectus (MR) Oculomotor (ipsi) Adduction –

Lateral rectus (LR) Abducens (ipsi) Abduction –

Superior rectus (SR) Oculomotor (contra) Elevation Intorsion

Inferior rectus (IR) Oculomotor (ipsi) Depression Extorsion

Superior oblique (SO) Trochlear (contra) Intorsion Depression

Inferior oblique (IO) Oculomotor (ipsi) Extorsion Elevation

In addition to the topographic organization of neurons according to the muscle

innervated, it is now recognized that there are at least three neuronal types within

each medial rectus subdivision, the so-called “A-group,” “B-group,” and “C-group”

neurons. All our information about these motoneuronal groups has come from anatomical

studies (Buttner-Ennever and Akert 1981 ; Spencer and Porter 1981 ) . No

studies as of yet have identi fi ed unique physiological characteristics of the “A,” “B,”

or “C-group” cells. However, the information available from anatomical studies is

potentially interesting. First, the location of the A, B, and C groups is distinct. While

the A- and B-group cells are located within the nucleus, the C-groups cells tend to

cluster at the boundary of the nucleus (see Fig. 4.8 ). Even more interesting are the

patterns of afferent and efferent projections of these cells. While the A-group and

B-group cells receive projections from pre-motor areas serving all types of eye

movements, the C-group cells do not receive afferent projections from saccadic or

VOR pre-motor areas (Ugolini et al. 2006 ) . In addition, while the A- and B-group

cells project to the singly-innervated twitch fi bers within the mid belly of the EOM,

the C-group cells innervate the multiply-innervated non-twitch fi bers at the distal

66 V.E. Das

end (Buttner-Ennever et al. 2001 ) . Such a differentiation in the pattern of afferent

and efferent projections of the C-group cells has led to the suggestion that perhaps,

the C-group → multiply-innervated non-twitch fi ber pathway could be preferentially

involved in driving slow eye movements including gaze holding (Ugolini et al.

2006 ) . However, an argument against this hypothesis is that fast myosins are found

through the length of the muscle and so it is unlikely that the so-called “slow” nontwitch

fi bers contribute only to slow eye movements (McLoon et al. 2011 ) . Further

investigation in the form of neurophysiological data is needed to understand whether

the C-group is functionally distinct from A- and B-group cells.

4.3.2.2 Neurophysiology

The response characteristics of medial rectus motoneurons in the oculomotor

nucleus are similar to those in the abducens nucleus and do not require specialized

description. They show a stereotypical burst-tonic response where the burst is proportional

to the eye velocity and the tonic level of activity is proportional to eye

position in the orbit. Neurons in the left oculomotor nucleus project to the left eye

medial rectus muscle and drive rightward eye movements, and neurons in the right

oculomotor nucleus project to the right eye medial rectus and drive leftward eye

movements. Across the various studies, the average conjugate position sensitivity is

approximately 4 spks/s/deg, the average conjugate velocity sensitivity ranges

0.5–1 spks/s/deg, and the constant term B is around 100 spks/s.

In addition to the motoneurons that innervate EOM, the oculomotor nucleus also

contains oculomotor internuclear neurons that mostly innervate the contralateral

abducens nucleus (Langer et al. 1986 ) . The function of the oculomotor internuclear

neurons is not clear. It was fi rst thought that the oculomotor internuclear neurons

could be the pathway that provided the abducens nucleus with a vergence signal but

a neurophysiological study that identi fi ed the oculomotor internuclear neurons

using antidromic activation methods did not fi nd any differences between the

response characteristics of the oculomotor internuclear neurons and other medial

rectus motoneurons in the oculomotor nucleus (Clendaniel and Mays 1994 ) .

4.4 Motor Control of Cyclovertical Eye Movements

The superior rectus, inferior rectus, superior oblique, and inferior oblique muscles

control cyclovertical (vertical and torsional) eye movements. Neurons in the oculomotor

nucleus innervate the ipsilateral inferior rectus and inferior oblique muscles

and the contralateral superior rectus muscle. Neurons in the trochlear nucleus innervate

the contralateral superior oblique muscle. Each rectus muscle has a primary

vertical and secondary torsional action, and each oblique muscle has a primary torsional

and secondary vertical action as shown in Table 4.1 . Unlike in the horizontal

system, the secondary actions of the cyclovertical muscles are signi fi cant and vary


67

Fig. 4.9 Geometric

arrangement of superior

rectus and superior oblique

muscles. This arrangement

results in the signi fi cant

primary vertical or torsional

and secondary torsional or

vertical actions of the

cyclovertical muscles

with horizontal position of the eye (Robinson 1982 ) . This is largely a product of the

geometrical arrangement of the eye in the orbit and EOM insertion points (Fig. 4.9 ).

Thus, the vertical recti are approximately 23 deg temporal in each eye and the

obliques are approximately 51 deg nasal in each eye. Therefore, if the eye is turned

out toward the temple (abduction), the obliques have more torsional action, and the

vertical recti have more vertical action. If the eye is turned in towards the nose

(adduction), the obliques have more vertical action, and the vertical recti have more

torsional action.

Just like the horizontal system, the cyclovertical system is organized into agonist–antagonist

pairs. Thus, the superior rectus and inferior rectus of each eye form

an agonist–antagonist pair and the superior oblique and the inferior oblique of the

same eye form another agonist–antagonist pair. In addition, the four cyclovertical

muscles in each eye are also arranged in yoked muscle pairs that help to ensure that

binocular alignment and binocular coordination is maintained in the vertical and

torsional planes. For example, the superior rectus of one eye and the inferior oblique

of the other eye form a yoked muscle pair. Simultaneous excitation of both these

muscles will result in a coordinated elevation and same-direction torsion of both

eyes. Similarly, the inferior rectus of one eye and the superior oblique of the other

eye form a yoked muscle pair because simultaneous excitation of both sets of muscles

results in a coordinated depression and same-direction torsion of both eyes.

Cyclovertical alignment must also be maintained during head tilt. In this condition,

the yoked muscle pairs are the superior rectus and superior oblique of the lower eye

(i.e., ear nearest shoulder upon head tilt) and the inferior rectus and inferior oblique

of the higher eye (i.e., ear farthest from shoulder upon head tilt). The pairing of

these muscles results in an incyclotorsion of the lower eye and excyclotorsion of the

upper eye with minimal vertical change in either eye. The pattern of anatomical

connection from the oculomotor and trochlear nuclei to cyclovertical muscles guarantees

that pre-motor excitation of the oculomotor and trochlear nuclei on the same

side of the brain results in a torsional movement of both eyes with little vertical

component. Note that the simultaneous excitation of the yoked muscles must be

68 V.E. Das

controlled by appropriate pre-motor input to the oculomotor and trochlear nuclei

(Moschovakis et al. 1990 ) .

The properties of cyclovertical motoneurons in the oculomotor and trochlear

nuclei are perhaps not as widely studied as the horizontal motoneurons in the

abducens and oculomotor nuclei. Essentially, they also exhibit burst-tonic behavior

like horizontal motoneurons (King et al. 1981 ) . King and colleagues determined

that the average position sensitivity ( K ) was 4.2 spks/s/deg, and the average velocity

sensitivity was 0.6 spks/s/deg. The average threshold was 25 deg in the off-direction

of the cells. Mays and colleagues examined the response characteristics of trochlear

motoneurons during vergence eye movements and found that activity in trochlear

motoneurons was correlated with the excyclotorsion observed during vergence

(Mays et al. 1991 ) .

4.5 Motoneuron Responses During Vergence Movements

The responses of motoneurons and pre-motor neurons during vergence eye movements

and combined saccade-vergence eye movements have received particular

interest in the last two decades because of the new insights into binocular control

achieved by studies that involve tasks combining conjugate and vergence eye movements.

During a purely vergence eye movement, both the medial recti must contract,

and both lateral recti must relax. In a Hering framework, the control of vergence is

mediated by neural structures that are different from those driving conjugate eye

movements. According to this hypothesis, for eye movements that include both a

conjugate and vergence component, the summation of conjugate and vergence drive

occurs at the level of motoneurons. In a Helmholtz framework, pre-motor commands

encode movements of an individual eye. While initial investigation suggested

that the Hering hypothesis was valid, weight of current evidence appears to

have shifted towards a more Helmholtz-like monocular framework (Chen et al.

2011 ; Cullen and Van Horn 2011 ) . It appears that during combined saccade-vergence

movements (disconjugate saccades), monocular control gets each eye rapidly

onto the target while a slow vergence (binocular signal) eye movement helps to

fi ne-tune the position of the eyes. The reader may get additional information from

several excellent reviews on this topic (Mays 1998 ; King and Zhou 2000 ; Cullen

and Van Horn 2011 ) . Studies that have recorded activity of abducens neurons and

medial rectus motoneurons during vergence eye movements have shown that indeed

motoneuronal activity is modulated during both conjugate and vergence eye movements

(Keller and Robinson 1972 ; Mays and Porter 1984 ) .

A complication that arose from studies of motoneuron activity during vergence

was the fi nding that average sensitivity of the population of abducens neurons during

a vergence eye movement was less than the average sensitivity of the same

population during a conjugate movement (Mays and Porter 1984 ) . In other words,

the reduction in fi ring rate of lateral rectus motoneurons for a convergence movement

to a particular position in the orbit was smaller than the reduction in fi ring rate


69

observed for a conjugate eye movement to the same orbital position. This meant that

the lateral rectus muscle was innervated more strongly in convergence than for conjugate

gaze, although the eye is at the same orbital position. In order to balance the

increased lateral rectus innervation during vergence, the medial rectus must also be

innervated more strongly (i.e., increased fi ring in oculomotor neurons) during convergence

to a particular orbital position than for conjugate movement to the same

orbital position. This was found to be mostly true (Miller et al. 2011 ) . These observations

lead to the prediction of co-contraction of the medial and lateral muscles

during vergence due to the increased forces in convergence compared to conjugate

eye movements. However, in two studies that used implanted strain gauges directly

onto the rectus muscles, no increased force in the medial and lateral rectus was

observed during convergence (Miller et al. 2002, 2011 ) . 2

So as of now, the “missing force” remains an unsolved paradox. There is therefore

a disconnect between the predictions from the recordings of motoneurons in

the abducens and oculomotor nuclei and the force measurements at the muscle.

These fi ndings have led some to propose abandoning the “ fi nal common path”

hypothesis since the path for vergence and conjugate eye movements do not appear

to be the same (Miller 2003 ; Miller et al. 2011 ) . It may be that the answer lies in

the complexity of the muscle structure. Other than the points mentioned already

about the different fi ber types and the different motoneuronal subtypes, it is also

known that there are complex serial and parallel connections between muscle

fi bers, and at the molecular level, there is a lot of variation in expression of myosins

along the muscle fi bers (McLoon and Wirtschafter 2003 ; McLoon et al. 2004,

2011 ) . There is also evidence for substantial muscle remodeling over time. Any of

these factors could affect the relationship between motoneuron fi ring and the force

generated by the motor unit. As suggested by Miller et al. ( 2011 ) , one resolution to

the paradox would be if neurons that have large differences in the conjugate and

vergence sensitivities do not contribute much towards an eye movement due to

innervation of an inherently weak muscle fi ber. Additional investigation into both

muscle structure and innervation of individual muscle fi bers is necessary to resolve

this rather thorny issue.

2

Studies from labs that examined motoneuron responses during combined saccade-vergence

movements have shown that many abducens motoneurons and medial rectus motoneurons surprisingly

encode a binocular signal (i.e., encode movements of either eye) although they might be

expected to only encode movements of the eye that they project to. For the purposes of this chapter,

it should be noted that the fi nding of unequal sensitivities for vergence and conjugate eye movements

is exactly equivalent to the fi nding of binocular encoding in motoneuronal activity by these

other studies. The reason that the two fi ndings are equivalent is that a simple linear mathematical

transformation can transform a conjugate/vergence representation of motoneuronal responses into

a right eye/left eye representation (King and Zhou 2002 ; Sylvestre and Cullen 2002 ) .

Conjugate = (right eye + left eye)/2

Vergence = Left eye − right eye

Right eye = Conjugate − vergence/2

Left eye = Conjugate + vergence/2

70 V.E. Das

4.6 Summary

The oculomotor system is perhaps unique in that this motor control system is driving

a plant with little to no inertia. Further, the load is unchanging unlike in hand motor

control, for example, where the plant load can change if the subject picks up an

object of any weight. However, since poor vision is not well tolerated, there are

other stringent requirements for neural control of the oculomotor periphery including

precise calibration, fast response times, and high speeds of muscle contraction.

All of this is somehow achieved with a great deal of precision and accuracy by the

neural control of six pairs of EOMs. Although the framework of neural control was

laid out as early as in the 1960s and 1970s, it is apparent now that this framework is

not completely accurate in certain conditions (disjunctive eye movements for example).

Anatomical and biomechanical studies of muscle structure in recent years have

outpaced neurophysiological evaluation of how this complex system is controlled.

Perhaps the most important issues yet to be resolved would be to identify whether

the different fi ber types contribute differently to eye movements and to identify

whether their neural control from motoneurons is also distinct. Not only are these

questions important from the point of view of understanding oculomotor control,

but they are extremely important in understanding disease conditions such as strabismus

and nystagmus.

Acknowledgments This work was supported by NIH grant EY015312. I wish to thank Dr. Anand

Joshi and the editors for critically reading the manuscript and providing helpful comments.

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Chapter 5

Extraocular Muscles Response

to Neuromuscular Diseases and Speci fi c

Pathologies

Fatima Pedrosa Domellöf

5.1 Introduction

The response of the extraocular muscles (EOMs) to neuromuscular diseases generally

differs signi fi cantly from that of the other muscles in the body. The EOMs may be

early or preferentially affected in diseases such as myasthenia gravis, oculopharyngeal

muscular dystrophy (OPMD), and Miller Fisher syndrome (MFS), but in contrast

they remain notoriously unaffected in the muscular dystrophies originating

from defects in the dystrophin–glycoprotein complex (DGC). Accumulating evidence

points towards a special response of the EOMs in amyotrophic lateral sclerosis

(ALS), also distinct from that of the other striated muscles in the body. From a

clinical point of view, it is important to realize that even very small disturbances of

ocular motility have a great impact on visual function and quality of life. We rely

upon perfect coordination of eye movements to align both foveas properly and send

a single coherent image to the brain, and the EOMs are the effector organ for ocular

motility.

Muscle is among the most plastic tissues in the body, having very high capacity

to adapt in speci fi c ways to different types of exercise, disuse, strain, and hormones.

The muscles of the body vary widely in overall size (e.g., the muscles of the thigh

vs. the small muscles in the hand), architectural organization of their muscle fi bers

(e.g., parallel fi bers in the biceps brachii, convergent fi bers in the deltoid), and fi ber

type composition (e.g., predominantly slow twitch contracting and fatigue resistant

in the soleus, fast contracting, and fatigable in the tibialis anterior) re fl ecting adaptation

to their particular tasks in their anatomical context. The EOMs are extreme

in their specialization, as they are very small, have an array of fi ber types that is

F. Pedrosa Domellöf , M.D., Ph.D. (*)

Department of Ophthalmology, Umeå University , Umeå , Sweden

e-mail: fatima.pedrosa-domellof@ophthal.umu.se




75

76 F. Pedrosa Domellöf

completely distinct from those occurring in all other muscles and combine both

high contraction velocity and fatigue resistance at once, a feature not seen in any

other muscles. The EOMs differ fundamentally from the remaining skeletal muscles

and have therefore been classi fi ed as a separate muscle allotype, a class of muscle

distinct from the limb and trunk muscles, on one hand, and from the masticatory

muscles, on the other hand, and which also represent a separate class/allotype. The

distinctness of the EOMs as a separate muscle allotype is re fl ected in their unique

structural and physiological properties, their developmental origin and their gene

expression pro fi le (Sadeh 2004 ; Fischer et al. 2005 ; Spencer and Porter 2006 ;

McLoon 2011 ) . The unique properties of the EOMs are thought to re fl ect evolutionary

adaptation to produce the precise and highly coordinated movements of the eye.

However, these unique properties have also rendered the EOMs more resistant or

more prone to certain diseases. Our understanding of the mechanisms underlying

the particular responses of the EOMs to disease is very fragmentary but such knowledge

has the potential to provide important clues for the development of new therapies

in the future.

5.2 Miller Fisher Syndrome

MFS is a very rare condition, clinically characterized by ophthalmoplegia (paralysis

of eye movements), ataxia (limb incoordination), and arre fl exia (loss of normal tendon

re fl exes) along with the occurrence of circulating autoantibodies against gangliosides,

typically against GQ1b (Chiba et al. 1993 , Willison and O’Hanlon 1999 ; Mori

et al. 2001 ; reviewed by Willison 2005 ) . MFS is considered a milder form of Guillain-

Barre syndrome, a far more common paralytic acute in fl ammatory demyelinating

polyneuropathy. The symptoms of MFS may last months but the disease generally has

a good prognosis with progressive recovery. Typically, MFS is preceded by a gastrointestinal,

e.g., Campylobacter jejuni, or respiratory infection, e.g., Haemophilus

influenza, and through a mechanism of molecular mimicry, autoantibodies against self

gangliosides are raised, due to molecular similarities between the lipo-oligosaccharides

on the bacteria and the gangliosides in the human peripheral nerves (Willison

2005 ) . In short, data from both human and experimental models indicate that antibodies

raised by the body to fi ght the initial bacterial infection are responsible for the

autoimmune injury that leads to peripheral nerve dysfunction. The injury occurs at the

neuromuscular junctions (NMJs), where the gangliosides are accessible outside of the

blood–nerve barrier, and involves a complement-mediated reaction (Chiba et al. 1993 ;

Wilison and O’Hanlon 1999 , reviewed by Willison 2005 ) .

Two particular features of the EOMs make them susceptible to MFS. The fi rst is

the particular composition of their NMJs, regarding relevant ganglioside epitopes

(Liu et al. 2009 ) ; the second is their extremely rich capillary supply, which likely

makes the availability of ganglioside autoantibodies much higher than in other muscles

(Kjellgren et al. 2004 ) . An immunohistochemical study (Liu et al. 2009 )

revealed that the NMJs of the human EOMs are highly reactive to antibodies against

5 Extraocular Muscle Response to Neuromuscular Diseases…

77

Fig. 5.1 Cross-sectioned human adult extraocular muscle showing speci fi c binding of antibodies

against gangliosides GQ1b, GT1a, and GD1b ( green ) at neuromuscular junctions (NMJs) identi fi ed

with alpha-bungarotoxin ( red )

GQ1b, GT1a, and GD1b gangliosides (Fig. 5.1 ), whereas the NMJs of limb muscles

do not bind these antibodies (Fig. 5.2 ). In other words, in spite of the limitations

inherent to ganglioside identi fi cation with antibodies, data show clear differences in

epitope availability between the NMJs of EOMs and other skeletal muscles, strongly

suggesting that these differences may be the molecular basis for the particular susceptibility

of the EOMs in MFS. This syndrome typically also includes ataxia and

arre fl exia, which have been proposed to be due to involvement of the muscle spindle

afferents. Immunohistochemical data also revealed that the nerve terminals in muscle

spindles bind antibodies against GQ1b, GT1a, and GD1b gangliosides, strongly

suggesting that the proposed pathophysiology of MFS truly relies upon differences

in ganglioside epitope availability to circulating autoantibodies.

5.3 Myasthenia Gravis

Myasthenia gravis (MG) is another autoimmune disease involving the NMJs,

although it is not speci fi c for the EOMs and is regarded as a chronic condition

(reviewed by Drachman 1994 ; Kusner et al. 2006 ) . Autoantibodies directed at nicotinic

acetylcholine receptors, produced in response to an unknown trigger and leading

to a de fi ciency of acetylcholine receptors at the NMJ, are a known underlying


Fig. 5.2 NMJs of human adult limb muscle do not bind antibodies against gangliosides GQ1b,

GT1a, and GD1b, in contrast to the extraocular muscles

cause of myasthenia gravis in approximately 85% of patients (Romi et al. 2005 ) .

Consequently, the fi nal step in signal transmission from the nerve to the muscle is

hampered and translates clinically into fatigable muscle weakness. However, these

autoantibodies are not always present in MG and false positives are found in other

autoimmune diseases, such as rheumatoid arthritis. Autoantibodies against other

muscle proteins such as muscle-speci fi c kinase (MuSK), titin, rapsyn, or ryanodine

may also be present in patients with myasthenia symptoms that are seronegative for

acetylcholine receptors (Romi et al. 2005 ) . Recently, matrix metalloproteinases 2,

3, and 9 have also been implicated in the pathogenesis of myasthenia gravis, independently

of the presence or absence of acetylcholine receptor antibodies (Helgeland

et al. 2011 ) . MG affects patients of all ages, with a peak in the second and third

decades for females and in the sixth and seventh decades for males, and it is associated

with thymus pathology in up to two-third of the patients and with thyroid

dysfunction in up to 10% of the cases.


79

The EOMs and the levator palpebrae are typically the fi rst muscles to be affected

in MG, 50–80% of the patients presenting with double vision (diplopia) and ptosis,

that get worse along the day or with fatigue (Kaminski et al. 1990 ; Elrod and

Weinberg 2004 ; Romi et al. 2005 ) . A classical sign is the worsening of the ptosis

following sustained upgaze, a sign that helps in the differential diagnosis of other

pupil-sparing disorders affecting ocular motility. The disease may be limited to the

EOMs and levator palpebrae, the so-called ocular myasthenia, or it may spread to

the other muscles, the so-called generalized form. The most feared complication

with time is a myasthenic crisis, an acute exacerbation of muscle weakness, e.g.,

after an infection, leading to respiratory failure. However, adequately treated with

acetylcholine inhibitors and different regimens of immunosuppression, the vast

majority of patients lives a normal life and has no major complications (Drachman

2008 ; Drachman et al. 2008 ) .

The pathological hallmark of MG is the loss of synaptic folds and their acetylcholine

receptors, which apparently result from a complement-mediated autoantibody

lesion localized to the NMJ. It has been proposed (Kaminski et al. 2002 ) that

differences in gene expression levels of elements of the complement cascade (Porter

et al. 2001 ) make the EOMs more susceptible to MG. However, a difference in the

levels of gene expression of the elements of the complement cascade could not be

con fi rmed on the human EOMs vs. limb muscles (Fischer et al. 2005 ) . Furthermore,

it remains unknown whether the levator palpebrae differs from the other muscles

regarding the complement cascade. The EOMs differ from the other muscles by

having very high fi ring frequencies and a low so-called safety-factor, a measure of

the overcapacity of the endplate potential. These two features may partly be the

reason why the EOMs are functionally affected earlier by the loss of acetylcholine

receptors. Further studies are needed to shed light on the triggering factors and on

the causes of the wide heterogeneity of the disease.

5.4 Mitochondrial Disorders and Chronic Progressive

External Ophthalmoplegia

The EOMs are typically affected in mitochondrial disorders with a myopathy

component, the most common of them being chronic progressive external ophthalmoplegia

(CPEO). A wide spectrum of clinical conditions resulting from anomalies

of the respiratory chain and leading to impaired oxidative phosphorylation is collectively

referred to as mitochondrial disorders (Zeviani and Di Donato 2004 ) .

These disorders have very diverse clinical implications and may show high phenotypic

variability between generations and complex patterns of inheritance, as both

nuclear and mitochondrial DNA (mtDNA) encode the elements of the respiratory

chain and the key enzymes needed for mtDNA replication and expression as well as

RNA translation within the mitochondria (Oldfors and Tulinius 2003 ; Zeviani and

Di Donato 2004 ) . The frequency of pathogenic mtDNA mutations that potentially

can cause disease in the offspring of female carriers has been estimated to be

approximately 1:200 in an unselected European population (Elliott et al. 2008 ) .


However, because of the frequent co-existence of both wild-type and mutant mtDNA

in the same cell, most mtDNA mutations only affect cellular function and become

clinically relevant when the proportion of mutant mtDNA exceeds that of wild-type.

CPEO is clinically characterized by ptosis and increasing limitation of eye movements

(ophthalmoplegia). The disease usually, but not necessarily, has a late onset

and the clinical course of the ptosis and of the ophthalmoplegia may diverge

signi fi cantly. The insidious and generally rather symmetric progression of the EOM

weakness is gradually compensated by head movements, and diplopia or discomfort

due to limited eye motility may therefore be absent (Schoser and Pongratz 2006 ) . In

contrast, the ptosis is asymmetric in most cases. Although the CPEO typically dominates

the clinical picture, other signs of mitochondrial disease such as muscle

weakness related to exercise and neurologic involvement should not be overlooked

and will strengthen the diagnosis. Thyroid-associated orbitopathy, myasthenia

gravis, and oculopharyngeal muscle dystrophy are part of the differential diagnosis

of CPEO.

A wide range of mutations has been reported to cause CPEO: large-scale mtDNA

rearrangements, single nucleotide mutations in transfer RNA genes as well as

anomalies of mtDNA maintenance genes which are encoded by the nuclear genome.

Altogether approximately 15% of the patients having an autosomal dominant or

recessive pattern of inheritance (Oldfors and Tulinius 2003 ; Zeviani and Di Donato

2004 ; Kolberg et al. 2005 ; Schoser and Pongratz 2006 ; Greaves et al. 2010 ) .

Kearns-Sayre syndrome combines early onset progressive external ophthalmoplegia,

retinopathy, stunted growth, muscle weakness, cardiac pathology, and cerebellar

ataxia. Progressive external ophthalmoplegia is also seen in MELAS, another

mitochondrial myopathy with encephalopathy, lactate acidosis and stroke-like episodes.

In MELAS, pigmentary retinopathy and short stature may also be present.

PEO is also present in other, more rare mitochondrial disorders, some of which are

considered separate syndromes such as MERF (myoclonic epilepsy and myopathy

with ragged-red fi bers), MNGIE (mitochondrial neurogastrointestinal encephalopathy),

SANDO (sensory ataxic neuropathy, dysarthria and ophthalmoparesis),

and NARP (neuropathy, ataxia and retinitis pigmentosa, for references see Schoser

and Pongratz 2006 ).

The muscle fi bers in the EOMs are extremely rich in mitochondria, and they

have high oxidative enzyme activity, having particular metabolic pro fi les adapted to

the constant activity needed for eye movements (Fischer et al. 2005 ; Patel et al.

2009 ; Garcia-Cazarin et al. 2010 ) . These may in part explain the particular susceptibility

of the EOMs to mitochondrial disorders, but there is very little data on the

particular changes that occur in these muscles in these diseases. Progressive loss of

cytochrome c oxidase (COX, a mitochondrial enzyme marker whose loss indicates

dysfunction) has been noted in the muscle fi bers of the aging human EOMs (Muller-

Hocker et al. 1992 ) . A recent study shows that these COX-negative muscle fibers that

accumulate exponentially in the aging human EOMs have high levels of mtDNA deletions,

suggesting an accelerated aging process in the EOMs compared to skeletal muscle

or other post-mitotic tissues (Yu-Wai-Man et al. 2010 ) . In a well-characterized

cohort of 13 CPEO patients, 11 surgical samples taken from the levator palpebrae

(LP) and from two EOMs had more COX-de fi cient muscle fi bers than the respective


81

skeletal muscle biopsies. Furthermore, lower proportions of deleted mtDNA resulted

in COX-de fi cient fi bers in the LP/EOMs, compared to the other muscles (Greaves

et al. 2010 ) .

5.5 Oculopharyngeal Muscular Dystrophy

OPMD is characterized by the onset of ptosis followed by progressive dysphagia

due to involvement of the pharyngeal muscles, as well as weakness and wasting of

the tongue and masticatory muscles in patients in their fi fth or sixth decade (Brais

2003 ) . Involvement of the EOMs with restricted ocular movements occurs later in

the course of the disease but it does not lead to a complete external ophthalmoplegia.

Other muscles of the body such as the diaphragm and pelvic and shoulder girdle

muscles may also become affected. Dysphagia may lead to nutritional and aspiration

problems and requires proper clinical management.

OPMD is usually autosomal dominant, although recessive forms and sporadic

cases also exist (reviewed by Brais 2003 ) . The underlying genetic defect consists of

short (GCG) 8–13

expansions on the polyadenylate-binding nuclear protein gene 1

(PABPN1). Mutated PABPN1 protein, together with heat shock proteins and ubiquitin,

forms typical tubulo fi lamentous intra-nuclear inclusions that are exclusively

present in the nuclei of muscle fi bers (Tomé et al. 1997 ; Croquet et al. 1983 ) .

However, the mechanisms behind the mutations and how the mutated protein affects

the muscle cells are only partially understood. It has been proposed that the turnover

of myonuclei seen in the muscle fi bers of the EOMs may also occur in other craniofacial

muscles and provide the basis for the earlier involvement of the eye and

pharyngeal muscles in OPMD (Wirtschafter et al. 2004 ) .

5.6 Thyroid Disease

Approximately 30–50% of the patients with Graves’ disease (Brent 2008 ) develop

clinically apparent thyroid-associated ophthalmopathy (TAO), also known as

thyroid eye disease (TED), but patients with no clinical symptoms or signs of eye

involvement may also show orbitopathy when adequate imaging techniques are

used (Lennerstrand et al. 2007 ). Risk factors for the development of TAO include

cigarette smoking, post-treatment hypothyroidism, and radioiodine treatment, as

well as high serum levels of thyrotropin receptor antibody (Thornton et al. 2007 ;

Eckstein et al. 2006 ; Ag and Smith 2008 ; Bartalena et al. 2008 ; Träisk 2009 ;

Träisk et al. 2009 ) .

An array of changes in the orbital tissues leads to the clinical picture of TAO.

Initially, the symptoms are related to in fl ammation and swelling and are dominated

by progressing discomfort, tearing, conjunctival injection, and edema. Eyelid retraction

gives these patients a typical appearance and contributes to the worsening of

lacrimation and discomfort. Eyelid retraction may become permanent due to


adhesions between adjacent palpebral and orbital structures. In a subgroup of

patients, the progressive increase in orbital tissue volume pushes the eye forward, a

condition termed exophthalmos or proptosis. Increased orbital volume imposes

mechanical constraints for the action of the EOMs. However, the most feared aspect

of TAO is compression of the optic nerve due to increased intraorbital pressure, as

it is may compromise vision irreversibly.

Diplopia has been reported to occur in approximately 20% of the patients who

develop TAO. Blurred vision, which may have different etiologies including discretely

disturbed eye motility, occurs in approximately 10% of patients with TAO

(Bartley et al. 1996 ) . The involvement of the EOMs in TAO may vary, from rather

discrete and not readily apparent from a clinical examination, to extensive fi brotic

restriction of eye movements. Imaging techniques such as CT and MRI are very

helpful for identifying and quantifying the extent of EOM involvement, whereas

velocity measurements of saccadic eye movements have, thus far, provided controversial

results and are not easy to use in a clinical setting (Träisk 2009 ) .

At the tissue level, the changes behind TAO include expansion of orbital connective

and fat tissue, in fi ltration of orbital tissues, including the EOMs, with mononuclear

cells and hyaluronan, and, in the long run, fi brosis and impaired eye motility

(Khoo and Bahn 2007 ) . The orbital fi broblasts are regarded as major players in

these processes, particularly regarding adipogenesis, and data indicate that they are

the primary targets in the orbit for the circulating autoantibodies against thyrotropin

receptor. Autoantibodies against insulin-like growth factor-1 (IGF-1) also play an

important role in recruitment and activation of T-cells and stimulation of hyaluronan

deposition. Deposition of hyaluronan in between muscle fi bers and in fatty

connective tissue leads to increased volume of the EOMs and orbital contents but

the process underlying TAO also includes in fl ammation and damage of the EOMs,

re fl ected by the presence of detectable autoantibodies against these muscles (Khoo

and Bahn 2007 ) .

5.7 Amyotrophic Lateral Sclerosis

ALS is a progressive, fatal, neurodegenerative syndrome affecting both the upper

and lower motor neurons and their supporting cells (Boillée et al. 2006 ; Andersen

2006 ) . It is clinically characterized by progressive loss of voluntary muscle function,

leading to early death due to respiratory failure. The incidence of ALS increases

with age, and it typically affects people in the sixth decade or older. The disease

may have a bulbar onset in 20–25% of the patients with initial symptoms of dysphagia

and dysarthria. However, a systemic onset, usually in a limb muscle, is more

common; the cranially innervated muscles are also involved at later stages. Strikingly,

involvement of the EOMs is not a typical feature of ALS, although it does occur in

some cases, particularly in patients who survived longer periods due to assisted

ventilation (Leveille et al. 1982 ; Hayashi et al. 1987 ; Palmowski et al. 1995 ) . Human

EOMs of donors who died of ALS without ventilator support show mild signs of


83

Fig. 5.3 Notice the impact of ALS on the limb muscles (( a ) control, ( b ) ALS) with fi brosis and

muscle fi ber atrophy on the left side of ( b ) and extremely hypertrophic muscle fi bers with internal

nuclei ( right side ) as well as fatty replacement ( white areas on the left ). In contrast, in the same

patient, the EOMs are notably less affected at the end-stage of ALS. Notice however the wider

variation in muscle fi ber size and the increased space between muscle fi bers in ( d ). ( a – b ): eosin

staining; ( c – d ): NADH-activity staining

denervation and muscle fi ber overuse, with a wider range of muscle fi ber area and

altered composition of contractile and extracellular matrix (ECM) proteins (Ahmadi

et al. 2010 ; Liu et al. 2011 ) . Wide variation in the extent of pathological changes

was seen between different donors and also between the EOMs of the same donor.

In all cases, the changes present in the EOMs were very mild when compared to the

devastating impact of ALS on the skeletal muscles of the same individuals at the

time of death (Fig. 5.3 ). We have therefore suggested that the EOMs are more resistant

to the pathophysiological process underlying ALS. However, our understanding

of the pathophysiology of ALS is rather limited, in spite of intensive research in

the fi eld (Boillée et al. 2006 ) . Approximately 90% of the cases of ALS are so-called

sporadic and of unknown pathogenesis. In the remaining cases, a familial pattern of

inheritance may be present or become apparent later on, and in 10–20% of these

patients, mutations in the SOD1 gene are present. Mutated SOD1 is thought to

cause ALS by a gain of toxic function, as the absence of SOD1 activity in animal

models does not cause ALS. The interplay of genetics, environment, and aging in

the pathophysiology of ALS is gaining increasing importance (Andersen 2006 ) .

Furthermore, recent data indicate that metabolic changes in skeletal muscle likely

play an important role in the early pathogenesis of ALS (Dupuis and Loef fl er 2009 ) .

Defects in energy metabolism such as hypermetabolism and hyperlipidemia are

regarded as negative factors contributing to the pathogenesis of ALS. Convincing

data show that motor neuron death starts at the NMJ and proceeds towards the

spinal cord (Fischer et al. 2004 ) . In two elegant proof of concept papers, it has been


shown that (1) metabolic changes in the muscle fi ber are capable of initiating

dismantling of the NMJ (Dupuis et al. 2009, 2011 ) and (2) skeletal muscle-restricted

expression of human SOD1 causes motor neuron degeneration and an ALS-like

syndrome in transgenic animal models (Wong and Martin 2010 ) . In other words, the

view on ALS is changing focus from the motor neurons and their supporting cells

centrally to the muscle and the NMJ. The human EOMs differ signi fi cantly from the

other muscles in the body with respect to their metabolic pro fi le and pathways,

structural components, developmental, and regeneration markers, by a total of 338

genes (Fischer et al. 2005 ) ; therefore, some of their intrinsic properties may make

them more resistant to the underlying process behind ALS. Most strikingly, the

EOMs are capable of maintaining a normal laminin composition in their NMJs, in

contrast to the limb muscles from matched ALS patients (Liu et al. 2011 ) . The latter

is particularly important because the ECM may regulate the availability of different

growth and trophic factors, and maintained specialization of the basement membrane

is crucial for proper synaptic function. We propose therefore that the EOMs

are a useful model to study ALS as they may provide insights on strategic adaptation

for longer motor neuron survival or for better preservation of muscle function

which may be important for the development of new therapies for ALS.

5.8 Duchenne and Related Muscle Dystrophies

The selective sparing in muscular dystrophies caused by defects in the dystrophin/dystroglycan

complex (DGC) is by far the most intriguing property of the

EOMs given that these are devastating diseases of childhood that lead to severe

handicap and early death. An understanding of the molecular basis for the selective

sparing of the EOMs in these muscle dystrophies holds the promise of therapeutic

advances for this group of diseases. This has been an active research area,

although the identi fi cation of speci fi c structural adaptations of the EOMs has

remained rather elusive (reviewed by Andrade et al. 2000 ) .

A number of genetic defects affecting almost any of the proteins involved in the

molecular link formed by the ECM on the surface of muscle fi bers, across the cell

membrane, and the subsarcolemmal cytoskeleton are known to cause muscle dystrophies

(Emery 2002 ) , Duchenne muscular dystrophy (DMD) being the most wellknown

of all. In Duchenne and Becker muscular dystrophy, the genetic defect

affects dystrophin (Hoffman et al. 1987 ; Koenig et al. 1988 ) , a cytoskeletal molecule

found in a subsarcolemmal location and a key element of the so-called DGC. The

DGC spans the cell membrane and comprises, among others, dystroglycans, sarcoglycans,

syntrophins, and dystrobrevins, and it connects to actin on the cytoskeletal

side and to laminin 211 (merosin) on the ECM side. The DGC has a fundamental

function providing the mechanical stabilization of the sarcolemma needed for muscle

fi ber integrity and force transmission, and it is also important for cell signaling

(reviewed by Ervasti and Sonnemann 2008 ) . Examples of muscle dystrophies


85

caused by defects in genes related to the DGC are some forms of limb-girdle muscular

dystrophy, which are due to defects in the different sarcoglycans (Bonnemann et al.

1995 ; Lim et al. 1995 ) and congenital muscle dystrophies (reviewed by Muntoni and

Voit 2004 ) caused by defects involving the laminin alpha-2 chain, also known as

merosin-de fi cient congenital muscular dystrophy (Helbling-Leclerc et al. 1995 ) ,

alpha-7-integrin (Hayashi et al. 1998 ) , or collagen VI genes.

The EOMs are clinically and histologically spared in DMD and in animal models

of muscle dystrophies due to mutations in dystrophin, the laminin alpha-2 chain,

and sarcoglycans (for references see Andrade et al. 2000 ) . The laminin chain composition

of the human EOMs differs from that of skeletal muscle fi bers. The EOMs

co-express laminin alpha-4, alpha-5, and beta-2 chains, in addition to alpha-2 and

beta-1 chains present in all skeletal muscle fi bers (Kjellgren et al. 2004 ) . The

co-expression of additional laminin chains is most likely a speci fi c mechanism that

protects the human EOMs in merosin-de fi cient congenital muscle dystrophy.

Supporting this hypothesis, the EOMs of the dy3k/dy3k mice, which completely

lack the laminin alpha-2 chain, remain unaffected, and co-express the additional

laminin chains, in contrast to the affected limb muscles (Nystrom et al. 2006 ) .

Possible general factors of importance for the selective sparing of the EOMs in

muscular dystrophy may be the very small diameter of muscle fi bers and the very

small loads that these fi bers work against. Differences in calcium homeostasis may

also be a relevant factor, as the EOMs have a superior capacity to handle calcium

and calcium overload is a part of the pathogenic process in these diseases. However,

an increased regenerative capacity may be the single most relevant property for the

selective sparing of the EOMs in DMD (Kallestad et al. 2011 ) . The gene expression

pro fi les of the EOMs differ from those of limb muscle by increased expression of

genes related to regeneration, growth, and development (Porter et al. 2001 ; Fischer

et al. 2005 ) . Experiments using incorporation of bromodeoxyuridine (brdU) indicate

that the EOMs have signi fi cant activation of muscle precursor cells and addition

of myonuclei to the muscle fi bers, even in the absence of disease (McLoon

et al. 2004, 2007 ) . A recent study identi fi ed a subpopulation of muscle cell precursors

with special properties that are present at higher numbers in the EOMs from

both mdx and mdx/utrophin −/− mouse models of DMD, compared to their limb muscles,

strongly suggesting an important role for successful regeneration in the sparing

of the EOMs (Kallestad et al. 2011 ) .

5.9 Summary

In summary, the EOMs display a complex disease pro fi le when compared with limb

skeletal muscles. Their propensity for, or sparing from, various forms of muscle

pathology are under intensive study in many laboratories. Hopefully, uncovering the

mechanisms for EOM sparing or involvement in speci fi c muscle disease entities

will help direct translational research towards new therapies for treatment.


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Part IV

Masticatory Muscles

Chapter 6

Masticatory Muscle Structure and Function

Mark Lewis , Nigel Hunt, and Rishma Shah

6.1 Introduction

The muscle group referred to as the muscles of mastication includes the temporalis,

the medial and lateral pterygoid, and the masseter muscles on both sides of the face

and jaws. These voluntary skeletal muscles are derived from the paraxial mesoderm

of the fi rst branchial arch whilst their connective tissue components are derived

from mesenchymal cells of neural crest origin. They are innervated by the mandibular

division of the fi fth (trigeminal) cranial nerve (CNV). Precision in the control of

jaw position and movement of the mandible is provided by the human mandibular

locomotor system. It is important to remember that this control of both jaw position

and function varies considerably throughout the life of an individual, principally to

support the activities of providing nutrition, speaking, and swallowing. For example,

in the newborn infant very fi ne movements of the jaw are associated with the important

tongue activity necessary for breast or bottle-feeding. Subsequently, as the

deciduous teeth erupt and later as the permanent teeth erupt, these changes in dentition

are associated with periods of rapid growth of the individual in general, and

therefore the need to create increased biting and chewing forces is developed. There

may be altered demands in relation to the ravages of such conditions as dental caries

and periodontal disease with the possibility that teeth may need to be extracted or

M. Lewis , Ph.D. (*)

School of Sport, Exercise and Health , Loughborough University, Loughborough,

Leicestershire, UK and UCL Eastman Dental Institute, London, UK

e-mail: mlewis@eastman.ucl.ac.uk

N. Hunt , Ph.D., MOrth., R.C.S. • R. Shah , Ph.D., MOrth., R.C.S.

UCL Eastman Dental Institute , 256 Grays Inn Road , London WC1X8LD , UK




91

92 M. Lewis et al.

lost leading to prosthetic replacement. The different embryological origin and innervation

of these muscles compared to somatic skeletal muscle coupled with their changing

and unique functions have led to the possibility of structural specialisation within

the muscles of mastication. Of the muscles in this group, the masseter muscle has

undergone most investigation particularly in relation to its ease of access compared

to the other muscles of the group.

6.2 Anatomy

The temporalis muscle is a fan-shaped muscle arising from the whole of the temporal

fossa except for that part formed by the zygomatic bone together with the deep

surface of the temporal fascia (Fig. 6.1 ). The anterior and posterior fi bres converge

to attach, via a tendon, to the medial surface, the apex, and the anterior and posterior

borders of the coronoid process and the anterior border of the ramus of the mandible

nearly as far forward as the last molar tooth. The anterior fi bres act to elevate the

mandible whilst the posterior fi bres are principally involved in drawing the mandible

back after protrusion of the jaw but also provide a backward pull during closing

of the jaw. Electromyographic investigations suggest the muscle is active during

forced elevation of the mandible but not in slow elevation.

The medial pterygoid muscle arises as two heads: the super fi cial head from the

bone around the maxillary tuberosity, and a deep head from the medial surface of

the lateral pterygoid plate. The muscle fi bres pass downwards, backwards and laterally

to insert into the deep surface of the angle of the mandible. The medial pterygoid

works in combination with the masseter and anterior fi bres of temporalis to

Fig. 6.1 The muscles of mastication. The masseter, temporalis, and medial pterygoid muscles are

responsible for jaw closure, whereas the lateral pterygoid muscle is associated with jaw opening

and facilitates lateral and protrusive mandibular movements

6 Masticatory Muscle Structure and Function

93

elevate the mandible, whilst simultaneous contraction of both the medial and lateral

pterygoids of both sides of the jaws protrudes the lower jaw. However, when the

medial and lateral pterygoid muscles contract on one side only the mandible rotates

and protrudes to the opposite side as occurs in chewing movements.

The lateral pterygoid muscle also has two heads: the superior head that arises

from the infratemporal surface of the greater wing of the sphenoid bone, and an

inferior head from the lateral surface of the pterygoid plate of the maxilla. The fi bres

from both heads converge as they pass posteriorly and laterally to be inserted into a

small depression on the anterior surface of the neck of the mandibular condyle and

the anterior aspect of the articular disc of the temporomandibular joint. Contraction

of the lateral pterygoid muscles draws the mandibular condyle downwards and forwards

onto the articular eminence as occurs during opening of the mouth. As noted

above, working together, the medial and lateral pterygoid muscles are involved in

many of the complex movements of the mandible as occur during suckling and

mastication.

The masseter muscle is a quadrilateral-shaped muscle composed of three superimposed

layers, which blend together anteriorly. The super fi cial layer is the largest

and arises as a thick aponeurosis from the zygomatic process of the maxilla and the

anterior two-thirds of the lower border of the zygomatic arch. The fi bres pass downwards

and backwards to be inserted into the angle region and the lower half of the

lateral surface of the ramus of the mandible. The middle fi bres arise from the deep

surface of the anterior two-thirds of the zygomatic arch and the lower border of the

posterior third and are inserted into the middle of the ramus of the mandible. The

deep fi bres arise from the deep surface of the zygomatic arch and are inserted into

the upper part of the ramus and coronoid process of the mandible.

The principal action of the masseter muscle is to elevate the mandible with a

small effect in lateral and protrusive movements and minimal activity in the rest

position. The relative involvement of the three different fi bre layers during functional

movements has been fully elicited through electromyographic studies (Vitti and

Basmajian 1977 ) .

The size, volume, thickness, cross-sectional area and the direction and orientation

of the masseter muscle have been measured using different types of magnetic

resonance imaging (MRI) (van Spronsen et al. 1992 ) , computerised tomography

(CT scan) (Kitai et al. 2002 ) , and bilateral ultrasonography (US) (Kiliaridis and

Kalebo 1991 ; Trawitzki et al. 2006 ). The masseter muscle has been reported as

short, thin, of low volume, and having a small cross-sectional area in orthodontic

Class III, prognathic (Ariji et al. 2000 ; Kitai et al. 2002 ; Trawitzki et al. 2006 ) and

long face patients (Kiliaridis and Kalebo 1991 ; van Spronsen et al. 1992 ) when

compared to patients with ideal antero-posterior and vertical facial balance and proportions.

Multi-disciplinary treatment of prognathic patients can increase the thickness

of the masseter; however, this is never to the levels seen in patients with

‘normal’ or ideal facial form (Trawitzki et al. 2006 ) . When compared to other facial

patterns, long face individuals showed the thinnest, whilst short face patients exhibited

the thickest masseter muscle volume compared to average face subjects

(Satiroglu et al. 2005 ; van Spronsen 2010 ) (Fig. 6.2 ).

94 M. Lewis et al.

Fig. 6.2 MRI scans indicating the greater thickness of masseter muscle in a short face (SF) and a

thinner muscle in a long face (LF) compared to an individual with normal (Nor) vertical facial

morphology (reproduced with permission of P.R. van Spronsen)

Furthermore, the orientation of the masseter muscle fi bres in prognathic patients

compared to controls was found to be in a more forward direction, forming an

obtuse angle with the Frankfort horizontal plane (Ariji et al. 2000 ; Kitai et al. 2002 ) .

It has been suggested that the more upright the direction of the masseter muscle

fi bres (as in short face patients) in relation to the Frankfort horizontal or functional

occlusal planes, the greater the occlusal forces (Kitai et al. 2002 ) .

Other studies have assessed the relationship between the volume of the masseter

muscle and speci fi c craniofacial skeletal parameters. The results have indicated a

positive correlation between masseter muscle volume and the ramus height (Kubota

et al. 1998 ) , posterior face height (Benington et al. 1999 ) , and the cross-sectional

area of the zygomatic arch (Kitai et al. 2002 ) , whilst a negative correlation was

observed in relation to mandibular inclination and gonial angle (Kubota et al. 1998 ;

Benington et al. 1999 ) . No relationship was found between masseter muscle volume

and cranial width (Kitai et al. 2002 ) . Furthermore, general anterior and posterior

craniofacial vertical dimensions were more related to masseter muscle volume than

cross-sectional area (Boom et al. 2008 ) .

6.3 Fibre Typing

The actin–myosin relationship is key to skeletal muscle contraction (Barany 1967 ;

Barany et al. 1967 ) . The sarcomeric myosin fi lament is one of the most important

elements of the contractile mechanism, consisting of two myosin heavy chains


95

(MyHC) and four myosin light chains (MyLC), which may be further subdivided

into essential (alkali) light chains and regulatory (phosphorylatable) light chains

(Lowey and Risby 1971 ) . The role of the MyLCs in human skeletal muscle has yet

to be clari fi ed, but it is the MyHCs that are responsible for force–velocity characteristics

of myo fi bres, although other factors in fl uence them (e.g., neural input and

architecture). The MyHC isoform present in a given myo fi bre is an important factor

for the classi fi cation of its physiological properties (Barany 1967 ; Barany et al.

1967 ; Brooke and Kaiser 1970 ; Weiss and Leinwand 1996 ) .

Eleven MyHC isoforms have been identi fi ed in mammalian skeletal muscle with

b /I, IIA, IIB and IID/X as the main isoforms in adult skeletal muscle. MyHC- b /I

represents the slow contracting MyHC, with MyHC- b designated to cardiac muscle

(Weiss and Leinwand 1996 ) and MyHC-I referring to skeletal muscle. The group of

MyHC-II isoforms produce fast contraction velocities with characteristic shortening

speeds relative to one another where IIB > IIX/D > IIA. It has been demonstrated

in knockout mice that MyHC-IIB and IIX/D are necessary for the normal function

of adult skeletal muscle, and the absence of these MyHCs leads to the presentation

of distinctive phenotypes (Acakpo-Satchivi et al. 1997 ) . With respect to human

skeletal muscle, the presence or absence of MyHC-IIB is still unanswered.

Histochemical studies have identi fi ed type IIB fi bres as a major constituent of fast

muscle, but Pereira et al. ( 1997 ) and others (Ennion et al. 1995 ) have shown that the

isoform is a homologue of MyHC-IIX found in rat and rabbit. Thus, absolute

clari fi cation is still required. Slow fi bres are better adapted for isometric contractions,

developing the same force as fast fi bres, but with less ATP consumption. Thus, developing

the maximum power with the most ef fi ciency at low velocity, slow fi bres are

found mainly in the postural muscles that are essentially fatigue-resistant. On the

contrary, fast fi bres (MyHC-II) develop maximum power with the greatest ef fi ciency

at high velocity and are best suited to short-lasting, faster, and more powerful movements,

such as those effected by sprinters (Yoshioka et al. 2007 ) and during

mastication.

Masticatory MyHC : Interestingly, the craniofacial muscles express other isoforms,

including a very fast masticatory MyHC (MyHCIIM) present in the jaw-closing

muscles of non-human primates and carnivores (Rowlerson et al. 1981, 1983 ) .

Studies into the jaw-closing muscles of humans and rabbits show they also express

a -cardiac myosin, normally found in heart muscle, and the a -cardiac MyHCpositive

fi bres in rabbit have slower shortening velocities than MyHC-IIA (Sciote

and Kentish 1996 ) .

Embryonic and neonatal MyHCs (MyHC-emb and MyHC-neo) are typically

expressed during embryonic myogenesis (Periasamy et al. 1984 ; Schiaf fi no et al.

1986 ; Bouvagnet et al. 1987 ) , within regenerating (Schiaf fi no et al. 1986 ; Sartore

et al. 1982 ; Matsuda et al. 1983 ) or denervated (Schiaf fi no et al. 1988 ) adult skeletal

muscle, and the extraocular muscles (Wieczorek et al. 1985 ; Sartore et al. 1987 ) .

The persistent expression of the developmental MyHC isoforms within the adult

human masseter shows a good deal of heterogeneity (Butler-Browne et al. 1988 ;

Sciote et al. 1994 ; Stal et al. 1994 ) .

96 M. Lewis et al.

Other MyHC isoforms : Additionally, extraocular MyHC (MyHC-EOM) has been

found in the extraocular (Sartore et al. 1987 ) and laryngeal muscles (DelGaudio

et al. 1995 ) . The fast contracting MyHC- a -cardiac is expressed in cardiac muscle;

however, it has been found occasionally in skeletal muscle, including masseter

(Suchak et al. 2009 ) .

The MyHC and related gene expression within the main jaw-opening muscles

has been studied extensively in humans (Vignon et al. 1980 ) and other mammalian

species (Rowlerson et al. 1983 ) . The jaw-opening mechanism is not particularly

different amongst the species, hence the predominant fi bres are fast, with relatively

fewer type I fi bres. Eriksson et al. ( 1982 ) have reported human digastric muscles

contain approximately 29 % type I fi bres, with the remainder type II. There are

appreciable differences in the kinetics of jaw closing which are controlled by the

expression of speci fi c fi bre types within individual muscle compartments and

between the different jaw-closing muscles. Human jaw-closing muscles contain

10–90 % type I fi bres and no type IIM (masticatory) fi bres (Sciote and Morris 2000 ) ,

which are found in primate jaw-closing muscles (Rowlerson et al. 1983 ) . The different

insertions of these jaw-closing muscles will produce different functionality: for

example, the insertion of the temporalis muscle nearer to the occlusal plane in

carnivores enables more rapid jaw closure (Sciote and Morris 2000 ) .

Moreover, differences are evident between human jaw-closing and limb muscles

such that healthy limb skeletal muscles are composed of a mosaic of type I and II

fi bres, with the type II fi bres displaying a relatively larger diameter. The myo fi bres

tend to be homogeneous for a speci fi c MyHC; however, combinations may co-exist

within the same myo fi bre (Sciote and Morris 2000 ) . In contrast, human jaw-closing

muscles tend to have equal proportions of type I and II fi bres, but the type II fi bres

tend to be of a smaller diameter (Ringqvist 1973a, b ) . Equally, the human masseter

muscle displays a number of phenotypes speci fi c to individual factors within any

given jaw. Hunt et al. ( 2006 ) demonstrated variation in both the relative size and

proportion of type II fi bres in masseter muscle in relation to vertical facial morphology.

Individuals displaying a long face deformity have smaller and fewer type II

fi bres whereas the type II fi bres were both larger and present in greater proportion

in individuals with reduced vertical facial dimensions . Muscle phenotypes may also

be modi fi ed by such things as the presenting dental occlusion (Sciote et al. 1994 ) .

As previously mentioned, the different muscle compartments within individual

muscles may house different fi bre types, and it has been suggested that the anterior

super fi cial aspect of the masseter muscle contains the largest variability in fi bre

types within this group of muscles (Serratrice et al. 1976 ) .

Individuals with craniofacial abnormalities may have differing expression of the

MyHC genes and their associated proteins, which are related to the presenting facial

abnormality. For example, a negative correlation has been noted between patients

who have an increased vertical facial form and upregulation of the MYH1 gene

representing the fast MyHC-IIX isoform (Suchak et al. 2009 ) . Following surgical

correction, e.g., orthognathic surgery, fi bre type transitions are observed that resemble

those seen in “regeneration” (Lee et al. 2000 ) . A number of investigations have

documented that the predominantly type I (slow) MyHC expressed in those with


97

increased vertical facial proportions shifts to a greater proportion of type IIA (fast)

MyHC after jaw surgery (Harzer et al. 2007 ; Maricic et al. 2008 ; Oukhai et al.

2011 ) . The functional adaptability of the masticatory muscles seems to be key to the

future surgical stability of severe craniofacial deformities.

6.4 Biochemistry

Cell–cell and cell–extracellular matrix (ECM) interactions lead to the upregulation

of speci fi c transcription factors and genes essential in the normal development and

maintenance of skeletal muscle (Maley et al. 1995 ; Melo et al. 1996 ; Grounds et al.

1998 ) . The three-dimensional ECM consists of the interstitial connective tissue and

basement membrane in intimate contact with satellite cells and myo fi bres.

The basement membrane, regulating cell polarity and separating tissue types, is

composed of mainly collagen IV, laminin, entactin, and heparan sulphate proteoglycans

(HSPGs) (Sanes et al. 1986 ) , whereas the interstitial ECM between myo fi bres

is composed of mainly collagen I, fi bronectin, and HSPGs (Cornelison 2008 ) .

Collagen provides tensile strength and the proteoglycans (PGs) create space for the

tissue and allow for diffusion; additionally, the ECM behaves as a storage depot for

cytokines and growth factors. The main ECM components form four groups—

collagenous glycoproteins, non-collagenous glycoproteins, proteoglycans, and elastin

(Lewis et al. 2001 ). The ECM differs between muscle groups, and all members play

an essential, co-ordinated, often synergistic role in functionality. The binding of

growth factors and their proteolytic fragments in the ECM has been demonstrated to

exert a number of important in fl uences, such as direct mitogenic effects (Foster et al.

1987 ) . Importantly, the majority of biologically active ECM molecules exhibit multiple

active binding sites with the capacity to bind different ligands and bring about

different activities. Structural integrity of the muscle tissue is crucial to normal function,

and the ECM, with its vast array of molecules, lends itself well to this role.

The adhesion molecules present on myogenic precursor cells (MPCs) consist of

fi ve groups, of which three, the ADAMs (a disintegrin and metalloproteinase

domain), cadherins (M-, N- and R-Cadherin), and immunoglobulin superfamily

(e.g., neural cell adhesion molecule 1 (NCAM-1) and vascular cell adhesion molecule

1 [VCAM-1]), are involved in control of direct cell–cell adhesion (Lewis et al.

2001 ). The dystrophin–dystroglycan complex and integrins, on the other hand, play

an important role in cell–ECM adhesion. The matrix metalloproteinases (MMPs),

secreted into the ECM as latent proenzymes, are essential to ECM maintenance—

for example, the gelatinases (MMP-2 and -9) degrade the major components of the

ECM, namely collagen IV and laminin (Lewis et al. 2001 ). Activation occurs by

proteolysis and is inhibited in a 1:1 manner by the tissue inhibitors of the metalloproteinases

(TIMPs) (Birkedal-Hansen 1995 ) with any disturbances in the

MMP:TIMP ratio manifesting clinically as disturbances in wound healing (Carmeli

et al. 2004 ; Guillen-Marti et al. 2009 ) . The molecules support muscle regeneration

by the MPCs in disease and injury.

98 M. Lewis et al.

Studies suggest MMP-2 is secreted by MPCs and the interstitial fi broblasts

(Kherif et al. 1999 ) and is expressed in healthy skeletal muscle where it is localised

to the perivascular regions, nerves and neuromuscular junctions (NMJs) (Lewis

et al. 2001 ). MMP-9, a product of in fl ammatory cells (Lewis et al. 2000 ; Schoser

et al. 2002 ) , is not expressed in normal adult non-cranial skeletal muscles, but it is

upregulated after muscle injury or disease, where it is located next to the blood

vessels, nerves, and NMJs (Kherif et al. 1999 ) . Interestingly, it is also expressed

within myo fi bres in healthy human craniofacial muscle (Singh et al. 2000 ) . The

differences in location between the craniofacial and somite-derived muscles could

be the consequence of their different developmental origins. Speci fi cally within the

human masseter muscle, TIMP-1 appears to be consistently expressed. The very

low levels of TIMP-2, MMP-2 and MMP-9 expression support the low level of

ECM turnover in the craniofacial musculature (Tippett et al. 2008 ) . The gelatinases

facilitate MPC migration during development (Chin and Werb 1997 ) and regeneration,

and their important role has been clari fi ed by in vitro (Allen et al. 2003 ) and

in vivo (El Fahime et al. 2000 ) studies whereby overexpression facilitated substantially

greater migration and blocking activity was suf fi cient to prevent MPC migration.

MMP-9 expression within the craniofacial muscles increases just prior to MPC

fusion. In contrast, MMP-2 mRNA and protein expression occur during all stages of

MPC differentiation (Kherif et al. 1999 ; Lewis et al. 2000 ; Carmeli et al. 2004 ) .

Studies have also suggested a synergistic role of growth factors on MMP expression

(Allen et al. 2003 ) .

6.5 Regeneration and Adaptation

Satellite cells are present as mitotically quiescent, undifferentiated mononuclear

cells located between the sarcolemma of individual muscle fi bres and their associated

basal lamina sheaths (Mauro 1961 ; Muir et al. 1965 ) . These cells are a normal

constituent of all vertebrate skeletal muscle, regardless of age, fi bre type and location

(Schultz 1976 ) , and comprise 2–10 % of the nuclei associated with any particular

fi bre (Bischoff and Heintz 1994 ) . Of the total number of nuclei in mature muscle,

satellite cells make up 1–5 % (Allbrook 1981 ; Alameddine et al. 1989 ) . Interestingly,

satellite cells are in greater number within oxidative muscles as compared to glycolytic

muscles, regardless of species (Gibson and Schultz 1983 ; Schultz 1989 ) . The

size of the population is, in part, regulated directly or indirectly by innervation as

well as the muscle functional state (Schultz et al. 1984 ) . The fi bre type distribution

of the regenerated myo fi bres takes on the characteristics of the host muscle bed.

Hence, it follows that innervation, recruitment pattern, and ultimate fi bre type may

be important determinants of satellite cell distribution. The distribution along individual

fi bres is relatively even with the exception of the motor endplate regions

where cell density is increased (Wokke et al. 1989 ) . Several reasons have been

suggested for this, including preservation of the NMJ and synthesis of molecules

important for the structure or function of motor endplates (Wokke et al. 1989 ) .


99

It has been found that the ratio of satellite cell nuclei to total nuclei number

varies between masticatory and somatic muscle groups with the latter demonstrating

a higher ratio (Renault et al. 2002 ) . This is despite the presence of a greater

mean number of nuclei per fi bre within the masseter muscle. Importantly, the ratio

of satellite cells decreases in both groups with age; however, it has been suggested

that generally the masseter muscle regenerates less effectively following a traumatic

injury than somatic muscle (Pavlath et al. 1998 ) . The contrast in regenerative

capability may be explained by the different embryological origins of craniofacial

and somatic skeletal muscle and variations within the myoblast populations.

Numerous animal models have been used to examine the structural and

functional characteristics of regenerating skeletal muscle (Carlson and Gutmann

1975a, b ; Faulkner et al. 1980 ) . Regardless of the nature, severity, and extent of the

injury, the process of muscle regeneration is comparable, although the outcome and

timetable of the reparative process may vary (Lee et al. 2000 ) . Some in vivo studies

have used differential labelling of satellite cells and myonuclei with 3H-thymidine

to demonstrate the satellite cell as the sole source of new MPCs (Schmalbruch

1976 ) . Recent studies have demonstrated that the population of satellite cells in

muscles is quite heterogeneous, both molecularly and functionally (Collins et al.

2005 ; Biressi and Rando 2010 ; Rossi et al. 2010 ) . In response to injury, satellite

cells become activated and proliferate to form a pool of MPCs (Lee et al. 2000 ) .

Some of the MPCs differentiate to provide a source of nuclei to damaged myo fi bres

or alternatively fuse together to form new multinucleated myo fi bres (Moss and

LeBlond 1971 ; Snow 1978 ; Campion 1984 ) , whereas some daughter cells replenish the

satellite cell population (Barof fi o et al. 1995, 1996 ; Yoshida et al. 1998 ; Beauchamp

et al. 1999 ) . The migration of MPCs through the basal lamina of myo fi bres both

within (Phillips et al. 1990 ) and between (Watt et al. 1994 ) skeletal muscles and

formation of the connective tissue network by the proliferating MPCs is key to successful

repair and regeneration (Hughes and Blau 1990 ; Li and Huard 2002 ; Hill

et al. 2003 ) .

Satellite cells were originally thought to be of somitic origin: classic quail-chick

chimera experiments revealed the association of satellite cell nuclei derived from

implanted quail somite with host chick myo fi bres (Armand et al. 1983 ) . However,

more recent studies have suggested a non-somitic origin of satellite cells (Ferrari

et al. 1998 ; De Angelis et al. 1999 ; Hawke and Garry 2001 ; Asakura and Rudnicki

2002 ; LaBarge and Blau 2002 ; Polesskaya et al. 2003 ) . For craniofacial muscles,

these cells are derived from the same source of craniofacial mesenchyme as the

muscles themselves (Harel et al. 2009 ) . Further, it has been proposed that MPCs

may still retain the plasticity to transcend the lineage boundary when exposed to

certain in vitro and in vivo environmental cues (Jackson et al. 1999 ; Lee et al. 2000 ;

Geiger et al. 2002 ; Wada et al. 2002 ; Cao et al. 2003 ; Zheng et al. 2007 ) , although

some evidence exists that they may arise from circulating blood-borne or other stem

cell populations. Another source of stem cells (muscle-derived stem cells, MDSCs)

is present in adult skeletal muscle with the ability to give rise to different cell types,

including MPCs (Royer et al. 2002 ; Tamaki et al. 2002 ; Wada et al. 2002 ) . Further

studies need to be undertaken to determine whether these cells truly are satellite cell

100 M. Lewis et al.

progenitors, a subpopulation of satellite cells, or an independent progenitor cell

population that is resident in the extracellular niche of skeletal muscle (McKinney-

Freeman et al. 2002 ) . Signi fi cantly, the potential to produce different tissues from

muscle-derived cells opens up another dimension for novel therapies, such as tissue

engineering (Qu-Petersen et al. 2002 ) .

Growth factors play a role in skeletal muscle development and growth. In particular,

insulin-like growth factors I and II (IGF-I and -II) play an important role in the

general growth and development of different tissues. The effects of IGFs, which are

under negative feedback, are initiated upon binding to cell surface receptors, which

are abundant in skeletal muscle (Livingston et al. 1988 ) , and modulated through

interactions with secreted IGF binding proteins (IGFBPs), of which there are six

members (Stewart and Rotwein 1996 ) . IGFBPs are secreted from cells that also

secrete IGFs (Ernst et al. 1992 ) , and it has been speculated that IGFBP-4 may be

necessary for in vivo enhancement of human skeletal muscle (Brimah et al. 2004 ) .

IGF-I appears to be essential for correct embryonic development in animal models,

as demonstrated by the underdeveloped muscle tissue and perinatal death of mice

homozygous for either a mutation of the IGF-I gene or IGF-I receptors (IGF-1Rs)

(Liu et al. 1993 ; Powell-Braxton et al. 1993 ) .

It is likely that the growth hormone (GH)–IGF axis plays a major part in mediating

the growth and differentiation of skeletal muscle. The direct action of GH is

unclear (Halevy et al. 1996 ) , despite establishing the presence of the GH receptor

mRNA in skeletal muscle. Data from recent studies in GH receptor knock-out mice

and established cell cultures have suggested that GH is not necessary for the control

of skeletal muscle during the embryonic and perinatal stages, but important for

postnatal myo fi bre growth involving the fusion of MPCs to nascent myotubes, as

well as the positive speci fi cation of type I fi bres (Sotiropoulos et al. 2006 ) . These

growth-enhancing actions of GH are facilitated by circulating or autocrine–paracrine

production of IGF-1 (Le Roith and Zick 2001 ) . Indeed, numerous studies have shown

increased IGF-1 mRNA within skeletal muscle tissue and MPC cell lines in response

to GH exposure (Florini et al. 1996 ) . There are three IGF-1 splice variants, IGF-

1Ea, IGF-1Eb and IGF-1Ec. Due to its upregulation in exercised and regenerating

human skeletal muscles, IGF-1Ec is also referred to as mechanogrowth factor

(MGF) (Yang et al. 1996 ) . IGF-1 is produced by MPCs within regenerating muscles

(Hawke and Garry 2001 ) , which promote MPC cell survival (Stewart and Rotwein

1996 ; Napier et al. 1999 ) , proliferation (Florini et al. 1996 ; Yang and Goldspink

2002 ; Ates et al. 2007 ) , differentiation (Galvin et al. 2003 ) , and hypertrophy (Baker

et al. 1993 ; Florini et al. 1996 ; Matsumoto et al. 2006 ; Quinn et al. 2007 ) , responses

that are temporally separate in MPCs (Allen and Boxhorn 1989 ; Florini et al. 1991 ) .

It has been demonstrated that MGF is upregulated after the surgical correction of

craniofacial abnormalities, thus indicating its role in regeneration and potential

adaptation in these specialised muscles (Maricic et al. 2008 ) .

Maximal stimulation of proliferation and the highest percentage of fusion of rat

satellite cells in vitro are produced by a combination of FGF and IGF-I (Allen and

Boxhorn 1989 ) ; however, differentiation with minimal proliferation can be achieved

with IGF-I alone. Proliferation is brought about by the activation of MAP kinases


101

(Coolican et al. 1997 ) , whilst differentiation is achieved by increasing levels of

mRNA for myogenin, the MRF most directly associated with terminal myogenesis

(Florini et al. 1991 ) , and activation of the phosphoinositol 3-kinase/Akt/70-kDa S6

protein kinase pathway (Coolican et al. 1997 ) . In exercised muscle/compensatory

hypertrophy, IGF-I exerts its effects by increasing protein (sarcomere) formation

(Adams and Haddad 1996 ; Adams and McCue 1998 ) . Notably, the age-related

changes of sarcopenia and muscular dystrophy were negated in mice expressing

muscle-speci fi c IGF-1 (Musaro et al. 2001 ; Barton et al. 2002 ) .

The micro-environmental cues provided by tissue-speci fi c ECM components are

essential in determining the fate of stem cells and their progeny, and this has been

discussed previously. The ‘stem cell niche’ itself protects the quiescent cells from

these in fl uences; however, upon escaping the niche, cells are not only directed by

the ECM components, but also by non-myogenic cells within the tissues. The nonmyogenic

cells that play an important role in skeletal muscle development, maintenance,

regeneration, and often chronic pathological conditions include platelets,

polymorphonuclear leukocytes (PMLs), macrophages, and fi broblasts.

In fl ammatory cells, in particular macrophages, play a role in tissue homeostasis

whereby upon injury they can undertake phagocytosis (Robertson et al. 1993 ) , antigen

presentation, and provide support through the delivery of mitogens and cell

contact-mediated survival signals (Nathan 1987 ; Cantini et al. 2002 ) . PMLs accumulate

within minutes at an injury site and by cytokine release can promote attraction

and activation of other in fl ammatory cells. The role for leukocytes is based on

the observation that quiescent satellite cells express VCAM-1 and in fi ltrating leukocytes

express the speci fi c co-receptor VLA-4 (integrin a 4 b 1). Thus, cell–cell interactions

may initiate genetic responses that promote regeneration.

Skeletal muscle injury leads to the in fl ux of newly recruited macrophages by 24 h,

which are responsible for the active removal of necrotic tissue and successful muscle

regeneration (Grounds 1987, 1991 ; Robertson et al. 1993 ; Bischoff 1997 ) . It has

been demonstrated that human MPCs, released after micro- and macro-injury, can

selectively and speci fi cally attract monocytes through the release of a variety of

chemokines (e.g., vascular endothelial growth factor [VEGF]) (Rissanen et al. 2002 ) .

Incidentally, the chemotactic in fl uence was highest in newly activated MPCs, aided

by close proximity to muscle capillaries (Schmalbruch and Hellhammer 1977 ) ,

which then declined towards the time of late differentiation and the formation of

multinucleated myotubes (Chazaud et al. 2003 ) . Others have also shown greater

in vitro MPC proliferation in the presence of primary rat monocytes (Cantini et al.

1995 ) , and superior primary rat and human MPC proliferation and myotube formation

in the presence of macrophage-conditioned medium, as compared to a negative

control (Cantini et al. 2002 ) . Additionally, in vivo administration of the macrophageconditioned

medium substantially improved regeneration with respect to speed and

volume within rat muscles subjected to tissue ablation (Cantini et al. 2002 ) .

As the monocytes differentiate into macrophages, reciprocal interaction with

MPCs ampli fi es the release of macrophage chemoattractants for additional monocytes

and MPCs (Chazaud et al. 2003 ) . It has been implied that the growth factors

released by macrophages (IGF-I and -II, HGF, FGFs, platelet-derived growth factor

102 M. Lewis et al.

BB (PDGFBB), epidermal growth factor [EGF], IL-6 (Robertson et al. 1993 ; Hawke

and Garry 2001 ) ) and involvement with cell adhesion molecules may not only rescue

MPCs from apoptosis, but also play similar roles for erythroblasts and neuronal

cells (Meucci et al. 2000 ; Chazaud et al. 2003 ) .

Within skeletal muscle, fi broblasts are surrounded by the peri- and endomysium

and are attached to the ECM via integrins (Mackey et al. 2008 ) enabling the cells to

register and respond to any mechanical stimuli transmitted through the ECM: this

ability has been suggested to be essential for correct fi broblast functioning (Sarasa-

Renedo and Chiquet 2005 ) . The endomysial collagen is primarily produced by

fi broblasts, and it has been demonstrated in vitro that fi broblasts produce factors

that may modify MPC response (Sinanan et al. 2008 ) .

In summary, the muscles of mastication, and especially the masseter muscle, differ

from non-cranial muscles in several important ways. Firstly, the range and variation

of MyHC protein isoforms, and in particular, the persistence of developmental isoforms

which can be considered part of the normal adult MyHC isoform population.

Secondly, the presence and location of certain metalloproteinases, especially MMP-9,

adjacent to myo fi bres in normal, healthy craniofacial muscle tissue is seen as

opposed to its presence only in response to disease or injury, and thirdly, differences

exist in the regenerative capability with a suggestion that the masseter muscle may

be less effective at this process compared to somite-derived muscle.

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Chapter 7

Motor Control of Masticatory Muscles

Barry J. Sessle , Limor Avivi-Arber, and Gregory M. Murray

7.1 Introduction

This chapter focuses on the brainstem and higher brain center mechanisms involved

in the execution, initiation, re fl ex regulation, and sensorimotor coordination of the

masticatory musculature. A brief overview is given of masticatory musculoskeletal

biomechanics, but other chapters may be consulted for general aspects of biomechanics

related to motor control and for the structural and functional features of

this musculature and its motor units and muscle fi bers and sensory innervation.

Mastication is a complex motor function that involves the simultaneous bilateral

coordinated activation and/or inactivation of the jaw, tongue and face muscles. Jaw

opening occurs by downward traction of the mandible by the anterior bellies of the

digastric muscles and the mylohyoid muscles and anterior traction of the condyles

by the lateral pterygoid muscles. Jaw closing occurs by activation of the masseter,

temporalis, and medial pterygoid muscles. Jaw protrusion requires activation of

the lateral pterygoid, the anterior fi bers of the temporalis and the super fi cial

masseter muscles, and jaw retrusion is brought about by activation of the posterior

fi bers of the temporalis muscles. During mastication, the tongue muscles (e.g.,

genioglossus—tongue protrusion; hyoglossus—tongue depression; styloglossus—

tongue retrusion; palatoglossus—tongue elevation) assist in maneuvering the food

bolus from side to side, and the lip muscles (e.g., orbicularis oris—perioral sphincter,

B. J. Sessle (*) • L. Avivi-Arber

University of Toronto , 124 Edward Street , Toronto , ON , Canada M5G 1G6

e-mail: barry.sessle@utoronto.ca

G. M. Murray

University of Sydney , Sydney , Australia




111

112 B.J. Sessle et al.

zygomaticus major—elevation and retraction of the modiolus) and cheek muscles

(buccinators—retraction of the modiolus), along with the tongue muscles, assist in

maintaining the food bolus within the mouth on the occlusal table (Dubner et al.

1978 ; Lang 1995 ; Miles et al. 2004 ) .

There are unique features of the orofacial motor system that distinguish it from

the spinal motor systems. Moreover, many orofacial movements involve muscles

innervated by several cranial nerves. In view of this and the large number of muscles

involved, intricate bilateral motor control is essential to ensure coordinated

and appropriate motor patterning is carried out. This is especially the case for those

motor functions involving the masticatory muscles. Yet, most of the literature on

motor control focuses on limb motor control. Reviews of the topic often completely

neglect the motor control mechanisms necessary for masticatory and other

orofacial movements, many of which necessitate complex processing to provide

for the exquisite motor control that is required for these muscles that serve important

and diverse functions, some of which are vital for sustaining the life of the

organism.

Each masticatory muscle may be guided in the various motor functions in which

it participates by brainstem motor outputs in fl uenced by higher brain centers.

Guidance also derives from sensory inputs to its motoneurons that derive from a

large array of different types of receptors. Many of these features are similar to

those in the spinal motor system, but some are associated with tissues unique to the

orofacial region (e.g., tooth, cornea, taste receptors). Some of the muscles are multipennate

(e.g., masseter, medial pterygoid) and functionally heterogeneous, and

thus the different compartments of these muscles may contribute differentially to

the various motor functions carried out by each of these muscles, as noted in the

next section.

7.2 Masticatory Musculoskeletal Biomechanics

Musculoskeletal biomechanics as applied to the masticatory system comprise

mechanics of the masticatory muscles themselves (i.e., muscle anatomy including

their attachments and angulations, internal muscle architecture, and activation

patterns) and mechanics of the teeth (including the periodontal ligament), bones and

joints (i.e., material and structural properties) that shape the amount, direction,

force, and rate of the complex orofacial movements. A detailed understanding of the

musculoskeletal biomechanics of this system is important not just for the understanding

of the effects of anatomical changes (e.g., tooth modi fi cations, reconstructions,

implants, surgery) on motor function but also for the diagnosis and management

of musculoskeletal disorders such as temporomandibular disorders (TMD). The following

only brie fl y reviews some aspects of musculoskeletal biomechanics as

applied to the human masticatory system. The reader is also referred to more detailed

and comprehensive descriptions (Hannam 1994 ; Herring 2007 ; Hannam et al. 2008 ;

Curtis 2011 ) .

7 Motor Control of Masticatory Muscles

113

7.2.1 Masticatory Muscles Mechanics

The generation of mandibular movement is brought about by active jaw muscle

tensions and passive soft tissue tensions. The anatomy of the jaw muscles is extraordinarily

complex (e.g., Hannam 1994 ; Hannam et al. 2008 ) . The motor units within

the masseter, temporalis, and medial pterygoid muscles (the jaw-closing muscles)

are arranged in a highly complex manner within each muscle. For example, masseter

muscle fi bers on the whole do not run from the zygomatic arch to the ramus but

rather there are small compartments of short fi bers divided by aponeurotic sheaths

and arranged in a so-called pennate (compartment) manner (Fig. 7.1 ). Therefore,

when motor units on one side of a compartment contract, forces can be generated at

an angle (the pennation angle) to the long axis of the muscle, with a force vector

(i.e., magnitude and direction of force) at an angle to the force vector that would be

generated if muscle fi bers passed directly from the zygomatic arch to the ramus

without pennation. These complexities of muscle- fi ber architecture, together with

selective activation of certain motor units within the muscle, provide a wide range

of directions with which forces can be applied to the jaw and thereby contribute to

the enormous range and sophistication of jaw movements that are possible. When

generating a particular movement of the jaw, the sensorimotor cortical regions that

drive voluntary movements are not organized in terms of speci fi c muscles to activate.

Rather, they send a command signal to activate those motor units, in whatever muscles

are available, that are biomechanically best suited to generate the force vector

(i.e., magnitude and direction of force) required for that particular jaw movement

(e.g., Widmer et al. 2003 ) .

7.2.2 Masticatory Motor Function Mechanics

The active and passive tensions mentioned above generate a range of jaw motions

and stresses, strains and forces throughout the various components (e.g., teeth, temporomandibular

joints [TMJs], bone) of the masticatory system. Anatomical and

functional studies in experimental animals and humans have documented some of

these variables (e.g., Herring 2007 ) . Because some of these approaches are highly

invasive, mathematical modeling has been used to clarify structure–function relationships.

These models can range from relatively simple 2D static analyses that

tend to focus on peak bite force, to more complex 3D models based on rigid body

mechanics, rigid body meaning that the jaws undergo no deformation. Some models

are becoming very sophisticated (Hannam et al. 2008 ; Curtis 2011 ) . For example,

Artisynth ( http://www.magic.ubc.ca/artisynth/pmwiki.php ; Hannam et al. 2008 ) is

a 3D biomechanical computer simulation that models the vocal tract and upper

airway and is capable of articulatory speech synthesis. The accuracy with which

these models re fl ect normal function, however, is dependent on the sophistication

and range of variables (e.g., muscle size, muscle site, muscle angulation, muscle


Fig. 7.1 ( a ) Location of the attachment of the multi-axis force transducer and the axes orientation

relative to the head. ( b ) Anatomical representation of the jaw-opening muscles (anterior digastric)

and jaw-closing muscles (temporalis, masseter, and medial pterygoid). Masseter muscle compartments

can be seen from the lateral and medial views, and the location of the fi ne-wire recording

sites for each compartment are depicted (adapted from Widmer et al. 2003 ) (Reprinted with permission

from Springer)


115

activity, ligament position, visco-elasticity, skeletal anatomy) that are incorporated

into the models. Once developed, these models can be used to predict force distributions,

for example in the TMJ, and rigid body motion. This is an example of forward

dynamics. These models can also be used to study the effects of perturbations to the

system, testing the effect of implants, surgery, prosthetic reconstructions, and the

like. The greater the number of input variables that are based on valid experimental

data, particularly from humans, the more reliable and valid these models will be in

predicting forces at various locations, such as teeth, joints, and effects of perturbations

to the system. Musculoskeletal problems also can be solved by inverse dynamics

which use body motions and external forces to calculate the muscle forces.

7.3 Types of Motor Functions

Mastication is a semiautomatic orofacial movement under the control of a brainstem

central pattern generator (CPG) that can be modulated by descending in fl uences

from higher brain centers and also re fl exively in fl uenced by inputs from orofacial

somatosensory receptors (Fig. 7.2 ). Voluntary movements, such as voluntary jaw

opening or voluntary jaw protrusion, are driven by higher centers such as the

primary motor cortex (MI) and the cortical masticatory area (CMA) that can themselves

also be modulated by somatosensory inputs to the cortex and brainstem motor

output circuits. Re fl exes are movements whereby an afferent input to the central

nervous system (CNS) can evoke a re fl ex jaw movement, e.g., biting on a hard

particle during chewing can protectively evoke a jaw-opening response.

Cerebral Cortex

Somatosensory and Motor Areas

Planning, initiation and

modulation of voluntary and

involuntary movements;

Sensory-motor integration;

Motor learning

Thalamus

Basal

ganglia

Sensory-motor

integration;

motor learning

Cerebellum

Other subcortical areas

(e.g., red nucleus, reticular

formation)

Muscle

contraction

Sensory

receptors

Brain stem

Central

Pattern

Generators

Motor V,VII,XII

Sensory V/

Mesencephalic

Involuntary movements

Initiation and modulation of

semiautomatic movements

Fig. 7.2 The principal inputs and outputs to/from face MI and face SI. There are extensive interconnections

(excitatory and/or inhibitory) between cortical and subcortical regions, and commissural

fi bers are responsible for bilateral coordination. The Central Pattern Generators provide the

programmed motor output to muscles participating in chewing (the “Chewing Center”) and swallowing

(the “Swallow Center”). (Adapted from Avivi-Arber et al. 2011 b ) (Reprinted with permission

from Elsevier)


Most of the masticatory motor functions are cyclic in nature, that is, they are regularly

recurring movements. These cyclic jaw movements and other associated facial

and tongue movements that characterize chewing are generated by muscles that are

driven by a program that resides in the brainstem CPGs and which itself can be

modulated by afferent inputs acting through brainstem re fl ex circuits or higher brain

centers. During chewing, there are a wide range of directions and magnitudes of bite

forces between opposing upper and lower teeth and a similarly wide range of directions

and magnitudes of forces from the tongue, lips, and cheeks that can be exerted

on the food bolus. This complexity demands highly coordinated processes that, for

example, on the one hand allow for light forces to explore and ascertain the texture

of a foodstuff and on the other hand allow for the generation of the large forces necessary

for biting through tough foodstuffs while avoiding self-injury (Lund 1991 ;

Woda et al. 2006 ) . Thus, there is the need for sophisticated neural circuits that allow

for integration bilaterally of these diverse and complex motor functions and for coordination

with other motor functions such as respiration and swallowing. Virtually all

of these functions are not purely “motor” but indeed are sensorimotor, since they

depend upon or utilize sensory inputs or feedback to initiate or guide them.

Chewing is a motor function learned after birth, distinct from swallowing which

develops in utero. Most mammals are born as suckling and swallowing animals, but

as the infant matures, the rhythmic jaw movements become increasingly under central

control and more sophisticated, engaging to a greater degree other muscle groups that

allow for more re fi nement and the emergence of chewing behavior in the full sense of

the word. The postnatal eruption of the teeth provides important sensory inputs from

periodontal receptors that also assist in the development of masticatory control.

7.4 Neural Processes

There are several features that distinguish orofacial motor functions and their underlying

mechanisms from spinal sensorimotor processes and movements (see Sessle

2009 ) . In addition to the number of muscles that may often require bilateral muscle

activities, these distinguishing features include the arrangement of the various sensory

nuclei and motor nuclei into distinct neuronal pools in the brainstem, and unique

aspects of the peripheral and central mechanisms (see below). The orofacial region

receives its sensory and motor nerve supplies from the brainstem. The major sensory

nuclei include the trigeminal (CNV) brainstem sensory nuclear complex (VBSNC)

that receives most of the general somatosensory afferent input from the orofacial

tissues, and the solitary tract nucleus (NTS) that receives visceral afferents (e.g., those

supplying lingual taste buds, and laryngeal and pharyngeal taste buds and mechanoreceptors).

The main cranial nerve motor nuclei include the CNV motor nucleus

(Motor CNV) that provides the motor innervation of most jaw muscles, the CNVII

motor nucleus supplying the muscles of facial expression, CNXII motor nucleus

supplying the intrinsic and extrinsic tongue muscles, and the nucleus ambiguus

(CNIX and CNX) that mainly supplies muscles of the palate, larynx, and pharynx.

These brainstem sensorimotor circuits are controlled by other brainstem systems


117

(e.g., CPGs) as well as by descending in fl uences from other subcortical and cortical

areas. The following considers these peripheral and central processes in turn.

7.4.1 Peripheral Mechanisms

The receptors and the afferent inputs involved in motor control of muscles including

the masticatory muscles have largely been covered in other chapters dealing with

spinal sensory or motor functions or speci fi cally with orofacial functions and will

not be considered in detail here. The orofacial tissues are characterized by a high

innervation density of exteroceptive, proprioceptive, and nociceptive primary afferent

fi bers, most of which occur in CNV and have their primary afferent cell bodies

in the trigeminal ganglion (CNV ganglion) and project into the brainstem. In addition

to perceptual information, they provide the CNS with crucial peripheral

feedback and feedforward information needed for the fi ne control of rapid and

complex orofacial motor functions (for review, see Dubner et al. 1978 ; Miles et al.

2004 ; Lund et al. 2009 ; Sessle 2009 ) . Jaw-closing muscles have muscle spindles

providing inputs about muscle stretch and length. Of particular importance are the

“specialized” nerve endings within the skin, mucosa, joints, and periodontium that

act as mechanoreceptors sensitive to deformation of underlying muscles during orofacial

movements or of the periodontal ligament during tooth movement thereby

acting as proprioceptors providing information regarding the position and movements

of the orofacial muscles and joints. This feature may be particularly important

for the control of facial and jaw-opening muscles that in contrast to the other

skeletal muscles, including the jaw-closing muscles, have few or no muscle spindles

(for review, see Dubner et al. 1978 ; Miles et al. 2004 ; Paxinos 2004 ) . It is noteworthy

that the primary afferent cell bodies of those jaw muscles that do have spindles

(i.e., jaw-closing muscles) occur not in the CNV ganglion but in the CNV mesencephalic

nucleus (MesV) within the CNS.

The orofacial region is further characterized by specialized chemoreceptive endings

in taste buds that can also affect the patterns of mastication (Neyraud et al.

2005 ) . Small-diameter, slow-conducting primary afferents (e.g., A-delta, C- fi bers)

with free nerve endings acting as nociceptors or lower-threshold thermoreceptors

also exist within the orofacial tissues and carry into the brainstem nociceptive and

thermosensitive afferent information used for motor control as well as perceptual

processes (for review, see Dubner et al. 1978 ; Miles et al. 2004 ; Paxinos 2004 ) .

7.4.2 Brainstem Re fl ex Processes

As noted above, there are other important sensory and cranial nerve motor nuclei

and these include the NTS, and the CNVII and CNXII motor nuclei and the nucleus

ambiguus. Furthermore, in addition to the VBSNC and NTS, there are other important

interneuronal sites such as the inter-trigeminal nucleus, the supra-trigeminal

nucleus, and components of the medial and especially lateral reticular formation that


lie immediately adjacent to the VBSNC and the NTS. These sites provide some of

the neural circuitry and processing that form the basis for the central programs

(central pattern generators, CPGs) so crucial in the initiation and control of complex

functions such as chewing and swallowing. These regions also provide a neural

substrate allowing for the initiation or modulation of brainstem re fl exes by receiving

and integrating afferent inputs from various orofacial tissues and from other

brainstem or suprabulbar areas, such as afferent inputs, descending controls, and

conscious state. As well as these afferent inputs being capable of evoking brainstem-based

re fl ex responses, afferent signals are also relayed from the brainstem to

higher brain centers involved in sensorimotor control of the muscles (Dubner et al.

1978 ; Murray et al. 2001 ; Sessle et al. 2005 ) .

7.4.2.1 Brainstem Re fl exes

The motoneurons supplying the masticatory muscles receive re fl ex afferent inputs from

free nerve endings as well as the specialized receptors in the orofacial tissues. Thus, the

masticatory neuromuscular system can be in fl uenced re fl exively by the somatosensory

inputs into the brainstem from receptors that signal pain, touch, joint position, muscle

stretch or tension, and the like. Through their connections with the previously mentioned

interneuronal circuits, these afferent inputs can activate or inhibit the cranial

nerve motoneurons supplying the masticatory musculature. Brainstem circuits also

underlie the autonomic re fl ex changes in heart rate, blood pressure, breathing, and salivation

and in more complex behaviors that can be evoked by non-noxious or noxious

stimulation of orofacial tissues. On the basis of these various types of responses, several

human behavioral paradigms have been developed in order to study the effects of

orofacial stimuli in humans; these include changes in autonomic functions (e.g., heart

rate, salivation), muscle re fl exes, and facial expression.

Given the large number of muscles in the orofacial region, and the diversity of

receptors and afferent inputs, the number of re fl exes is also vast. This applies to the

masticatory muscles as well. For example, mechanical stimulation of the jaw-closing

muscles can result in several jaw re fl ex responses that involve brainstem circuits and

are modulated by afferent and descending in fl uences. Jaw muscle stretch evokes

myotatic stretch re fl exes through activation of jaw muscle spindle afferents (Dubner

et al. 1978 ; Lund and Olsson 1983 ) . As indicated above, the primary afferent cell

bodies of these spindle afferents are located in MesV, and impulses in their central

axons can monosynaptically activate jaw-closing motoneurons in Motor CNV.

Synapses occur on these primary afferent cell bodies, and they and their central

axons have intriguing electrophysiological and neurochemical features that have

recently been reviewed (Lund et al. 2009 ) . The jaw-opening re fl ex and the re fl ex

effects of stimulation of periodontal receptors around the root of the tooth are two

examples of other well-studied jaw re fl exes. A brief excitatory re fl ex in the jaw

muscles may be elicited under certain conditions, but an inhibitory re fl ex involving

one or more so-called “silent” periods in the jaw-closing muscles has received

particular attention over the years. This inhibitory re fl ex is usually thought to provide


119

a protective or regulatory function, for example bite force, during jaw-closing

movements, and its occurrence and/or duration has been proposed, with little

scienti fi c rigor, as a useful diagnostic tool in certain orofacial pain or motor disorders.

However, it is subject to considerable variation because of several interacting

factors. Furthermore, inhibitory periods in the jaw-closing muscles can be induced

by stimulation of different types of receptors in various orofacial tissues other than

periodontal tissues. Re fl ex excitatory or inhibitory effects can also be elicited in

tongue, facial, and other muscles in the orofacial region (Dubner et al. 1978 ;

Aramideh and De Visser 2002 ) . The jaw re fl ex effects of noxious stimulation of

orofacial tissues have received considerable attention particularly in the last two

decades. Brief high-intensity stimulation can elicit a transient jaw-opening re fl ex, or

transient inhibitory effects in jaw-closing muscles, as noted above. However, the

application of algesic chemicals (e.g., hypertonic saline, capsaicin, glutamate, mustard

oil) to the TMJ, muscle, or other orofacial tissues of anesthetized animals can

result in prolonged increases in electromyographic (EMG) activity of both the jawopening

and jaw-closing muscles. These effects involve activation of neurons in

subnucleus caudalis or in other components, for example subnucleus oralis of the

VBSNC, as well as several chemical mediators and receptor mechanisms (e.g.,

NMDA, opioids, GABA) in Motor CNV and the interneuronal sites involved (see

Sessle 2006 ) . It has been suggested that the co-contraction of the masticatory muscles

may be the mechanism for a “splinting” effect that has the effect of limiting jaw

movements in pathophysiological conditions affecting deep tissues such as the TMJ

and muscles. Despite these important observations in experimental animals, there is

no consensus on whether the EMG activity of these muscles decreases, increases or

remains unchanged during experimentally induced or clinical orofacial pain in

humans. In fl uences from brainstem and higher brain centers involved in stress,

emotion, alertness, sleep, and wakefulness are possible factors that may account for

the disparity in experimental and clinical pain data. Thus, the issue of how pain

interacts with the neuromuscular system is not entirely clear, and some hypotheses

have been proposed to account for the motor effects of pain that are seen clinically.

The Vicious Cycle Theory proposes that pain can lead to muscle hyperactivity and

vice versa, whereas the Pain Adaptation Model proposes that changes in agonist and

antagonist jaw muscles allow the masticatory system to adjust to or adapt to the

painful condition. Most of the limited scienti fi c evidence available favors the latter

concept, but some limits and inconsistencies have been noted not only in the orofacial

sensorimotor system (Murray and Peck 2007 ) but also in the spinal motor

system (for review, van Dieen et al. 2003 ) . In addition, nociceptive activity can

in fl uence higher brain centers involved in motor control, such as the sensorimotor

cortex, and thereby in fl uence masticatory muscle function.

7.4.3 Descending In fl uences

Descending modulatory (i.e., excitatory or inhibitory) in fl uences from various

cortical and subcortical structures as well as segmental modulatory in fl uences


(Dubner et al. 1978 ; Sessle 2006, 2009 ) have profound effects on many of the

neurons in the VBSNC or NTS that relay to thalamus or other brain regions

(Fig. 7.2 ). Because many of these neurons also contribute as interneurons to re fl ex

and other behavioral responses evoked by stimulation of orofacial tissues, responses

can also be regulated by these modulatory in fl uences on the interneurons or in some

cases, on the motoneurons themselves that are part of the re fl ex circuits. These

descending modulatory in fl uences include those from the amygdala and other parts

of the limbic system, the lateral hypothalamus, the lateral habenular nucleus, the

basal ganglia, the anterior pretectal nucleus, the red nucleus, the cerebellum, the

sensorimotor cerebral cortex, the cortical premotor and supplementary motor areas

(SMAs), and the cortical masticatory and swallowing areas. It is through these

descending excitatory or inhibitory in fl uences that the higher brain centers can exert

control over the brainstem processes and activities of motoneurons supplying not

only the masticatory but also all the orofacial musculature, and thereby initiate,

guide or regulate orofacial motor functions. The next sections examine in more

detail these higher brain center in fl uences and processes.

7.4.4 Subcortical Processes

Several areas in the CNS exert modulatory in fl uences on motor behavior via direct or

indirect projections to cranial nerve motoneuron pools. The numerous connections

between these areas mean that the neural circuitry involved in the CNS control of

motor function is extensive and complex. Only limited study has been made on these

pathways as they apply to orofacial motor control as compared to limb motor control.

In the case of the brainstem, the descending inputs as well as the afferent inputs

from peripheral receptors access the re fl ex interneurons that project to and modulate

motoneurons in the cranial nerve motor nuclei. Several of these regions also act in

concert to form the neural circuitry of the CPGs for chewing, swallowing, and other

analogous complex motor behaviors (Lund 1991 ; Jean 2001 ; Lund et al. 2009 ) .

Most research attention has focused on the CPGs underlying swallowing and especially

mastication. For the latter, this CPG (the “chewing center”) can generate

chewing-like movements independent of orofacial sensory inputs. Nonetheless,

studies in humans and animals indicate that it can utilize these inputs, especially

those from periodontal mechanoreceptors and jaw muscle spindles, in concert with

other brain regions accessing it, to provide for modi fi cation and guidance of masticatory

movements (Fig. 7.2 ). The CPG-dependent stereotyped movements typical

of chewing can be varied, and function in an integrated manner with movements of

the cheeks and tongue to allow for repositioning of the food bolus and for alterations

in masticatory force, velocity and jaw displacement as the food is crushed and

manipulated. These features explain how several factors, for example the number of

teeth, food composition and hardness, and bite force, can in fl uence the masticatory

process and provide for the appropriate reduction of food to a size suitable for swallowing.

As part of this process, the CPG can also modulate sensory inputs, such that


121

central control can mask out undesirable perturbations and re fl exes that might

disrupt the ongoing masticatory process, yet also allow nociceptive re fl ex inputs to

access the masticatory motoneurons and thereby provide protection of the masticatory

apparatus. One common example of this process in operation is the interruption

of chewing by the jaw-opening re fl ex elicited by a noxious stimulus such as a fi sh

bone piercing the oral mucosa. In the case of the CPG for swallowing (the “swallow

center”), it appears to involve neurons within and adjacent to the NTS. Collectively,

the output of these neurons provides the time-locked, patterned drive to the different

motoneuron pools supplying the muscles that participate in swallowing. While the

swallow CPG neurons are triggered into action by sensory inputs, the CPG is nonetheless

relatively insensitive to sensory feedback or descending controls once the

swallow has started. It thus contrasts with chewing which is sensitive to both sensory

inputs and CNS controls (Dubner et al. 1978 ; Jean 2001 ) .

Several higher brain centers directly or indirectly access motoneurons via the

various brainstem interneuronal groups, including the CPGs (for review, see Dubner

et al. 1978 ; Lund 1991 ; Sessle 2006, 2009 ) . Many cerebral cortical output pathways

project indirectly to the brainstem via various components of the basal ganglia and

substantia nigra, as well as directly to the brainstem. Orofacial motor de fi cits can

arise after lesions of some of these components. Recordings in basal ganglia neurons

(e.g., in putamen and globus pallidus) show activity during orofacial movements

such as chewing, and many of these neurons may receive orofacial sensory

inputs. The importance of these structures to orofacial motor control is underscored

by pharmacological studies. For example, there is evidence that abnormal motor

functions, such as those seen in oral dyskinesia and sleep bruxism, may be partly

due to an imbalance in dopamine (by drugs that alter dopamine actions, such as

amphetamines and cocaine) that changes basal ganglia functional activity. As in the

subcortical processes involved in limb motor control, several other neurochemicals,

subcortical structures, and interconnecting circuits are involved in orofacial motor

control. They include acetylcholine, GABA, glutamine, serotonin, vasopressin, catecholamines,

and opioids. Brain structures include the hypothalamus, amygdala,

subthalamic nucleus, red nucleus, anterior pretectal nucleus, superior colliculus,

periaqueductal grey, and cerebellum.

7.4.5 Cerebral Cortical Processes

Several areas in the cerebral cortex exert descending in fl uences on brainstem and

other subcortical regions. Studies utilizing transcranial magnetic stimulation (TMS)

or imaging (e.g., fMRI, PET) in humans have revealed that movements involving

the masticatory muscles may be associated with activation of several cortical areas,

including the face primary motor cortex (face MI), face primary somatosensory area

(face SI), premotor cortex, SMA, CMA, anterior cingulate gyrus and insula (Martin

2009 ; Avivi-Arber et al. 2011b ) . Different cortical areas and different patterns of

activation are associated with different types of movements (e.g., chewing vs.


Fig. 7.3 An example of a face MI neuron that fi red rhythmically during the jaw-opening phase of

chewing by an awake monkey. ( a ) Neuron’s activity in relation to a single masticatory trial. ( b )

Neuron’s activity in relation to 11 masticatory trials aligned to the point of maximum jaw closing

( vertical line in the fi gure) during the food-preparatory phase. The traces showing movements of the

mandible and the EMG activity of the masseter, genioglossus, and anterior digastric muscles are

derived from averaged data. ( c ) A neuron’s phasic activity in relation to 33 rhythmic chewing cycles

aligned to the point of maximum jaw opening ( vertical line in the fi gure) during the rhythmic-chewing

phase, but shown in prolonged time scale. ( d ) Neuron’s swallow-related activity by aligning seven

chewing trials to the point of the GG-de fi ned swallow onset (the vertical line shown in ( d )). Inset :

the orofacial mechanoreceptive fi eld of the neuron and the tongue movement direction ( arrow )

evoked by ICMS (threshold T for movement, 30 m A) applied at the neuronal recording (adapted

from Yao et al. 2002 ). (Reprinted with permission from The American Physiological Society)

swallowing vs. clenching or tapping the teeth together), in part re fl ecting whether the

movement does or does not involve evoked sensory inputs that project to and activate

the cortical area(s). Intracortical microstimulation (ICMS) and neural recording

studies in monkeys and subprimates (e.g., rats) have revealed consistent fi ndings

(Murray et al. 2001 ; Yao et al. 2002 ; Avivi-Arber et al. 2010 ; Figs. 7.3 and 7.4 ).

Thus, ICMS can evoke speci fi c movements from speci fi c cortical sites, and the


123

Fig. 7.4 ( a, b ) Surface views of the cortical sites from which jaw and tongue muscle activities

were evoked by ICMS (60 m A) at AP planes 2.5, 3.0, 3.5 and 4.0 mm anterior to bregma and within

the left cortex of a rat that 1 week earlier had its incisor extracted and a rat that 1 week earlier had

undergone sham extraction. Scale bar = 1 mm. ( c ) Number of sites from which ICMS (60 m A)

within the left and right face MI and face SI could evoke EMG activity in the left and right anterior

digastric muscles. The left and right anterior digastric muscles had a signi fi cantly larger number of

ICMS sites within the contralateral face MI (ANOVA, Bonferroni: P < 0.0001). Within the left face

MI, the number of right anterior digastric sites was signi fi cantly larger in rats of the extraction

group than in rats of the sham-extraction and naive groups (*ANOVA: P < 0.0004, Bonferroni:

P < 0.0015 and 0.0016, respectively) ( AP anterior-posterior; LAD left anterior digastric; RAD right

anterior digastric; MI primary motor cortex; R right face MI; L left face MI; ICMS intracortical

microstimulation) (adapted from Avivi-Arber et al. 2010 ). (Reprinted with permission from John

Wiley and Sons)

pattern of some of these evoked movements, for example mastication, may vary

between sites. Furthermore, the ICMS studies have demonstrated that each orofacial

muscle or movement is represented multiple times within face MI, indicating


that each output zone of face MI controls one of the many contextual functions in

which a muscle participates. This multiple representation includes ipsilateral and/or

contralateral elemental movements, for example jaw-opening, tongue protrusion, or

facial twitch, as well as complex activities such as chewing and swallowing which

can be evoked by ICMS not only from the deep and principal parts of the classical

CMA, lateral to face MI, but also from within face MI and even within the face SI

in the monkey, rabbit, and cat. Furthermore, selective cold block or ablation of each

of these regions can disrupt chewing and swallowing to varying degrees, indicating

that each may be involved differentially in the production and patterning of chewing

and swallowing. This includes the coordination of the tongue, facial, and jaw movements

that is necessary for the proper ingestion and transport of food or liquid

(Hiraba et al. 1997, 2007 ; Murray et al. 2001 ; Lund et al. 2009 ; Sessle 2009 ) .

It is also noteworthy that ICMS-evoked orofacial movements have been observed

for the SMA, an area which, like premotor cortex, has been implicated in the preparation

for movement. However, little information is available on the role of this region

in orofacial motor control except for recent studies indicating that premotor cortex as

well as other cortical areas (e.g., parietal cortex) may be involved in the preparation

and planning for ingestion, visuomotor control, and perhaps even in cognitive functions

related to the understanding and communication of ingestive motor actions,

facial recognition, and other complex behaviors involving the orofacial region.

Ablation or cold block of the monkey’s face MI or SI also disrupts the animal’s

ability to perform a learned tongue task (Murray et al. 2001 ; Sessle et al. 2007 ; Avivi-

Arber et al. 2011b ) and lesioning of the cat’s SI, MI or masticatory cortex disrupts

masticatory movements (Hiraba and Sato 2005a, b ) . Interestingly, face MI or SI ablation

or block causes much less disruption of a biting task. This is consistent with

ICMS fi ndings and single neuron recordings showing a very limited representation

of jaw closing in face MI. Single neuron recordings in monkeys or subprimates also

have revealed that many face MI and SI neurons discharge in relation to chewing or

swallowing (e.g., Fig. 7.3 ). However, most also discharge in association with more

elemental movements, with some being active in relation to jaw movements, especially

jaw opening, and many others being active in relation to tongue movements.

These fi ndings are consistent with the above ICMS fi ndings. Although single neuron

recordings in face MI also have revealed that some neurons are active during preparation

for movement, many more neurons in premotor areas appear to show this

feature. This is consistent with other studies that have placed more emphasis on

cortical and subcortical regions in addition to MI in mechanisms involved in

motor planning and preparation (Murray et al. 2001 ; Sessle et al. 2007 ; Avivi-Arber

et al. 2011b ) .

The neuronal recording and ablation fi ndings outlined above have underscored

the importance of the somatosensory cortex as well as the motor cortex in the fi ne

motor control of orofacial movements. The face SI can in fl uence orofacial movements

by its projections to face MI and other cortical areas and to subcortical regions

such as the VBSNC, NTS, reticular formation, and the cranial nerve motor nuclei

(Murray et al. 2001 ; Sessle et al. 2007 ; Avivi-Arber et al. 2011b ) . The face SI has a

somatotopically arranged array of somatosensory inputs which are predominantly


125

from facial skin and intraoral structures but may also include some inputs from deep

tissues, such as muscles. The face MI and CMA also receive somatosensory inputs.

While limb MI neurons receive inputs primarily from deep tissues, face MI neurons

receive inputs especially from super fi cial tissues of the face, mouth, and jaws, such

as skin, mucosa, and teeth (Hatanaka et al. 2005 ; Henry and Catania 2006 ; Kaas

et al. 2006 ; Iyengar et al. 2007 ) . Although most face MI neurons receive somatosensory

inputs from the same orofacial areas within which movement is evoked by

ICMS applied to the same neuronal recording site receiving the somatosensory

inputs, a substantial number of face MI neurons receive somatosensory inputs from

distant orofacial regions that have no close spatial relation with the ICMS-evoked

movement area. In addition, a well-described feature of neurons not only in face SI,

but also face MI and CMA, is that these neurons receive bilateral inputs from the

orofacial tissues. This organization of somatosensory inputs to face MI is probably

related to the need for extensive somatosensory feedback from wide bilateral peripheral

orofacial areas for the fi ne control, coordination, and modulation of the bilateral

orofacial muscle activities during orofacial movements (Murray et al. 2001 ) . These

bilateral inputs may be used by CMA, for example, to help guide masticatoryrelated

movements. Face MI may also utilize its orofacial afferent inputs for generating

and regulating orofacial movements in order to re fi ne ongoing cortical motor

activity and shape the appropriate motor response. For example, this is seen in the

control of voluntary orofacial movements such as the manipulation of the food

bolus after it is placed in the mouth, since many face MI neurons are active during

the food preparatory phase. Sensory inputs from the orofacial regions presumably

are utilized by these MI neurons for this purpose. Pain may also in fl uence masticatory

muscle function by actions on the sensorimotor cortex as will be discussed in

the following section.

Face MI and SI rely on orofacial afferent inputs to guide, correct, and control

movement by the use of sensory cues prior to movement and by using sensory

information generated during movement. These processes may involve intracortical

processing, cortical gating, and transfer of somatosensory information, as well as

corticofugal projections to subcortical sites that modulate and select somatosensory

information ascending through subcortical relay neurons in the brainstem, such as

VBSNC, NTS, and thalamus. These inputs also play critical roles in motor learning

and in the motor adjustments or adaptations that take place after a change in the

peripheral environment. This brings us to a consideration of neuroplasticity, especially

as it applies to the cortical mechanisms of orofacial motor control.

7.5 Cortical Neuroplasticity and Control

of Masticatory Muscles

Neuroplasticity is the capacity of the nervous system in general to alter its structure

(e.g., synaptogenesis, dendritic branching) and function (e.g., excitability, longterm

depression or potentiation) throughout life (Ebner 2005 ; Barnes and Finnerty


2010 ; Plowman et al. 2010 ) . Neuroplasticity induced by altered afferent inputs has

been well documented in the VBSNC in relation to the central processing of tactile

and nociceptive information from the orofacial region (Sessle 2006 ) . Numerous

studies also have shown that both SI and MI undergo neuroplastic changes following

manipulations of afferent inputs or in association with learning of novel motor

skills. While nearly all these studies have focused on SI and MI representing the

limbs and the facial vibrissae in rodents, as well as subcortical regions such as the

basal ganglia and thalamus, there is some recent evidence that comparable neuroplastic

changes may occur in face SI and face MI representing the oral tissues

(Avivi-Arber et al. 2010, 2011b ) . For example, dental extraction can lead to a loss

of dental representation and an enhanced representation of adjacent orofacial structures

within face SI of the mole rat (Henry et al. 2005 ) . Alteration of the dental

occlusion by trimming or extraction can be associated with modi fi cations of the jaw

and tongue motor representation within face MI and face SI (Fig. 7.4 ) (Sessle et al.

2007 ; Avivi-Arber et al. 2010, 2011a ) . Lingual nerve transection has been associated

with a signi fi cantly decreased MI representation of tongue protrusion after 1–2

weeks, and after 3–4 weeks with a signi fi cantly increased tongue-protrusion representation

(Adachi et al. 2007 ) . Noteworthy is that extraction of a rat mandibular

incisor results in an increased representation of jaw-opening muscle along with

increased overlapping representations of the jaw-opening and tongue-protrusive

muscles within face MI and face SI (Fig. 7.4 ) (Avivi-Arber et al. 2010 ) . An increased

overlapping of motor representations within the limb MI is one of the most consistent

fi ndings associated with limb motor skill training, and is considered crucial for

coordinating movements involved in the acquisition of novel limb motor skills (see

Nudo et al. 1996 ) . Modi fi cation to the dental occlusion in humans and rodents

induced by dental extraction or trimming affects muscle activities and patterns of

jaw movements during mastication (Hannam et al. 1977 ; Miehe et al. 1999 ) . In

addition, adaptation to an altered pattern of mastication would require repetition of

novel motor movements somewhat analogous to learning a novel motor skill. Thus,

it is possible that the reorganization of motor representations within face MI and

face SI, including co-activation of jaw and tongue muscles, plays a role in motor

adaptation to an altered oral state.

Indeed, recent studies in monkeys and humans suggest a role for face MI neuroplasticity

in orofacial motor skill acquisition. In rats, tongue force training has been

associated with decreased thresholds of ICMS-evoked tongue motor response but

with no signi fi cant change in the tongue motor representation within face MI

(Guggenmos et al. 2009 ) . In awake monkeys, training in a novel tongue-protrusion

task results in a signi fi cantly increased proportion of ICMS sites representing tongueprotrusion

movement, a decreased proportion of ICMS sites representing lateral

tongue movement, and signi fi cantly increased proportions of neurons in MI and SI

showing tongue protrusion-related activity and lingual mechanosensory inputs

(Sessle et al. 2007 ) . It is interesting to note that analogous changes were not apparent

in the CMA/swallow cortical areas, suggesting a differential expression of taskrelated

neuroplasticity within different cortical areas that are involved in the control

of orofacial motor functions. Analogous studies in humans using TMS have shown


127

that training in a novel tongue-protrusion task results in a signi fi cantly improved

successful task performance in 1 week, but even as quickly as within 15 min. This

has been associated with a signi fi cantly increased tongue motor representation and/

or decreased threshold of TMS-evoked tongue responses within the face MI

(Svensson et al. 2006 ; Boudreau et al. 2007 ; Zhang et al. 2010 ) . While tongue MI

changes may re fl ect changes in motor experience consistent with the concept of

“use-dependent neuroplasticity” (Nudo et al. 1996 ) , the close correlation between

successful tongue task performance and the rapid onset of tongue MI neuroplasticity

suggests that the tongue MI changes are necessary for achieving the improved

motor performance of the learned novel task consistent with the principle of “use it

and improve it” (Kleim and Jones 2008 ) .

Many dental procedures can be associated with postoperative acute pain that

sometimes develops into a chronic pain condition. Clinical practice indicates that

pain conditions can modify patients’ orofacial motor behaviors and jeopardize their

motor performance (Svensson et al. 2004 ; Sessle 2006, 2010 ; Sessle et al. 2008 ) .

While acute pain is commonly known to evoke protective brainstem re fl ex circuits,

intraoral pain induced by injection of the algesic glutamate into the tongue in rats

and application of capsaicin to the tongue in healthy humans has been associated

with decreased face MI excitability (Boudreau et al. 2007 ; Adachi et al. 2008 ) , consistent

with the “Pain Adaptation Model,” whereby decreased face MI excitability

and limitation of movements serve as a protective mechanism of the orofacial tissues/muscles

(Lund et al. 1991 ; Murray and Peck 2007 ) . Chronic pain conditions,

such as TMD in humans, have been associated with face SI and face MI neuroplasticity

(Moayedi et al. 2011 ; Weissman-Fogel et al. 2011 ) . However, it is not clear

whether the cortical changes predispose subjects to develop chronic pain or whether

they are adaptive, or maladaptive, responses to the pain condition. Neuroplasticity

within SI and MI also is associated with behavioral maladaptation and sensorimotor

dysfunctions such as embouchure dystonia in woodwind and brass musicians, or

dysphagia, dysarthria, or impaired mastication following CNS injuries such as stroke

(Sessle et al. 2007 ; Martin 2009 ; Haslinger et al. 2010 ) .

7.6 Conclusions

In summary, the fi ndings reviewed in this chapter underscore the crucial role played

by face sensorimotor cortex in sensorimotor integration and control of the masticatory

muscles and its remarkable capacity for neuroplasticity. Neurophysiological

changes occur within the face SI and face MI when the oral environment is altered,

and raise the possibility that such cortical changes re fl ect adaptive mechanisms that

may be crucial in determining how well a person adapts to oral alterations, such as

dentures, implants, pain, and/or nerve damage. Yet, the cortical plasticity also may

re fl ect changes that can lead to the susceptibility of healthy subjects to develop a

variety of chronic sensorimotor dysfunctional conditions. They also suggest that

there may be cortical templates for a variety of familiar, learned orofacial motor


activities. Speech is one such activity involving the masticatory muscles. While its

consideration is beyond the scope of this chapter, cortical mechanisms are clearly

crucial to the fi ne control and coordination of the various muscles, including masticatory

muscles, participating in voice production and articulation of speech sounds,

both when a child is learning to speak and once speech has been learned. In addition,

since alteration in somatosensory inputs to the CNS has been associated with

neuroplasticity within other cortical and subcortical regions (e.g., brainstem)

involved in the control of masticatory muscles (Kis et al. 2004 ; Sessle 2006 ) , it is

possible that some of the neuroplastic changes observed within face MI and face SI

are secondary to changes manifested within the other cortical or subcortical

regions.

Acknowledgements Studies of the authors were supported by: grant DE04786 of the US National

Institute of Dental and Craniofacial Research; CIHR grant MT-4918, the Australian Dental

Research Foundation, Inc.; and NHMRC of Australia , grant #512309. BJS is the recipient of a

Canada Research Chair.

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Chapter 8

Masticatory Muscle Response to Neuromuscular

Diseases and Speci fi c Pathologies

Sadie L. Hebert , Christy L. Willoughby , Francisco H. Andrade ,

and Linda K. McLoon

8.1 Introduction

The masticatory muscles are a complex bilateral set of four muscles (masseter,

temporalis, medial and lateral pterygoid muscles) that control movement of the

temporomandibular joint, between the maxillae and the only moveable bone in the

human skull, the mandible. These muscles are capable of fi ne-tuned gradients of

force and movement, as they are required for production of large forces often needed

in crushing of hard food items, and fi ner movements needed for chewing and human

speech production. As with other craniofacial muscles, the masticatory muscles

have unique phenotypes distinct from limb muscle due to their specialized function

and unique developmental origin. Their characteristics include small myo fi ber

cross-sectional area, fi ber-type speci fi c grouping (Eriksson and Thornell 1983 ) , and

a wide range of myosins that allow for a spectrum of force and contraction speeds

(Stål et al. 1994 ; Korfage et al. 2000 ) .

The masticatory muscles’ distinct development makes them susceptible to a host

of developmental anomalies. In contrast with other craniofacial muscles such as the

extraocular muscles and laryngeal muscles, the masticatory muscles are not as

robustly spared in many skeletal muscle diseases, with relatively complete sparing in

only two conditions that have thus far been reported: spinocerebellar ataxia (SCA)

S.L. Hebert , Ph.D. (*) • C.L. Willoughby

Departments of Ophthalmology and Neuroscience , University of Minnesota,


e-mail: sjhebert@umn.edu


Department of Physiology , University of Kentucky , 800 Rose Street ,

Lexington , KY 40536-0298 , USA


L.K. McLoon, Ph.D.

Department of Ophthalmology, University of Minnesota, 2001 6th Street SE,

Minneapolis, MN 55455, USA




131

132 S.L. Hebert et al.

type 3 and critical illness myopathy. However, these muscles do not seem as resistant

to pathology as other craniofacial muscles, such as Duchenne muscular dystrophy

(DMD) or amyotrophic lateral sclerosis (ALS). They are also vulnerable to functionspeci

fi c pathology. The high forces and impact produced during chewing make the

masticatory muscles prone to pathology related to these high stresses and impact.

Further, masticatory muscles are adaptable, and so their phenotype and pathology is

in fl uenced by external factors such as stress, dentition, and diet, as well as to changes

in temporomandibular joint and respiratory function.

8.2 Developmental Anomalies

The masticatory muscles develop from cranial mesoderm of the fi rst pharyngeal

arch. The core of each pharyngeal arch is comprised of mesodermal and neural crest

cells. Proper development of the masticatory muscles is dependent on the speci fi c

migration and interaction between these two cell types. Syndromes of the fi rst pharyngeal

arch are typically caused by either improper migration or development of

mesodermal or cranial neural crest cells (Kapur et al. 2008 ; Passos-Bueno et al.

2009 ; Heude et al. 2011 ; Johnson et al. 2011 ) .

Hemifacial microsomia, a syndrome of the fi rst pharyngeal arch, encompasses a

wide variety of phenotypes including defects of the masticatory muscles, jaw, external

ear, as well as microphthalmia. As a result, this syndrome is also referred to by

a multitude of names—Goldenhar–Gorlin syndrome, fi rst arch syndrome, lateral

facial dysplasia, unilateral craniofacial microsomia, otomandibular dysostosis,

oculoauriculovertebral dysplasia, auriculo-branchiogenic dysplasia, and oculoauriculovertebral

spectrum. Patients with hemifacial microsomia may display defects

on one or both sides of the face.

The defects of the masticatory muscles differ widely across patients with hemifacial

microsomia. The affected side(s) of the face in these patients can exhibit reduced

size or complete absence of the masticatory muscles. Typically, the masseter, temporalis,

and medial and lateral pterygoids are hypoplastic and show reduced activity on

the affected side(s) though in some cases the masseter and temporalis are completely

absent (Moss and James 1984 ; Kapur et al. 2008 ; Heude et al. 2011 ) . While the exact

cause of hemifacial microsomia is not currently known, it has been hypothesized to

be due to a defect in the cranial neural crest cells (Heude et al. 2011 ) .

8.3 Sparing in Skeletal Muscle Disease

The masticatory muscles are completely spared in very few skeletal muscle diseases.

Masseter function is spared in some forms of SCA, but not in others. Patients with

SCA type 3 display a bilaterally normal masseter re fl ex response, while patients

with SCA type 2 have an abnormal masseter re fl ex (Garcia et al. 2009 ; Alvarez-

Paradelo et al. 2011 ) . The preferential sparing of masseter in certain subtypes of

8 Masticatory Muscle Response to Neuromuscular Diseases and Speci fi c Pathologies

133

SCA indicates that masseter re fl ex could be a useful diagnostic tool in distinguishing

between different subtypes of SCA.

Most cranial skeletal muscles are also spared or less affected in critical illness

myopathy—an acute acquired myopathy in critically ill patients (Larsson 2008 ) . The

limb and trunk muscles become extremely weak and undergo atrophy in critical illness

myopathy, and 80% of the patients who develop this condition can display persistent

quadriplegia and generalized weakness after a month-long ICU stay. Masseter,

along with other craniofacial muscles, is functionally and morphologically spared

(Aare et al. 2011 ) . While the mechanism is unknown, the difference between the

retention of normal morphology and function in masseter muscle compared to the

signi fi cant decrease in muscle size and function limb muscle is quite striking.

Sparing of masticatory muscles in DMD and ALS presents a more complex picture,

in contrast to the clearly demonstrable sparing in the extraocular and laryngeal

muscles. In ALS with primary lower motor neuron involvement, an electromyographic

(EMG) study showed that a relatively high percentage of patients showed

evidence of “motor unit potential (MUP) reinnervation” in their masseter muscles—

despite no clinical evidence of involvement (Preston et al. 1997 ) . However, it was

also noted that evidence for active denervation in the masseter was seen only in a

few patients, while this was relatively common in the tongue muscles examined.

A similar story is seen in the analysis of masticatory muscles in DMD patients (see

below). It appears that in the continuum of muscle phenotypes, the masticatory

muscles are closer to the extraocular and laryngeal muscles than to limb muscles in

their morphologic and functional sparing in these two diseases, but they are not

completely and unequivocally spared from signs of degenerative changes.

8.4 Masticatory Muscle Speci fi c Diseases/Conditions

8.4.1 Primary Pathology

The masticatory muscles as a group are susceptible to a greater number of skeletal

muscle diseases than extraocular or laryngeal muscles. The disease pro fi le of these

muscles in DMD is illustrative of these differences. During the disease course of

DMD, both masseter and temporalis muscles show evidence of pathological

changes, with increased numbers of myo fi bers with centralized nuclei and some

increased fi brosis, although not as signi fi cant as that seen in limb muscles (Spassov

et al. 2010 ) . Other studies have shown that compared to diaphragm or limb skeletal

muscle, the pathological changes in masseter are more limited (Muller et al. 2001 ) .

In human DMD patients, however, it is clear that as the disease progresses there is

a signi fi cant loss in masticatory muscle force with resultant changes in orofacial

anatomy and function (Kiliaridis and Katsaros 1998 ; Botteron et al. 2009 ) .

Other diseases of limb skeletal muscle directly involve the masticatory muscles

in the early stages of the disease. While the initial phase of myasthenia gravisinduced

muscle weakness occurs in the extraocular muscles, the masticatory muscles

show an early involvement in the course of the disease (Yarom et al. 2005 ) .


This early development of weakness, particularly in jaw-closing muscles, can be

diagnostic of the presence of myasthenia gravis in human patients (Pal and Sanyal

2011 ) . Comparative weakness in the strength of jaw-opening muscles was seen to

correlate with patients suffering from myositis (Pal and Sanyal 2011 ) . These observations

suggest that examination of masticatory muscle force changes could aid in

the diagnosis of muscle pathologic processes in many patients. Patients with bulbar

myasthenia gravis (characterized by weakness of craniofacial muscles innervated

by the lower brainstem) have poor masticatory performance (Weijnen et al. 2002 ) .

Some patients with severe myasthenia gravis have to manually assist the lower jaws

during meals and may have signi fi cant weight loss.

A recent study examined orofacial function in Parkinson’s disease patients, and

these patients all were seen to have impaired mastication and jaw-opening strength,

and these impairments worsened with disease progression (Bakke et al. 2011 ) .

While other examples of disease involvement may exist, few studies examining the

speci fi c involvement of the muscles of mastication have been performed.

8.4.2 Conditions Secondary to Other Craniofacial

and Systemic Problems

As discussed by Sessle et al. (see Chap. 7 ), the masticatory muscles generate high

forces during chewing, imposing mechanical stress on the teeth, and the maxillary

and mandibular bones, including the temporomandibular joint. In addition, diet,

stress, and other external factors can cause signi fi cant alterations in the masticatory

muscles. Masticatory muscle pain is a rather common symptom resulting from

systemic and local muscle disorders, both neurovascular (e.g., migraines) and neuropathic

(e.g., trigeminal neuralgias), and typically is accompanied by other symptoms

such as fatigability, stiffness, and weakness (Benoliel and Sharav 2010 ) . One

common cause is bruxism , a condition characterized by involuntary grinding or

clenching of teeth. When it occurs at night, it is called sleep bruxism, and it is considered

a sleep disorder. If bruxism is frequent and severe enough, it causes headache,

localized masticatory muscle tenderness, temporomandibular pain, and

damaged teeth (Manfredini and Lobbezoo 2010 ) . On the other hand, trismus is the

inability to fully open the mouth because of mechanical impediments (such as

temporomandibular joint damage or in fl ammation, or mandibular abscesses), drug

use, infections (tetanus is a classical example), or masticatory muscle diseases.

Oromandibular dystonia may cause painful bruxism and trismus; as with other focal

dystonias, it can be treated by botulinum toxin injections (Bhidayasiri et al. 2006 ) .

8.4.3 Aging

As a group, craniofacial muscles are spared in aging as compared to limb muscle.

The extent to which masticatory muscles alter as they age is understudied, and


135

analysis is complicated by confounding factors in an aging population, including

decreased nutrition and altered hormones, and aging of joints and teeth (Hatch et al.

2001 ) . Studies suggest that masticatory muscles undergo changes in myosin composition

and synapse remodeling, but the extent to which this impacts the functioning

of the muscles themselves is unclear.

The masticatory muscles have anatomically distinct regions, and age-related

changes are often region-speci fi c. The super fi cial and posterior regions of masticatory

muscles are primarily composed of fast myo fi bers in order to generate the

quick force needed when biting. The deep anterior aspects of the muscles contain

more slow-type motor units, which likely allow for fi ne control of muscle force for

chewing and biting behaviors. In the aging masticatory muscles, pronounced phenotypical

changes occur which includes changes in fi ber type and myosin heavy

chain (MyHC) isoform composition. These changes are muscle and region speci fi c.

The masseter muscle has a large number of slow myo fi bers containing MyHC type 1.

With aging, myo fi bers expressing the fast MyHC isoforms increase in number with

a proportionate loss of myo fi bers expressing the slow MyHC isoform. This is interesting

and contrasts with aging limb muscle, e.g., the biceps brachii, which shows a

shift towards a slower phenotype with aging (Monemi et al. 1999a, b ) . Further, aged

masseter muscle increases the expression of fetal MyHC and hybrid fi bers which

co-express more than one MyHC isoform (Monemi et al. 1996, 1999a ) . In the pterygoids,

a similar trend occurs. The pterygoids do not have many fi bers that are solely

fast and express MyHC type IIA, but the number increases signi fi cantly in aging

muscle (Monemi et al. 2000 ) . In addition to changes in MyHC isoform expression,

cross-sectional area of the masticatory muscles may also decrease with aging

(Newton et al. 1987 ; Monemi et al. 1999b ) . It is unknown if the changes in MyHC

isoform content are due to re-innervation by other motor neurons or due to changes

in the activity pattern of the original innervating motor neurons.

Animal studies have suggested that changes may occur in the innervation itself.

The nerve innervating the masseter in aged cats has decreased axon diameters and

disrupted myelin, which corresponds to a decreased velocity of action potentials

(Chase et al. 1992 ) . Aged mice also show decreased axon diameter and nerve terminal

areas (Elkerdany and Fahim 1993 ) . Speci fi c changes are seen in the neuromuscular

junctions of aged mice, including nerve terminal area, perimeter, and length

decreases, while branching of the nerve increases. These changes suggest increased

degeneration and regeneration of the nerve terminals in aging masticatory muscles

in these rodents.

How the potential changes in nerve and myo fi ber phenotype potentially correlate

with changes in use of the masticatory muscles with aging is unclear. Many studies

have demonstrated that elderly adults do not lose masticatory function with age

(Hatch et al. 2001 ) and maintain adaptability of their muscles (Peyron et al. 2004 ) .

Bite force decreases with aging (Bakke et al. 1990 ; Hatch et al. 2001 ) , but could be

due to other components of the masticatory system. The literature is mixed on this

issue. For example, EMG activity changes in aged masticatory muscles. The transition

from adult to elderly may show no (Peyron et al. 2004 ) or only a slight effect in

masticatory muscle EMG values (Cecílio et al. 2010 ) . Other studies have shown


that EMG values in the masseter and temporalis may be lower in the elderly only

while chewing hard but not soft foods (Galo et al. 2007 ) . When the contraction

characteristics of the aged anterior deep masseter muscle from aged rats were

directly assessed in vitro, no change in muscle weight nor optimal length for contraction

was seen (Norton et al. 2001 ) . Additionally, they found no change in isometric

tetanic tension, contraction time, half-relaxation time, and twitch-to-tetanus

ratio. In comparison with the EMG data, this suggests that the masseter muscle may

retain robust function, and that EMG recordings may be complicated by the variance

in the human population and other components of the masticatory system.

Further studies are needed to investigate the extent aging in fl uences the properties

of the masticatory muscles, as only a few labs utilize animal models to investigate

potential mechanisms for aging related changes. Further research is needed to

clarify how aging may alter the properties of masticatory muscles, as well as delineate

how other components of aging in fl uence the muscles’ performance. Such

research could allow the development of new approaches to improve masticatory

function in aging populations.

8.5 Conclusions

As is clear from these studies, the masticatory muscles represent a unique set of

skeletal muscles. Their pattern of susceptibility or sparing in skeletal muscle

pathology is distinct from trunk and limb muscles, which may be due to their separate

developmental origin and their unique phenotype and physiological role.

Pathology and treatment in other muscle groups cannot necessarily be generalized

to the masticatory muscles because of these phenotypic differences in function.

Continued study of diseases that might spare or involve the masticatory muscles is

essential to both enrich our general knowledge of skeletal muscle physiology, as

well as allow the maintenance of patient masticatory function in both disease and

aging in the future.

Acknowledgements Supported by grants T32DE007288 from NIDCR (SLH) and T32 AR007612

from NIAMSD (CLW).

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Part V

Laryngeal and Pharyngeal Muscles

Chapter 9

Structure and Function of the Laryngeal

and Pharyngeal Muscles

Lisa A. Vinney and Nadine P. Connor

The muscles of the pharynx and larynx subserve critical airway, deglutitive and

communication functions. The laryngeal muscles protect the lower airway from

invasion and allow voice production for the purposes of communication. The muscles

of the pharynx serve deglutitive functions by creating appropriate pressures to

receive and propel a bolus and to shape the airway to modulate resonance during

voice and speech production. Thus, the laryngeal and pharyngeal muscles are critically

important to survival and to communication. The structure and function of

these muscles are summarized in Table 9.1 . A subset of these muscles will be discussed

in this chapter as related to voice, swallowing, and airway functions.

Laryngeal and pharyngeal skeletal muscles, albeit similar at a conceptual level to

skeletal muscles found elsewhere in the body, have important structural and functional

differences that will be described in this chapter. For example, there is evidence

that some of the muscles listed in Table 9.1 may be structured to offer

biologically important, hard-wired neuromuscular redundancies, such as low innervation

ratios and multiple innervations to provide a stable foundation for the critical

life-sustaining functions they subserve (Feinstein et al. 1955 ; Faaborg-Andersen

1957 ; Palmer 1989 ; Perie et al. 1997 ) . The large body of knowledge found in the

literature concerning skeletal muscles in the limbs will not provide a speci fi c understanding

of the muscles of the pharynx and larynx. Unfortunately, laryngeal and

pharyngeal muscles have been relatively understudied until recently compared with

other muscles. Although there are glaring gaps in knowledge related to laryngeal

and pharyngeal muscles, currently available information points to their unique characteristics

especially regarding muscle fi ber type, innervation, distribution of neuromuscular

junctions (NMJs), and mitochondrial density. Thus, this chapter will

integrate the established information regarding the unique structure and function of

these muscle systems.

L. A. Vinney , M.S. • N. P. Connor , Ph.D. (*)

Departments of Communicative Disorders and Surgery , University of Wisconsin-Madison ,

600 Highland Avenue K4/711 , Madison , WI 53792 , USA

e-mail: connor@surgery.wisc.edu




141

142 L.A. Vinney and N.P. Connor

Table 9.1 Muscles of the larynx and pharynx

Muscles

Function

Larynx (extrinsic)

Suprahyoid muscles ( above hyoid bone )

Digastric (anterior and posterior bellies)

Stylohyoid

Geniohyoid

Infrahyoid muscles ( below hyoid bone )

Thyrohyoid

Sternohyoid

Omohyoid (inferior and anterior bellies)

Sternothyroid

Larynx (intrinsic)

Thyroarytenoid

Lateral cricoarytenoid

Posterior cricoarytenoid

Interarytenoids (transverse and oblique)

Cricothyroid

Pharynx

Superior constrictor

Middle constrictor

Inferior constrictor

Mylohyoid

Raises hyoid bone and pulls anteriorly or posteriorly;

assists in depressing lower jaw when hyoid

is fi xed

Elevates hyoid bone and base of tongue

Elevates tongue and hyoid; draws both forward

when mandible is fi xed

Elevates larynx by decreasing distance between

thyroid cartilage and hyoid bone via depression

of hyoid or elevation of thyroid

Depresses hyoid

Depresses and pulls back on hyoid

Draws thyroid cartilage downward; may increase

pharyngeal size by drawing larynx down/

forward

Relaxes vocal folds and assists in glottic closure

when unopposed; will increase vocal fold

tension when opposed by other intrinsic muscles

Rotates muscular processes of arytenoids forward

and inward to adduct membranous portion of

vocal folds

Abducts vocal folds by pulling muscular processes

of the arytenoids posterolaterally

Adduct cartilaginous portion of vocal folds by

drawing arytenoids together

Increases distance from thyroid cartilage and vocal

processes of arytenoids to elongate and increase

longitudinal tension of vocal folds; generally

results in increased vocal pitch

Narrows pharyngeal cavity by anterior movement

of posterior pharyngeal wall and anterior and

inward movement of lateral pharyngeal wall;

sometimes thought of as a cluster of four

individual muscles including pterygopharyngeus,

buccopharyngeus, mylopharyngeus, and

glossopharyngeus

Narrows pharyngeal cavity by anterior movement

of posterior pharyngeal wall and anterior and

inward movement of lateral pharyngeal wall

Narrows lower pharynx by anterior movement of

lower posterior pharyngeal wall and anterior and

inward movement of lateral pharyngeal wall;

contains thyropharyngeus and cricopharyngeus

Elevates hyoid and pulls it forward

(continued)

9 Structure and Function of the Laryngeal and Pharyngeal Muscles

143

Table 9.1 (continued)

Muscles

Cricopharyngeus

Thyropharyngeus

Levator veli palatini

Tensor veli palatine

Stylopharyngeus

Palatopharyngeus

Salpingopharyngeus

Function

Relaxes to allow esophageal opening and transfer of

food or liquid from hypopharynx to esophagus

Serves to propel food bolus downward during

swallowing

Elevates/retracts soft palate in order to seal off

nasopharynx from oropharynx; prevents nasal

regurgitation

Tenses/raises soft palate in order to seal off

nasopharynx from oropharynx; prevents nasal

regurgitation; assists in opening Eustachian tube

during swallowing and yawning

Elevates larynx; pulls pharyngeal wall laterally

resulting in widening of pharyngeal lumen

Pulls lateral pharyngeal wall up and in to narrow

and elevate pharynx; shuts off nasopharynx

Decreases pharyngeal width by elevating and

pulling lateral wall of pharynx posteriorly

9.1 Intrinsic Muscles of the Larynx

The intrinsic laryngeal muscles are vital to airway protection, breathing, and phonation.

These muscles can be classi fi ed by function into the adductor muscles and one

abductor (see Table 9.1 ). Each intrinsic muscle has speci fi c functional properties

that allow it to produce the necessary laryngeal movements to serve airway and

phonatory functions. The intrinsic laryngeal muscles work in concert and display

speci fi c movement patterns to allow for phonatory function, airway protection during

deglutition, and appropriate breathing patterns during both sleep and wakefulness.

9.1.1 Role of Intrinsic Laryngeal Muscles in Phonation

The intrinsic muscles of the larynx produce highly precise movements for phonation,

breathing, and airway protection. The intrinsic laryngeal muscles are shown in

Fig. 9.1 in a canine larynx. The adductor muscles consist of the paired thyroarytenoid

muscles (TA), the paired lateral cricoarytenoid (LCA) muscles, the interarytenoid

muscles (IA), and the paired cricothyroid muscles (CT) that serves to elongate the

vocal folds in the elevation of vocal pitch. These muscles are generally rapidly contracting,

but there is some variation in muscle fi ber types across the intrinsic muscles

that is discussed in greater detail below. The posterior cricoarytenoid muscle (PCA)

is an abductor. All of the intrinic muscles of the larynx, with the exception of the

cricothyroid muscle (CT) are innervated by the recurrent laryngeal nerve of the


Fig. 9.1 Posterior view of canine larynx showing interarytenoid (IA) and posterior cricoarytenoid

(PCA) muscles. Cricoid (CrC), thyroid (TC), and arytenoid (Ar) cartilages, aryepiglottic (AryF)

folds, epiglottis, and piriform sinuses (PS) are also shown. Photograph courtesy of Dr. Seth Dailey

vagus, the tenth cranial nerve (CNX). The CT is innervated by the external branch

of the superior laryngeal nerve that also originates from the vagus nerve.

The TA muscle makes up the main muscular component of the vocal folds and

contributes to vocal fold adduction and tension. The TA is found immediately deep

to the vibrating laryngeal mucosa of the vocal folds and makes up the bulk of the

vocal fold. Typical divisions of the TA muscles are into a more medial thyrovocalis

(or simply “vocalis”) muscle and a more lateral thyromuscularis muscle. Other synonymous

nomenclature is medial or lateral thyroarytenoid muscles, respectively.

The TA muscle components attach to the laryngeal cartilages for which they are

named and provide tension within the vocal folds during phonation. This tension

affects vocal pitch and may oppose the action of the CT or complement it. Although

it is generally thought that the TA is innervated by the recurrent laryngeal nerve of

the vagus, additional innervation from the external division of the superior laryngeal

nerve was found in one canine study (Nasri et al. 1997 ) . There appears to be more

study of the TA than other intrinsic laryngeal muscles, perhaps due to its important

role in voicing and ease of identi fi cation. However, relative to the studies of limb

muscles, the number of TA muscle studies is limited. In a Medline search we

conducted for literature containing a major subject heading of “limb muscle”

between the years 1980 and May 2011, we obtained 1,217 citations, whereas a


145

similar Medline search using the terms “thyroaytenoid muscle” for these years

yielded only 285 articles.

The LCA muscle is a vocal fold adductor and contains a large proportion of

rapidly contracting muscle fi bers in rat, canine, and human (Jung et al. 1999 ;

Shiotani et al. 1999a, b ; Suzuki et al. 2002 ; Wu et al. 1998 ) . Thus, the idea that

rapidly contracting fi bers may be necessary for airway protection is supported.

As noted previously, there has not been nearly the study of the LCA as there has

been of the TA (Nagai et al. 2005 ; Sanders et al. 1993 ; Shiotani and Flint 1998a ;

Shiotani et al. 1999a, b ; Jung et al. 1999 ; Suzuki et al. 2002 ; Wu et al. 1998 ) .

The interarytenoid muscle (IA) contributes to the adduction of the vocal folds.

The innervation of the transverse and oblique fi bers of the IA is typically attributed

to the recurrent laryngeal nerve of the vagus. However, its innervations may be distinct

from the other laryngeal adductors in that a study of the human larynx reported

that the IA had motor innervation from the internal branch of the superior laryngeal

nerve (Sanders and Mu 1998 ) .

As the only muscle of abduction, the action of the PCA is to open the vocal folds,

and this action allows for inhalation. It is antagonistic to the TA, LCA, and IA

muscles. Studies have shown that, overall, muscle fi bers within the PCA muscle are

more slowly contracting than other intrinsic muscles of the larynx (Shiotani et al.

1999b ). However, recent research in humans has con fi rmed that the PCA contains

two separate bellies (horizontal and vertical) with distinct histological characteristics

(Asanau et al. 2011 ; Wu et al. 2000 ) . The horizontal belly of the PCA reportedly

consists primarily of slowly contracting fi bers, whereas rapidly and slowly contracting

fi bers are found in similar amounts in the vertical belly (Asanau et al. 2011 ) . The

vertical belly of the PCA may modulate occasional adjustments in laryngeal tension

and stability during swallowing and voicing. On the other hand, the horizontal belly

likely allows for the “permanent rhythmic activity” of the PCA “during the inspiratory

phase of respiration” (Asanau et al. 2011 ) . The faster contracting vertical belly

of the PCA may also allow for swift abduction of the larynx to allow for rapid inhalation

and the reversal of airway hunger.

The properties of the CT muscle allow for precise adjustments in vocal pitch.

When contracted, this muscle pulls downward on the anterior aspect of the thyroid

cartilage and serves to elongate the vocal folds and elevate pitch. There is the greatest

electromyographic (EMG) activity in the CT when producing high pitch phonation,

and little if any CT activity during extreme low-pitched phonation during vocal

fry (Shipp 1975 ) . The term “vocal fry” refers to the perception of a low-pitched,

pulsating or rattling vocal quality that typically occurs below 70 Hz (Titze 1994 ) .

9.1.2 Role of the Intrinsic Laryngeal Muscles in Breathing

and Swallowing

Muscles of the intrinsic larynx are active during breathing; however, the same

intrinsic muscle may exhibit different degrees of rapid or tonic (slow and sustained)


Fig. 9.2 Endoscopic images shown with simultaneous EMG information from one individual’s

10 mL bolus swallow. A arytenoid adduction begins; B total arytenoid adduction; C open glottis

and forward tilt of arytenoid cartilages; D inversion of epiglottis just before whiteout; E just after

whiteout (open glottis); SM submental muscle; CP cricopharyngeus muscle; LP longitudinal

pharyngeal muscle; GG genioglossus muscle; SPC superior pharyngeal constrictor muscle; TA

thyroarytenoid muscle; PCA posterior cricoarytenoid muscle. Used with permission by the fi rst

author and publisher from Van Daele et al. ( 2005 )

muscle contractions depending on whether inspiration or expiration is occurring

(for review, see Woodson 1999 ) . For example, during wakefulness, the PCA is phasically

active on inspiration and tonically active on expiration (Kuna et al. 1990 ) .

The IA and TA muscles, on the other hand, are typically phasically active during

expiration and tonically active during inspiration (Kuna et al. 1988, 1991 ; Kuna and

Insalaco 1990 ) . Thus, vocal fold position during quiet breathing in awake individuals

results from the interaction of muscle antagonists (Kuna et al. 1990 ) .

The activity of the TA muscle during wakefulness is particularly unique.

Speci fi cally, the TA appears to promote a degree of vocal fold adduction during

expiration and its action has been linked to resistance at the lungs and below the

epiglottis during expiration (Kuna et al. 1988 ) . When expiration begins, TA activity

typically increases and then either levels off or gradually increases or decreases

depending on expiratory length. These changes in activation patterns are associated

with amount of expiratory air fl ow and time of expiration. Longer expirations and

less air fl ow occur at the end of the expiratory cycle when TA activations are high

(Kuna et al. 1988 ) . The TA actively in fl uences an increase in expiratory durations

because it increases resistance at the glottis. This action can be thought of as a

“laryngeal braking mechanism” (Kuna et al. 1988 ) .

Intrinsic muscles of the larynx are active during swallowing. As shown in

Fig. 9.2 , combined EMG and endoscopy recordings have indicated that laryngeal


147

closure during deglutition generally patterns itself in the following order: (1) arytenoid

adduction in conjunction with PCA activity ceasing; (2) hyolaryngeal elevation;

(3) decline in cricopharyngeus muscle activity; (4) retraction of the tongue; (5) contraction

and rise of the pharynx; (6) TA activity in conjunction with vocal fold

closure; and (7) suprahyoid muscle activity of the geniohyoid and mylohyoid (Van

Daele et al. 2005 ) . Thus, actual vocal fold closure occurs over 500 ms after arytenoid

closure and, endoscopically, the vocal folds appear to be in a partially open position

just prior to whiteout of the laryngeal image on fi ber optic endoscopic evaluations

of swallowing (Van Daele et al. 2005 ) . Given that the delay between swallow onset

and vocal fold closure can range from approximately 0.5 and 1 s (Van Daele et al.

2005 ) , the TA must have the ability to close extremely rapidly just before bolus passage.

The TA’s fast contracting fi ber types may subserve this biological requirement.

Clearly, the adduction of the vocal folds during swallowing is one of the

laryngeal muscles’ most important protective mechanisms. The other mechanisms

are the elevation of the larynx behind the base of the tongue and the depression of

the epiglottis to cover the airway, facilitated by muscles of the pharynx, discussed

later in this chapter. These protective functions are typically described as the primay

function of these muscles, with communicative functions being secondary.

9.1.3 Muscle Fiber Types and Mitochondria Characteristics

in the Intrinsic Laryngeal Muscles

Two characteristics that distinguish muscle fi bers are their shortening velocities and

the major pathway used for formulation of the fi ber’s energy supply (Widmaier et al.

2004 ) . Shortening velocity, either fast or slow, is re fl ected by composition of myosin

heavy chain (MyHC) properties within the muscle as well as the speed with which

ATP is broken down by ATPase. A single MyHC isoform may characterize a muscle

fi ber or a fi ber may co-express multiple isoforms. Slow fi bers (Type 1) are generally

fatigue resistant, while fast fi bers (Type 2) provide short surges of speed and strength

and are more prone to fatigue. Type 2 MyHCs can be further divided into Types 2A

and Type 2X in human limbs. Another fast fi ber type thought not to be found in large

mammals, speci fi cally primates, is Type 2B. The speed and power of Type 2B is

greatest, followed by Type 2X and then Type 2A (Powers and Howley 2004 ) .

Different energy pathways, either oxidative or glycolytic, also characterize slow

vs. fast muscle fi ber types. Speci fi cally, oxidative fi bers use oxygen to create adenosine

triphosphate (ATP) via a series of chemical reactions that take place in mitochondria.

Oxidative fi bers depend on blood fl ow for the provision of oxygen to

produce ATP (Widmaier et al. 2004 ) . Thus, these fi bers are typically situated near

blood vessels and contain myoglobin. When mitochondrial capacity is depleted or

oxygen is not available, nonaerobic glycolysis is the pathway used for creation of

ATP. Although glycolytic fi bers produce ATP more rapidly than oxidative fi bers,

fewer ATP molecules are created. Thus, oxidative fi bers sustain periods of moderate


Fig. 9.3 Micrograph of rat skeletal muscles showing presence of mitochondria ( m mitochondria).

Accompanying graphs show mitochondrial volume density (% of muscle fi ber volume occupied by

mitochondria) in soleus, posterior cricoarytenoid, and thyroarytenoid, supporting the idea that

mitochondrial volume density is lower in limb than laryngeal muscles. Used with permission from:

Andrade FH (2011), unpublished data

muscular work over time without fatigue, whereas glycolytic fi bers engage in rapid

and intense activity that leads to fatigue. Type 1 fi bers are slow-oxidative fi bers and

thus, are slowly contracting and fatigue resistant. Their relative ef fi ciency results in

less ATP use per unit of work than fast contracting fi bers (Powers and Howley

2004 ) . Although Type 2A fi bers or fast oxidative fi bers contract quickly, their resistance

to fatigue is moderate (Widmaier et al. 2004 ) because they have high mitochondrial

volumes and adequate blood supply/myoglobin to allow maintenance of

energy stores. In contrast, Type 2X or fast glycolytic fi bers exert the fastest contraction

speeds and forces, but fatigue quickly due to smaller energy stores and more

ATP use per unit work than Type 1 fi bers (Widmaier et al. 2004 ) .

Energy requirements of muscles may be determined by examining mitochondrial

volume or density, which is measured as the percent of muscle fi ber volume occupied

by mitochondria (Andrade 2010 ) . More mitochondria allow muscles to engage

in continuous work at low or moderate intensities without fatigue. Reports have

indicated that the density of mitochondria in laryngeal muscles is high especially

when compared with limb muscle (McMullen and Andrade 2006 ; Rosen fi eld et al.

1982 ) . For example, mitochondrial density in rat soleus muscle, a slowly contracting,

fatigue-resistant muscle, has been reported as 6.1 ± 0.9% (Mathieu-Costello

et al. 1992 ) whereas the mitochondrial density in rat PCA and CT muscles averages

15 ± 1.1% and 10.9 ± 0.7%, respectively (Hinrichsen and Dulhunty 1982 ) . Recent

data have shown that the average mitochondrial density in 6-month-old rat TA muscle

is the highest of the laryngeal muscles at approximately 18% (Francisco Andrade

2011, personal communication). Figure 9.3 contains a comparison of mitochondrial

densities among rat soleus and laryngeal muscles (Hinrichsen and Dulhunty 1982 ;

Mathieu-Costello et al. 1992 ; Francisco Andrade 2011, unpublished work).

The high density of mitochondria in the PCA and TA is likely related to the

muscles’ energy needs. Both muscles must provide slow, sustained contraction to


149

allow for breathing and sustained phonation. Thus, the high density of mitochondria

in these muscles likely allows continual engagement in respiratory and phonatory

movements without fatigue. Interestingly, reports examining aged rat and human

TA have reported that this muscle is signi fi cantly more fatigable than in younger TA

muscles from the same species (McMullen and Andrade 2006 ; Kersing and

Jennekens 2004 ) . One of the causes of this change in endurance may be an accumulation

of ragged red fi bers in the TA (McMullen and Andrade 2006 ; Kersing and

Jennekens 2004 ) . Ragged red fi bers are associated with defective mitochondria

found with aging (McMullen and Andrade 2006 ; Kersing and Jennekens 2004 ) .

These fi bers appear to occur at a higher degree in aged TA than in aged limb muscles

(Kersing and Jennekens 2004 ) . Likewise, an increase in the amount of glycolytic

muscle fi bers in the TA of older rats has been reported (McMullen and Andrade

2006 ) . Both of these fi ndings represent changes that will decrease the endurance of

the TA. Speci fi cally, fewer healthy mitochondria are available to subserve muscle

endurance and an increase in fatigable glycolytic fi bers with age will likely result in

a proportional decrease in nonfatigable oxidative fi bers.

Myosin heavy chain composition (MyHC) with the laryngeal musculature has

distinct differences from MyHC isoform composition in the well-studied muscles of

the extremities. In contrast to MyHC isoforms found within limb muscles, hybrid

fi bers with more than one MyHC isoform, and isoforms other than MyHC types 1,

2A, and 2X have been reported in all laryngeal intrinsic muscles but the cricothyroid

(Shiotani et al. 1999a, b ; D’Antona et al. 2002 ; Sciote et al. 2002 ; Wu et al.

2000 ; Han et al. 1999 ) . Likewise, muscle fi ber types identi fi ed within the extremities

may occur in different proportions within the larynx (D’Antona et al. 2002 ;

Shiotani et al. 1999a, b ). In one report, the laryngeal adductors (TA, LCA, and IA)

had a higher percentage of the fast glycolytic contracting fi bers (type 2X) and a

lower percentage of type 1 fi bers than the abductor PCA and tensor CT in human

(Shiotani et al. 1999a, b ). However, all of these muscles (TA, LCA, IA, PCA, and

CT) had a relatively high percentage of fast oxidative 2A muscle fi bers. In the work

of Shiotani et al. ( 1999a, b ), the TA muscle exhibited the greatest percentage of type

2X fi bers, followed by the LCA, then IA, PCA, and fi nally, the CT. The percentage

of type 1 oxidative intrinsic laryngeal muscle fi bers is reportedly greatest in PCA

followed by CT, then IA, LCA, and fi nally, TA (Shiotani et al. 1999a, b ). In light of

these fi ndings, the TA muscle appears to be rapidly contracting. The PCA and CT,

on the other hand, possess relatively slow contraction speeds.

For some mammals, contraction time measures in TA are very short, being about

14 ms in dog and primate and 22 ms in cat (Hast 1969 ) . There are some differences

across species. Speci fi cally, PCA and TA MyHC isoforms in humans, when considered

together, have a generally slower pro fi le than the isoforms found in rat or canine

TA and PCA (Wu et al. 2000 ) . However, the rat exhibits the fastest isoform pro fi le

for these muscles; perhaps providing support for the idea that larger species have

slower MyHC pro fi les (Wu et al. 2000 ) . Similarly, human and canine PCA and TA

musculature have a larger percentage of type I MyHC isoform, whereas type 1 fi bers

are nearly absent in rat (Wu et al. 2000 ) .

Another interesting characteristic of MyHCs in the laryngeal musculature is that,

unlike the limb muscles, a large percentage of hybrid fi bers have been discovered


(D’Antona et al. 2002 ; Sciote et al. 2002 ; Wu et al. 2000 ) . Human vocalis muscle

fi bers that are comprised of more than one isoform appear to have properties intermediate

to those expressed by each individual fi ber type alone (D’Antona et al.

2002 ) . In D’Antona et al. ( 2002 ) , 33% of fi bers studied within the human vocalis

were hybrids including the following types: I-2A, 2A-2X, 1-2A-2X, and 2A-2L.

Additionally, human TA and PCA muscles with mixed MyHC expression had a

large range of contraction speeds, some which were almost twice as fast as limb

muscles (Sciote et al. 2002 ) . Wu et al. ( 2000 ) also reported hybrid expression in

20% of the fi bers in dog PCA and 40% of fi bers in human and dog LCA. Hoh ( 2005 )

hypothesized that laryngeal muscle fi ber hybrids may have originated because of

the multiple, diverse neural inputs to these muscles to perform complex and differing

tasks. For example, perhaps the quality of muscle contraction for phonation vs.

coughing is different. If this is the case, then adductor muscle fi bers might contain

hybrids to allow for different degrees or con fi gurations of contraction speed, tension,

or fatigability. Theoretically, co-expression of MyHC isoforms within one

muscle fi ber would allow the muscle to participate in diverse tasks including phonation

and airway protection/coughing.

In the process of studying the MyHC isoforms in laryngeal muscles, several

investigators discovered additional MyHCs that are not found within the limbs.

Speci fi cally, D’Antona et al. ( 2002 ) found a possible “new” isoform in human

vocalis muscle labeled MyHC L. This isoform is believed to be similar to extraocular

(EO) MyHC in rats. EO MyHC is very fast contracting and found in the extraocular

muscles in most animal species. Much controversy exists as to whether EO

MyHC occurs within human laryngeal muscles due to the assertion that TA muscle

contraction may occur at speeds similar to the extraocular muscles (Hoh 2005 ) . On

the other hand, MyHC type 2L (which represents EOM MyHC in larynx) has also

been reported in rat TA (Wu et al. 2000 ; Shiotani and Flint 1998a ; DelGaudio et al.

1995 ; Merati et al. 1996 ) . Likewise, MyHC isoform bands from human extraocular

muscles have been found to co-migrate with some bands from laryngeal muscle

during electrophoresis (Sciote et al. 2002 ) . This occurrence may suggest its expression

in human larynges. According to D’Antona et al. ( 2002 ) , the mystery myosin

that was thought to possibly represent EOM MyHC was found only in a hybridized

form with type 2A. The type 2A-L fi ber was estimated to appear in only 3% of

muscle fi bers observed by these researchers. Hoh ( 2005 ) reasoned that because of

the ultra fast speeds attributed to EOM MyHC, when this MyHC was hybridized

with 2A MyHC, this mixture would likely result in faster shortening speeds than

type 2A alone. However, as indicated earlier, D’Antona et al. ( 2002 ) found that

hybridized type 2A-L fi bers exhibited slower contraction speeds than Type 2A

fi bers alone. Hoh ( 2005 ) concluded that this new fi ber was more likely a slow tonic

MyHC than EO MyHC.

Slow tonic fi bers have been found in the vocalis muscle (Han et al. 1999 ) . Unlike

other fi ber types, slow tonic fi bers are not typically found in mammals (Han et al.

1999 ) , although a large group of these fatigue-resistant fi bers have been discovered

in human vocalis muscle (Han et al. 1999 ) . Slow tonic fi bers do not exhibit a twitch

contraction like type 1 and 2 fi bers, and instead, respond to very slow, repetitive


151

neural impulses with gradually rising tension and slow tension decline after these

impulses cease (Han et al. 1999 ) . The unique characteristics of slow tonic fi bers

were hypothesized to be an adaptive mechanism that allows for human vocalization

speci fi c to speech (Han et al. 1999 ) . Slow tonic fi bers would allow for precise adduction

of the vocal folds without fatigue; however, the quick adjustments that are made

during vocalization (such as beginning to phonate immediately after a breath or

singing staccato notes) may not be served well by them. Perhaps hybrid fi bers or

fast contracting MyHC are responsible for rapid phonatory tasks and airway protection,

while slow tonic fi bers decrease the possibility that continuous phonation will

result in fatigue. Therefore, the high concentration of hybridized fi bers, fast contracting

fi bers, and STFs as well as fi ber types that are still under investigation

contribute to the functional properties of the adult larynx.

MyHC composition is reportedly unique in infant laryngeal musculature relative

to that found within limb skeletal muscle (Perie et al. 2000 ) . Speci fi cally, the persistence

of fetal (IIF) MyHC was present in 7-month-old human PCA and TA muscles.

Fetal isoforms have not been reported in adult laryngeal muscles. In most cases,

adult MyHC isoforms replace fetal MyHC during fetal development. For instance,

in limb muscles, slow and fast MyHC isoforms typically replace fetal isoforms

between prenatal months 6 and 9, and are gone very soon after birth occurs.

However, fetal MyHC persist in some muscles through adulthood such as masseter

and extraocular muscles (Wieczorek et al. 1985 ; Soussi-Yanicostas et al. 1990 ) .

The presence of fetal isoforms well after birth in laryngeal muscles may indicate

“a delayed maturation of the human laryngeal neuromuscular system” in comparison

to limbs, “and could be related to the progressive development of these muscles

during the fi rst few years of life” (Perie et al. 2000 ) . The idea of an immature neuromuscular

system persisting into infancy is further supported by the fi nding that up

until 7 months, TA, PCA, IA, and CT muscles exhibit motor end plates innervated

by more than one axon mixed with those only innervated by a single axon (Perie

et al. 1999 ) . In adults, only uni-neuronal innervations patterns have been found in

these muscles.

Additionally, an unknown isoform was discovered in infant larynx. This isoform

was found to have a similar mobility and, hence, molecular weight as 2-month-old

rat MyHC IIL during electrophoresis. Like in rats, the concentration of this isoform

in human infant was higher in the TA vs. the PCA muscles. The presence of this

isoform in infants may be associated with their differing functional needs. Perhaps

conversion of this isoform to its adult form occurs as phonation evolves for use in

speech (Perie et al. 2000 ) .

9.1.4 Nerve–Muscle Connections

A detailed discussion of concepts related to the motor unit can be found in any basic

physiology textbook (Widmaier et al. 2004 ) . An excellent review of muscles of

interest in this chapter was written by Palmer ( 1989 ) . In general, a motor unit is a


Fig. 9.4 Exemplar of a

confocal digital micrograph

of an NMJ from an old rat TA

muscle obtained after 3-color

fl uorescent

immunohistochemical

staining. Receptors appear in

red , axons in blue , and

Schwann cells and nerve

terminals in green. Scale

bar = m m

single motoneuron, the connection between the motoneuron, and all of the muscle

fi bers innervated by that motoneuron. Motor units throughout the body vary in size.

That is, the innervation ratio, or number of muscle fi ber innervated by a particular

motoneuron differs. Of interest with regard to the larynx is that innervation ratios

are relatively small within the intrinsic muscles compared with those found in other

skeletal muscles systems. For instance, as noted by Palmer ( 1989 ) , innervation

ratios can be 2 or 3 within the larynx compared with 2000 within the gastrocnemius

(Feinstein et al. 1955 ; Faaborg-Andersen 1957 ) . Thus, the capacity for fi ne-grained

control of laryngeal movements and postures is implied by the density of innervation

of muscle fi bers. This is yet another example where the anatomic and physiologic

characteristics of the laryngeal sensorimotor system differ from characteristics

found within limb skeletal muscle systems.

Connections between nerve and muscle take place at the NMJ, which contains parts

of three different types of cells, the nerve terminal, Schwann cells, and the motor end

plate postsynaptically on the muscle, as shown in Fig. 9.4 (Sanes and Lichtman 1999 ) .

With regard to the muscles of the larynx, NMJ structure within the instrinsic

muscles has been reported in only a handful of studies (Rosen et al. 1983 ; Gambino

et al. 1990 ; Yoshihara et al. 1998 ; Connor et al. 2002 ; McMullen and Andrade

2009 ). These papers typically report comparisons of NMJs in normal TA and/or

PCA muscles with aging (Gambino et al. 1990 ; Connor et al. 2002 ; McMullen and

Andrade 2009 ) or with a pathological state, such as amyotrophic lateral sclerosis

(Yoshihara et al. 1998 ) . Very few offer comparison of limb and cranial motor systems.

However, in one study, motor end plate distribution in the TA muscle from

cats and humans was examined histologically using achetylcholinesterace enzyme

activity as a marker (Rosen et al. 1983 ) . Results suggested that endplate distribution


153

Fig. 9.5 Wide fi eld fl uorescent image (×4 objective) of a 50- m m-thick transverse section from a rat

larynx showing the distribution of motor endplates in the thyroarytenoid (TA) muscles. Motor

endplates are labeled with Alexa Fluor 488 conjugated alpha-bungarotoxin (Molecular Probes/

Invitrogen, Eugene, OR) which has a high af fi nity to acetylcholine receptors in skeletal muscle.

Note the difference in the distribution between the horizontal endplate band in the lateral TA compared

to the diffuse distribution along the length of the medial TA. Courtesy of Aaron Johnson

in cat and human specimens was similar. That is, while most skeletal muscle appears

to have a distinct endplate band at the midbelly of the muscle, the TA muscle

appeared to have widely distributed endplates throughout the length and width of

the muscle in both cats and humans (Rosen et al. 1983 ) . We have also observed this

widespread distribution of endplates in rat medial TA in our laboratory (Connor

et al. 2002 ) , but not in lateral TA (Fig. 9.5 ) where motor endplates were con fi ned to

an endplate band and clustered together as is observed in limb muscle.

Endplate band clustering of NMJs has also been shown for CT muscle (Rosen

et al. 1983 ) . Thus, the medial TA muscle appears to be richly supplied with NMJs in

a complex geometry that is unique to this muscle when compared with other laryngeal

and limb muscles, perhaps to serve the sensorimotor control needs of this critical

muscle of the airway and voice. The abundance of NMJs is reduced with aging in

the TA and PCA muscles, thus supporting that aging putatively affects the NMJs in

a manner similar to that seen with denervation (Connor et al. 2002 ; McMullen and

Andrade 2009 ) . However, there are alternative explanations for these fi ndings, such

as muscle fi ber atrophy and/or reductions in muscle fi ber size or length.


9.1.5 Summary

The intrinsic laryngeal muscles represent the fi nal common path for the fi nely tuned

actions that allow for breathing, airway protection, and phonation. Muscle fi ber type

morphology and mitochondrial density likely subserve the unique functions of these

muscles. While the innervation patterns of these muscles are considered well known,

con fl icting reports exist regarding the IA and TA. Anatomic and physiologic studies

of the intrinsic laryngeal muscles have been performed in humans and cadaveric

models, as well as in animal models. There appear to be some species differences,

but there are more similarities than differences across species. For instance, in the rat

larynx there has been note of a muscle not found in humans, the alar cricoarytenoid

muscle (Inagi et al. 1998 ) . Because the larynx and pharynx are dif fi cult to access in

humans, the use of animal models in research concerning muscles of larynx and

pharynx is necessary. Thus, some species differences must be tolerated but considered

when making interpretations relative to human muscle anatomy and physiology.

Clearly, the larynx has unique muscular components including a large density of

mitochondria as well as a large percentage of hybrid, slow tonic, and fast twitch

fi bers. These muscle fi ber types contribute to the specialized functions of the larynx.

Differing fi ber types found in human larynx compared to other species may be

linked to differences in body size and functional differences (i.e., speech in humans).

Controversy still remains as to whether adult or infant human vocal fold musculature

contains EO MyHC, but this fi nding would support the rapid contraction speeds

of muscles like the TA. As knowledge about laryngeal muscle fi bers increase, further

conclusions may be drawn about their in fl uence on laryngeal movement in normal

and voice-disordered populations. Thus far, it is clear that the variable composition

of different laryngeal muscles suits each to differing task requirements. It is not

clear whether particular laryngeal adductor muscles predominate in speci fi c phonatory

or airway protection tasks, and how different muscle characteristics may exert

in fl uence on voice disorders.

9.2 Extrinsic Muscles of the Larynx

9.2.1 Role in Voice

The extrinsic laryngeal muscles contribute to voice production and modulation by

allowing for modi fi cations in laryngeal posture. While the intrinsic muscles of the

larynx have connections solely within the larynx, the extrinsic muscles have an

external origin or insertion. For example, the sternothyroid and the thyrohyoid muscles,

while not located wholly within the larynx, function to control the vertical

position of the larynx and are active up to 200 ms prior to phonation onset (Shipp

1975 ) . One example of vertical position change of the larynx was provided by

Shipp, speci fi cally, the superior laryngeal movement observed during glissando


155

with increasing pitch. Vertical position of the larynx appears to be altered with pitch

change, but the level of change is highly variable across individuals (4–22.5 mm)

(Shipp 1975 ) .

The infrahyoid muscles are often referred to as the strap muscles. The strap

muscles typically include the sternohyoid (SH), omohyoid (OH), thyrohyoid (TH),

and sternothyroid (ST); with the SH and OH comprising the most super fi cial layer

of these muscles and the TH and ST comprising the deepest layer. All four strap

muscles are located deep to the platysma and sternocleidomastoid muscle.

Strap muscles have an important role in voice production, particularly with

regard to pitch modulation during phonation. By impacting the position of the

thyroid cartilage, they increase and decrease the distance between the thyroid and

cricoid, resulting in increases in vocal fold tension or relaxation (Kenyon 1992 ) .

In general, the literature has focused on the role of the TH, SH, and ST, but has typically

omitted the omohyoid. Figure 9.6 contains a photograph of a canine larynx

showing the ST and TH muscles.

Some studies examining the ST in human via EMG or canine or primate via

stimulation have found it to be active during pitch elevation (Faaborg-Andersen and

Sonninen 1960 ; Shipp 1975 ; Niimi et al. 1991 ; Ueda et al. 1972 ; Sapir et al. 1981 )

and/or pitch lowering (Shipp 1975 ; Ueda et al. 1972 ). Other studies (again human

EMG studies or animal stimulation studies), however, have indicated that the ST is

not active or inconsistently active with pitch decrease (Shin, Hirano, Maeyama,

Nozoe, and Ohkubo 1981 ; Collier 1975 ; Atkinson 1978 ; Niimi et al. 1991 ; Sapir

et al. 1981 ) and/or pitch increase (Collier 1975 ; Sapir et al. 1981 ) . TH activity has

been noted during increased pitch across a majority of human EMG studies (Faaborg-

Andersen and Sonninen 1960 ; Shipp 1975 ; Baer et al. 1976 ) ; although a few human

EMG studies indicated that the TH was not active during increases in pitch (Erickson

et al. 1977 ) , or active during pitch lowering in addition to pitch raising (Baer et al.

1976 ) . However, the majority of human EMG studies indicate that the TH is not

active during pitch lowering (Faaborg-Andersen and Sonninen 1960 ; Shipp 1975 ;

Collier 1975 ) . In canine stimulation and human EMG studies, the SH has generally

been associated with pitch increases (Baer et al. 1976 ; Ueda et al. 1972 ) and decreases

(Baer et al. 1976 ; Atkinson 1978 ; Ueda et al. 1972 ), although one human EMG study

did not fi nd any activity in this muscle during pitch increase (Atkinson 1978 ) . Thus,

the way in which these muscles truly affect pitch is still unclear due to the contradictory

fi ndings reported in the literature (Hong et al. 1997 ; Vilkman et al. 1996 ) .

As can be gleaned from the above paragraph, studies examining SH, TH, and ST

function have typically involved electrical stimulation in animals or humans (Sonninen

1956 ; Ueda et al. 1972 ; Sapir et al. 1981 ) or EMG (during singing and speech) in

humans (Erickson et al. 1977 ; Faaborg-Andersen and Sonninen 1960 ; Shipp 1975 ;

Niimi et al. 1991 ; Collier 1975 ; Atkinson 1978 ; Baer et al. 1976 ) varying from 1 to 25

participants (Vilkman et al. 1996 ) . Cadaver experiments have also been undertaken to

provide insight into strap muscle function (Sonninen 1956 ; Vilkman et al. 1996 ) .

These studies have typically drawn conclusions about function by manipulating muscle

position (Vilkman et al. 1996 ) . The hypotheses, models, and literature related to

SH, TH, and ST function have been extensively reviewed (Vilkman et al. 1996 ) .


Fig. 9.6 Left lateral view of a canine larynx showing external laryngeal strap muscles including

the sternothyroid and thyrohyoid. Photograph courtesy of Dr. Seth Dailey

9.2.2 Role in Swallowing

The extrinsic laryngeal muscles play a vital role in swallowing. Speci fi cally, they

are active in producing laryngeal elevation to protect the airway (Burnett et al.

2005 ) . Reduced or delayed laryngeal elevation is associated with aspiration (Kahrilas

1997 ; Lundy et al. 1999 ) . Thus, damage of these muscles due to brain injury or

stroke, or their surgical removal often results in dysphagia. The relative contributions

of some of the extrinsic muscles to laryngeal elevation have been explored

through the application of intramuscular electrical stimulation to the geniohyoid

and thyrohyoid (Burnett et al. 2003 ) . Stimulation of these muscles resulted in 30%

of the laryngeal elevation and about 50% of the velocity that occurred during a


157

normal swallow (Burnett et al. 2003 ). When stimulation was applied bilaterally to

the thyrohyoid alone approximately 50% of normal laryngeal elevation and 80% of

normal speed of elevation was found (Burnett et al. 2003 ). Regarding temporal

factors, thyrohyoid activation was closely linked with laryngeal rise and fall with its

activation occurring an average of only 52 ms prior to laryngeal elevation (Burnett

et al. 2005 ) .

Electrical activity of the strap muscles during swallowing as measured with surface

EMG demonstrated different average electrical activity depending on swallowing

parameters (Vaiman et al. 2004 ) . For instance, electrical activity during continuous

drinking of 100 mL of water was the smallest in magnitude, followed by activity

during a single saliva swallow (Vaiman et al. 2004 ) . However, electrical activity during

single water swallows and fi xed 20 mL water swallows was stronger and similar

to one another in magnitude (Vaiman et al. 2004 ) . Interestingly, electrical activity of

the infrahyoid area has been found to decrease with age (Vaiman et al. 2004 ) .

9.2.3 Summary

Extrinsic muscles of the larynx contribute to laryngeal position during swallowing

and pitch change by altering the distance among laryngeal cartilages. Extrinsic

muscles are vital to promoting airway protection through laryngeal elevation and

exhibit different levels of electrical activity depending on age and the type of swallow.

Reports about the correspondence between pitch lowering/raising and extrinsic

muscular activity are con fl icting. Likewise, methodologies for examining strap

muscle functional properties vary widely from manipulating muscle position in

cadavers to use of electrical stimulation in human or animals or use of EMG in

humans only. Thus, while the role of the extrinsic musculature is broadly known,

the speci fi c function of each individual extrinsic muscle is not completely clear.

9.3 Muscles of the Pharynx

There are many muscles of the pharynx throughout the extent of the nasopharynx,

oropharynx, and the hypopharynx that have a primary role in swallowing function.

For instance, muscles within the nasopharynx (tensor palatine, levator palatini) function

to elevate the soft palate and close the nasopharynx to the bolus, while altering

pharyngeal pressures to receive and propel the bolus. Movement of the pharyngeal

wall toward the soft palate as well as elevation and anterior displacement of the larynx

during the swallow is accomplished by muscles such as the mylohyoid, palatopharyngeus,

salpingopharyngeus, and stylopharyngeus (Table 9.1 ). Increased velopharyngeal

pressure relative to baseline results from these actions and has been recorded

during a swallow using high resolution manometry (Hoffman et al. 2010 ) . In combination

with reduced hypopharyngeal pressure during the swallow, a pressure gradient

is established that works in favor of bolus fl ow toward the esophagus.


9.3.1 Structure, Function, and Muscle Fiber Types

In general, the majority of the pharyngeal muscles (Table 9.1 ) receive motor

innervation from the pharyngeal plexus of the vagus nerve (CNX). There are a few

exceptions, including the tensor veli palatine (innervated by the medial pterygoid

nerve, a branch of the mandibular nerve branching from the trigeminal CNV),

stylopharyngeus (the only muscle receiving motor innervation by the glossopharyngeal

nerve CNIX), and palatopharyngeus (innervated by the pharyngeal plexus of

the vagus CNX and the spinal accessory nerve CNXI). Although these are commonly

noted innervation patterns at the most basic level, reports vary as to the

speci fi c branches of the cranial nerves supplying certain pharyngeal muscles (Hixon

et al. 2008 ) . We will highlight one such controversy related to the cricopharyngeus

later in this section.

Mylohyoid muscle fi ber characteristics in human samples were reported in one

recent study as having a hybrid composition of unusual myosin properties, such as

embryonic, neonatal, a -cardiac, and slow-tonic, in combination with typical skeletal

muscle myosins including type I, Type IIA, and Type IIX (Ren and Mu 2005 ) .

Notably, these hybrid fi bers comprised 84% of the total number of fi bers analyzed

in adult human samples. Thus, the muscle fi ber type composition in the mylohyoid

muscle is unique and distinct from skeletal muscles found in the extremities and is

more similar to those found in other cranial muscles. Ren and Mu ( 2005 ) interpreted

their fi ndings as suggestive of specialization of this muscle for chewing, swallowing,

and breathing, and the need for postural stability and endurance during these

critical functions.

9.3.2 The Upper Esophageal Segment

The terms cricopharyngeus (CP) and upper esophageal sphincter (UES) are often

used interchangeably, but the CP muscle is really one muscular component of the

UES; thus, these terms are not synonymous. The CP along with the inferior pharyngeal

constrictors and inferior cervical esophageal muscle make up the UES.

Although there has been some controversy over the CP’s role in UES function

(Goyal et al. 1993 ) , the CP is typically thought to facilitate the contraction and

relaxation patterns that lead to the pressure changes exhibited by the UES as a

whole. In fact, the CP is the only component of the UES which contracts and relaxes

during tasks associated with UES opening, including swallowing, emesis, and

belching (Belafsky 2010 ; Kahrilas 1997 ) . The terminology UES can be used interchangeably

with the pharyngoesophageal segment (PES) (Belafsky 2010 ) . Both

refer to the same area of the esophagus, although the UES is de fi ned as the “2–5-cm

high-pressure zone located between the pharynx and esophagus” that is “measured

by manometry” (Belafsky 2010 ) . On the other hand, “the PES refers to the anatomic

components that make up the high-pressure zone” (Belafsky 2010 ) .


159

Fig. 9.7 Drawing of

cricopharyngeus muscle

showing the muscle’s

horizontal and oblique

compartments known as the

pars obliqua and pars

fundiformis, respectively. CC

cricoid cartilage; CPo

oblique compartment of

cricopharyngeus muscle; Cph

horizontal compartment of

cricopharyngeus muscle; CT

cricothyroid muscle; IPC

inferior pharyngeal

constrictor muscle; T trachea;

TC thyroid cartilage; UE

upper esophagus. Used with

permission from the fi rst

author: Mu and Sanders

( 2002 )

Muscle fi ber properties of the CP muscle have been identi fi ed as predominantly

slow contracting Type I fi bers based on MyHC assays (Davis et al. 2007 ) . When the

CP muscle and the pharyngeal constrictors were compared in human samples, the

CP was found to have muscle fi bers with a smaller cross sectional area, while no

distinct differences in fi ber type composition were observed (Sundman et al. 2004 ) .

In this study, slow muscle fi ber types predominated in the CP and the constrictors,

but across samples in the CP there were fi ndings of hybrid fi bers, on average, (Type

I and Type IIA) 9% of the time and 28% of the time in the pharyngeal constrictors

(Sundman et al. 2004 ) .

As shown in Fig. 9.7 , the CP has two compartments known as the pars oblique

(or simply, oblique) and pars fundiformis (Plant 1998 ) . The pars fundiformis compartment,

also known as the horizontal compartment (Mu and Sanders 2002 ) is

what is typically referred to when the CP is discussed (Plant 1998 ) . The fundiformis

is a sling shaped (Belafsky et al. 2010 ; Belafsky 2010 ) , striated skeletal muscle that

attaches to the posterior aspect of the cricoid cartilage. It is composed of small fi bers

(typically 25–35 m m) that are predominantly Type I to allow for sustained contraction

of the UES (Mu and Sanders 2002 ) .

Innervation of the CP is controversial (Halum et al. 2006 ; Mu and Sanders 1998 ;

Sasaki et al. 1999 ) . The branches of the vagus reportedly innervating the CP have


been identi fi ed as the pharyngeal plexus (Hwang et al. 1948 ) , SLN (Kirchner 1958 ) ,

RLN (Hammond et al. 1997 ) , and the cervical sympathetic chain (Hirano 1969 ) or

combinations of these nerves such as the pharyngeal plexus and RLN (Lund 1965 ;

Mu and Sanders 1998 ; Sasaki et al. 1999 ) . In one study, EMG recordings of the CP

were examined to determine how similar they were to EMG recordings of different

muscles with known innervation (Halum et al. 2006 ) . The authors obtained EMG

recordings for the CP muscle and examined either the ipsilateral inferior constrictor,

TA, or CT muscles simultaneously. The authors’ logic was that if the same nerve

innervated the CP and one or all of these other muscles, then EMG signals in patients

with nerve injury would have common characteristics. EMG test results fell into

one of the following categories: normal, inactive axonal injury, or neurogenic active

axonal injury. The authors found that in 27 out of 28 studies, the ipsilateral inferior

pharyngeal constrictor and CP muscle had the same muscle fi ndings whereas only

40 of 50 studies and 31 of 50 studies were the same between the CP and TA, and CP

and CT, respectively. Based on these fi ndings, the pharyngeal plexus appeared to

predominantly contribute to CP innervation because greater commonality was found

between CP EMG patterns and those of the inferior pharyngeal constrictor, which is

innervated by the pharyngeal plexus (Halum et al. 2006 ) .

Although passive tone is typically always present in the CP, muscular tension

increases as the muscle is stretched (Lang and Shaker 1997 ) . As previously mentioned,

when swallowing occurs, the CP relaxes to allow bolus passage (Lang and

Shaker 1997 ; Plant 1998 ; Kahrilas 1997 ) . While pressure from the bolus contributes

slightly to UES opening, the anterior–posterior movement of the hyoid bone creates

a strong negative pressure that facilitates UES opening and relaxation (Belafsky

2010 ; Plant 1998 ) . The larger the bolus, the more the UES and CP will relax to

widen the UES opening and increase bolus fl ow rates (Plant 1998 ) .

High-resolution manometry (HRM) provides information on pressure changes

during swallowing as well as excellent spatial and temporal resolution. Thus, it has

been used to examine how bolus size and postural changes may in fl uence UES

opening and pressures during deglutition. Durations of UES opening have been

found to vary with different volumes of a liquid bolus based on HRM measures

(Hoffman et al. 2010 ) . Speci fi cally, larger liquid bolus volumes have resulted in

increased UES opening durations (Hoffman et al. 2010 ) . Additionally, examination

of normal swallows via HRM indicated that maximal UES pressure was signi fi cantly

lower in swallows performed in a neutral position vs. those performed with a head

turn. UES pressure was also signi fi cantly higher post swallow with head rotation vs.

neutral positioning. The time that the UES remained open was also greater via head

turn (Fig. 9.8 ).

The CP’s main functions include preventing re fl ux from entering the airway

(Belafsky et al. 2010 ) and preventing passage of air into the esophagus and

abdomen during swallowing (Belafsky et al. 2010 ; Kahrilas 1997 ; Plant 1998 ) .

A healthy CP also allows for quick and ef fi cient swallowing to occur. Thus, when

CP relaxation is delayed or inadequate, the fl ow rate of swallowed materials may

slow and result in residual food materials collecting in the pharynx. The failure of the

CP to relax and allow for the UES to widen has been associated with progressive


161

Fig. 9.8 High-resolution manometry data showing pressure changes across time and spatial position

with 5 mL bolus swallow using head turn. Upper esophageal sphincter is plot’s upper border and

plot’s lower border is nasopharynx. Used with permission from McCulloch et al. ( 2010 )

weakening of the pharynx (Belafsky et al. 2010 ) . Maneuvers such as the effortful

swallow have been found to elicit longer UES relaxation durations and improve

swallow function impacted by CP dysfunction (Hiss and Huckabee 2005 ) . Recently,

Belafsky ( 2010 ) determined that manual control of the UES was possible by placing

a traction suture around the cricoid cartilage’s anterior edge and speci fi cally

placing an implant near the cricoid cartilage. This implant would then open up the

UES when an external magnet was placed on the neck. This Swallow Expansion

Device (SED) reportedly improved UES opening in patients with oropharyngeal

dysphagia. Testing of the suture in sheep and cadavers before implantation into

humans did not result in any cricoid abrasion but did improve opening of the UES

by over 1 cm and prevent aspiration in an ovine model. Thus, there is the possibility

of using novel devices in the treatment of dysphagia related to CP muscle dysfunction

as new technology emerges.

While pharyngeal muscles primarily subserve deglutition, there is some evidence

that they may be active under some respiratory conditions. These muscles are not

typically recruited during rest breathing, but there have been reports of pharyngeal

muscle activity with airway obstruction and high respiratory drive (van Lunteren

and Strohl 1986 ) . Likewise, the superior constrictor muscle may adjust air fl ow

resistance during expiration (Collett et al. 1986 ) .


9.3.3 Summary

Pharyngeal muscles have primary roles in deglutition and as a secondary protective

mechanism. Muscles of the pharynx also act to prevent re fl uxate from the stomach

or esophagus from entering the airway and also restrict air from entering the digestive

tract. The mylohyoid’s complex hybrid muscle fi bers likely correspond to its

varying functional roles in breathing, swallowing, and chewing. CP muscle fi bers

allow for fatigue resistance and sustained muscular contraction. Studies using HRM

and examining novel devices like the SED are likely to improve understanding of

and treatments for dysphagia resulting from CP dysfunction.

9.4 Conclusion

The laryngeal and pharyngeal muscles subserve the highly specialized functions of

breathing, airway protection, phonation, and deglutition. Intrinsic laryngeal muscles’

high mitochondrial densities, low innervation ratios, motor endplate distributions,

and the presence and proportion of their hybrid, slow tonic, and fast contracting

fi bers are notable features that make them distinct from limb skeletal muscle. These

characteristics provide evidence for their high energy requirements, specialized

nature, and diverse functional properties. Given the common presence of hybrid

fi bers in the CP, pharyngeal constrictors, and mylohyoid, the pharyngeal muscles

also appear to have multiple functional properties. Likewise, reports indicate

unknown MyHC isoforms have been discovered in pharyngeal and laryngeal muscles

such as the mylohyoid and vocalis muscles. There are still many gaps in knowledge

about laryngeal and pharyngeal musculature that need to be addressed in future

research. For example, controversies that require further study include: the presence

of the EO MyHC in intrinsic laryngeal muscles, the innervation of CP, IA, and TA,

the speci fi c function of each individual extrinsic laryngeal muscles, and why and

how intrinsic laryngeal muscle fi bers in infant vary from adults. Although there is

certainly a need for more investigation into both the basic properties of these muscles

and ways to improve measurement and treatment of disorders related to their

impaired functioning, there is no question the laryngeal and pharyngeal musculature

must be considered distinct and unique from limb skeletal muscle.

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Chapter 10

Motor Control and Biomechanics of Laryngeal


Christy L. Ludlow

10.1 Introduction to the Integrative Systems Controlling

the Laryngeal and Pharyngeal Musculature

The purpose of this chapter is to review motor control and biomechanics of the

laryngeal and pharyngeal muscles with an emphasis on their control for voice,

speech, respiration, and swallowing in humans. The amount of knowledge in this

area is relatively sparse compared with limb control. The laryngeal and pharyngeal

muscles are controlled by several integrative systems in the central nervous systems

which differ in their origin, development and motor control, and biomechanical

demands. Vocalization for the expression of emotion and pain in mammals, such as

the birth cry in humans and the isolation cry in young mammals, depends upon a

complex integration of vocal fold closure, expiratory air fl ow from the lungs to set

the vocal folds into vibration with the build-up of subglottal pressure, and oral

opening to emit the resulting cry. The neural substrates important for this innate

vocalization system have been studied in mammals such as the cat and the squirrel

monkey and involve the periaqueductal gray, the pons, and the reticular integrative

system in the medulla (Jurgens 2009 ) . Voice for speech requires integration of

vocal fold adduction (closing) with expiratory air fl ow and oral shaping, in addition

to precise control of intrinsic laryngeal muscles to alter vocal fold tension controlling

frequency of vibration (the fundamental frequency). In addition, rapid and

small changes in laryngeal muscles are needed for vocal fold opening and closing

C. L. Ludlow , Ph.D. (*)

Department of Communication Sciences and Disorders, Rm. HHS 1141, MSC 4304 ,

James Madison University , 801 Carrier Drive , Harrisonburg , VA 22807 , USA

e-mail: ludlowcx@jmu.edu




167

168 C.L. Ludlow

for voiced and voiceless consonants. Both the laryngeal and pharyngeal muscles

are used in voice and speech for communication in humans; Not only are the laryngeal

muscles used to control the fundamental frequency and voicing, the shape and

position of the tongue and pharynx are used to alter resonance to amplify certain

harmonics of the fundamental frequency for producing vowel sounds (Borden and

Harris 1984 ) .

Speech gestures are learned in humans from infancy and differ in neural control

mechanisms from innate vocalizations present in other mammals. These largely

depend upon functional relationships between cortical regions involved in speech

perception and production. The production of speech sounds is guided by speech

perception (Hickok et al. 2011 ) ; the infant must learn to manipulate air fl ow on

exhalation to produce similar sounds to those in their environment. With language

acquisition, they are able to produce novel combinations of speech sounds that are

recognizable by listeners of the same language. This becomes a relatively automatic

motor control behavior by late adolescence (Smith and Zelaznik 2004 ) . Table 10.1

summarizes the intrinsic laryngeal muscles and their actions.

Swallowing involves patterns of neural control in the medulla that produce a

rapid sequence of pharyngeal muscle contractions producing sequential pressures

for bolus passage via the hypopharynx through the upper esophageal sphincter

(Kahrilas et al. 1992 ) . With development in childhood, swallowing can come under

volitional cortical control in humans. By adulthood the cortical activation during

both volitional and spontaneous swallowing is somewhat similar (Martin et al.

2001 ) . With the descent of the larynx in the upper airway in humans, prevention of

bolus entry into the airway depends upon laryngeal elevation and epiglottic inversion

during swallowing. The need to integrate swallowing with breathing in adult

humans is critical with normal swallowing occurring primarily during expiration

(Hardemark Cedborg et al. 2009 ) .

Therefore, the neural control of the laryngeal and pharyngeal muscle groups for

innate vocalization, voice and speech, and swallowing, may involve different integrative

neural control systems, some which are present at birth while others emerge

with development to involve cortical mechanisms and learning. By adulthood, the

laryngeal and pharyngeal muscles are controlled by relatively automatic patterns,

involving both re fl exive and volitional control in the central nervous system. These

functions are not under explicit motor control in humans. The patterning of the

laryngeal muscles for these functions varies across individuals and from time to

time (Poletto et al. 2004 ) . This has made them dif fi cult to study in humans, while

the cortically based neural substrates involved in these functions in animals are

dif fi cult to study because of anesthesia or decerebrate preparations being required.

Few have studied the neural mechanisms involved in laryngeal and pharyngeal

muscle patterning for vocalization and swallowing in naturally behaving awake

animals (Grohrock et al. 1997 ) .

Given these limitations, this chapter will address current understanding of the

motor control and biomechanics of the laryngeal and pharyngeal muscles for vocalization,

speech, and swallowing in mammals and humans in particular.

10 Motor Control and Biomechanics of Laryngeal and Pharyngeal Muscles

169

Table 10.1 Intrinsic laryngeal muscles, their insertion points, contraction effects, function for voice, respiration and swallowing, and innervations

Muscle Insertions Effects of contraction Task function Innervation

Adductor muscles

Thyroarytenoid Anterior surface of the arytenoid

cartilage to the inner surface

of the thyroid

Lateral

cricoarytenoid

Muscular process of the arytenoid

to the upper lateral surface of

the cricoid’s rim

Interarytenoid Lateral fi bers between the

arytenoids and diagonal fi bers

form the tip of the arytenoids

to the lateral aspect of the

opposite arytenoid

Abductor muscle

Posterior

cricoarytenoid

From muscular process to the

posterior surface of the

cricoid, various angles of

insertion of different

compartments

Lengthening muscle

Cricothyroid Upper surface of the cricoid to the

internal surface of the thyroid

cartilage (rectus) and lateral

surface of the cricoid to the

thyroid cartilage (oblique)

Shortens the vocal fold and

pulls the vocal process

downward

Pulls the muscular process

forward towards the

cricoid’s rim

Fixes the two arytenoids

during adduction

Opens the vocal folds by

pulling the muscular

process backwards

rocking the arytenoids

cartilage and elevating

and opening the vocal

process

Pulls the thyroid cartilage

forwards and downwards

over the cricoid’

cartilage stretching the

vocal folds

For sphincteric closure during

swallowing, partial adduction in

active respiration, vocal fold closure,

and co-contraction with cricothyroid

to tense to increase fundamental

frequency of vibration during voice

Vocal fold adduction, bursts seen on

vocal fold closure, and opening

during speech

Not well studied because of inaccessibility

in human for

electromyography

Opens the vocal folds for inhalation and

sniff and for voice offset for

voiceless consonants during speech.

May contract during increase in

fundamental frequency to stabilize

the arytenoids during high levels of

thyro arytenoid and cricothyroid

co-contraction

Active during sniff to stretch the vocal

folds as they open, co-contraction

with the thyroarytenoid to tense the

vocal fold to increase fundamental

frequency during vibration

Adductor branch of the

recurrent laryngeal

nerve, unilateral

only


recurrent laryngeal

nerve


recurrent laryngeal

nerve, may have

some bilateral

innervation

Abductor branch of the

recurrent laryngeal

nerve

External branch of the

superior laryngeal

nerve

170 C.L. Ludlow

10.2 Innervation of the Laryngeal Muscles

Only the cricothyroid is innervated by the external branch of the superior laryngeal

nerve (eSLN) while all of the other intrinsic laryngeal muscles are innervated by

branches emerging from the recurrent laryngeal nerve (RLN). The pathway of the

RLN descends from the vagus around the aortic arch on the left side and then

ascends in the tracheoesophageal groove to the posterior larynx where branches

emerge as it enters the larynx posteriorly. However, the pathway of the RLN both

between individuals and between the left and right sides is variable. On the right

side, the RLN loop downwards and then back upwards in the tracheoesophageal

groove but about 0.5% of persons have a non-RLN on the right, based on data from

thyroidectomies (Toniato et al. 2004 ) . However, a non-RLN may be misidenti fi ed

and confused with other nerves such as the communicating branch of the recurrent

(Maranillo et al. 2008 ) , leading to disagreements about the prevalence of non-RLN

on the right in persons (Raffaelli et al. 2000 ) . In addition, branching and a more

variable path occurs more often on the right (Chiang et al. 2012 ) leading to a more

variable outcome affecting vocal fold movement following thyroid and parathyroid

surgery (Casella et al. 2009 ) . Variability in the number and character of extralaryngeal

branches on either the left or right sides may occur in 64.5% of cases (Cernea

et al. 2009 ) leading to more laryngeal complications post-surgery (Coady et al.

2000 ) .

The RLN branches to the different intrinsic laryngeal muscles as it enters the

larynx on each side are also variable. The predominant pattern involves a branch

coming off the RLN near the posterior cricoarytenoid (PCA) muscle, the only muscle

providing abduction (opening) of the vocal folds. However, the branch going to

the PCA may have as many as three branches dividing from the RLN or branching

again after the abductor branch emits from the RLN when examined in cadavers

from normal cases (Damrose et al. 2003 ) . Variations in branches coming off the

RLN before entry into the larynx have been reported in 8.65% of cases undergoing

thyroidectomy and may account for transient vocal fold paresis (Shao et al. 2010 ) .

After branching to the PCA the course of the adductor branches can also be variable.

The anterior branch to the interarytenoid was also variable in its branching pattern

when examined in cadavers (Damrose et al. 2003 ) . A more recent study of RLN

branches going to the adductor intrinsic muscles in 75 postmortem larynges showed

extensive variability in the human RLN branching pattern with the adductor branch

coming off the PCA branch in 88% of cases (Maranillo et al. 2005 ) . As many as

8 branches and more commonly 5–6 branches were identi fi ed that could innervate

parts of the adductor muscles including the interarytenoid, lateral cricoarytenoid

(LCA), and the thyroarytenoid (TA) muscles. Only the interarytenoid received both

ipsilateral and contralateral RLN innervation as well as from the internal branch of

the superior laryngeal nerve (iSLN). Branches from the iSLN went to both the

mucosa, into the interarytenoid intramuscularly or to join with branches from the

RLN in a super fi cial arytenoid plexus in 84% of larynges containing both ipsilateral

and contralateral fi bers.


171

The LCA muscle primarily received branches from the ipsilateral RLN; only in

a few cases fi bers from the eSLN were identi fi ed as innervating this muscle

(Maranillo et al. 2005 ) , and the numbers of branches from the RLN to the LCA

varied from 1 to 8. The thyroarytenoid muscle also varied in the numbers of branches

from the RLN (1–6, with a mean of 1.6) and arose either from the branch to the

PCA, IA, or LCA. Only 4.6% of larynges received innervation from another nerve

than the RLN, the source being the eSLN (Maranillo et al. 2005 ) .

Interlaryngeal variation in RLN branches to the intrinsic laryngeal muscles

complicates the interpretation of the bases for reductions in vocal fold motion in

abduction and adduction. It also impacts the outcome of attempts to selectively

stimulate individual laryngeal muscles or to reinnervate particular intrinsic laryngeal

muscles for breathing (PCA), voice (TA, LCA) or for closure airway protection

during swallowing (IA, TA).

In spasmodic dysphonia, abnormal bursting of motor neuron fi ring patterns leads

to voice disruptions during speech (Ludlow et al. 2008 ) . Currently, anastomosis of

the RLN branch(es) to the TA to the ansa cervicalis is used to permanently denervate

the TA muscle from axons in the RLN which produce spasms in these patients (Berke

et al. 1999 ) . This procedure identi fi es the adductor branch of the RLN going to the

TA muscle and prevents reinnervation of the TA muscle by the RLN. On the other

hand, following laryngeal denervation, consideration of the RLN branching pattern

may be considered for selective reinnervation of the PCA and IA to restore volitional

abduction and adduction of the vocal folds, respectively (Kwak et al. 2010 ) .

10.3 Central Nervous System Control of the Laryngeal

Motor Neurons

The laryngeal muscles are innervated by motor neurons in the ipsilateral nucleus

ambiguus in the medulla (Davis and Nail 1984 ) with the CT motoneurons located

more rostrally while the PCA, TA, and LCA motoneurons are located more caudally.

Injury to the motor neurons in the nucleus ambiguus affects the ipsilateral

laryngeal muscles except the interarytenoid which may have some bilateral innervation.

Vagal or recurrent nerve injury results in at least short term unilateral vocal fold

paralysis. However, central nervous system injury rarely results in unilateral vocal

fold movement impairment except when there is damage to the laryngeal motor

neurons or disruption of the pre-synaptic input to the motor neurons in the brain

stem as in lateral medullary stroke or Wallenberg syndrome (Kim et al. 2000 ;

Aydogdu et al. 2001 ) . Cortical lesions do not result in unilateral vocal fold paralysis

suggesting that there is bilateral supramedullary input to the laryngeal motor neurons

in the medulla. However, unilateral vocal fold movement reduction (bowing)

can occur in Parkinson disease (Hanson et al. 1984 ) on the same side as limb involvement

suggesting more laterality in control above decussation in the substantia nigra

and medulla, regions involved early in Parkinson disease (Braak et al. 2003 ) .

172 C.L. Ludlow

Transcranial magnetic stimulation has been used in human to map the cortical

region controlling the laryngeal muscles (Khedr and Aref 2002 ; Rodel et al. 2004 ) .

Both groups reported bilateral muscle response latencies of approximately 10.8 ms

in the CT and TA muscles, respectively, when the primary motor cortex was stimulated

unilaterally while the left and right TA muscles had latencies of 11.7 ms and

10.7 ms, respectively. These latencies are dif fi cult to explain given the difference in

length of the RLN which innervates the TA muscle and eSLN which innervates the

CT. Further no difference in latency was noted between responses in the right and

left TA muscles despite the signi fi cant length differences due to the longer course of

the left RLN which descends below the aortic arch on the left. In fact, previous

research in both dogs and human has shown a 3 ms latency difference in latency of

TA response between the right and left sides (Atkins 1973 ) and similar latency differences

between the left and right sides were found when transcranial magnetic

stimulation was applied over the mastoid where the vagus emits from the skull (Sims

et al. 1996 ) . A 2.3 ms latency was found between the right and left TA muscles, a

4.86 latency between the TA and CT on the left and 1.6 ms difference on the right.

Given the cortical to muscle latencies of 10.7 which are less than a millisecond later

than the peripheral responses, it is likely that these reports (Khedr and Aref 2002 ;

Rodel et al. 2004 ) include direct nerve responses as the magnetic fi eld at the cortex

induced peripheral nerve responses as has been found in other cranial nerve using

TMS (Benecke et al. 1988 ) . A more careful TMS study using more focal coils is

needed to examine the cortico-bulbar pathway to the laryngeal muscles in humans.

10.4 Pharyngeal Muscles

The pharyngeal muscles can be divided into those that open (dilate) the oropharynx

airway (Jordan and White 2008 ) and those that close the airway or constrict the

pharynx to propel a bolus through the upper esophageal constrictor during swallowing

(Perlman et al. 1989, 1999 ) . During inspiration, the upper airway muscles dilate

in a sequential chain beginning at the nares to reduce resistance to air fl ow inwards

(Strohl et al. 1980 ) . The dilator pharyngeal musculature have been studied by respiratory

physiologists concerned with obstructive sleep apnea when the dilator musculature

is reduced in activity resulting in a collapse of the upper airway (Horner

and Guz 1991 ) . These include the genioglossus (GG), the palatal, and the hyoid

muscles (Table 10.2 ). The genioglossus has received the greatest attention as its

contraction will move the posterior tongue forward opening the posterior oropharynx

to allow air fl ow through the posterior pharynx and into the glottis. The GG is

innervated by the hypoglossal motor neurons which are activated by respiratory

modulators including hypercapnia (Nicholas et al. 2010 ) and negative pressure in

the airway (Brennick et al. 2001 ) . Because of the signi fi cant role of the genioglossus

in upper airway dilation, use of hypoglossal nerve stimulation for prevention of

obstruction in patients with obstructive sleep apnea is continuing to receive attention

(Smith et al. 1996 ; Eisele et al. 1997 ; Mann et al. 2002 ; Oliven et al. 2003 ) .


173

Table 10.2 Dilator and constrictor pharyngeal muscles: their insertion points, contraction effects, function for respiration and swallowing, and innervations


Dilator muscles for inspiration

Levator veli From the petrous part

palatini

of the temporal

bone to the soft

palate

Tensor palatini From the medial

pterygoid plate to

the aponeurosis of

the palate

Genioglossus Genu of mandible to

tongue surface

Anterior belly of

the digastric

Internal surface of the

mandible to the

lateral surface of the

hyoid bone

Mylohyoid Lateral inner surface of

the mandible to the

aponeurosis of the

mylohyoid and the

anterior hyoid bone

Geniohyoid From the anterior hyoid

to the inner surface

of the mandible

Thyrohyoid Hyoid to the middle of

the lateral surface of

the thyroid cartilage

Elevates the velum to the

posterior wall of the

pharynx

Increased stiffness and pulls the

soft palate upwards towards

the posterior wall of the

pharynx

Moves the tongue forward,

tongue protrusion

Pulls the jaw open or elevates

the hyoid if the jaw is closed

Elevates the hyoid by stiffening

and shortening to elevate the

fl oor of the mouth

Inspiratory phase of respiration, also

active to close the nasopharynx

during swallowing and most speech

sounds

Aids in inspiration to elevate the soft

palate and during swallowing

prevents entry of the bolus into the

nasopharynx

Pharyngeal branch of the

vagus

Medial pterygoid nerve of

the mandibular branch

of the trigeminal

Inspiratory phase of respiration Medial branch of the

hypoglossal

Inspiratory phase of respiration, jaw

opening during most speech sounds

Active during swallowing to pull the

hyoid bone upwards towards the

mandible

Pulls the hyoid anteriorly Important for dilation of the hypopharynx

and elevation of the hyoid and

vestibule closure to prevent

aspiration during swallowing

Either lowers the hyoid or

elevates the thyroid cartilage

if the hyoid is held upwards

Active during swallowing to pull the

thyroid and larynx up beneath the

epiglottis

Mylohyoid nerve, a

branch of the inferior

alveolar nerve, and the

mandibular division of

the trigeminal

Mylohyoid nerve, a branch

of the inferior alveolar

nerve, off the

mandibular nerve, off

the trigeminal nerve

First cervical spinal nerve

branching off the

hypoglossal

First cervical spinal nerve

branching off the

hypoglossal

(continued)

174 C.L. Ludlow

Table 10.2 (continued)


Constrictor muscles for swallowing

Hyoglossus Hyoid to the root of the

tongue

Styloglossus Side of the tongue to

the styloid process

Upper pharyngeal

constrictor

Middle pharyngeal

constrictor

Lower pharyngeal

constrictor

Hamulus of the

pterygoid bone,

pterygomandibular

raphe, mylohyoid

line of mandible

and lateral on the

tongue muscles

Superior and inferior

horns of the hyoid

bone, stylohyoid

ligament

Thyroid cartilage and

lateral side of

cricoid cartilage

Cricopharyngeus Circular muscle

meeting at the

median raphe

posteriorly

Pulls the root of the tongue

downwards towards the

epiglottis to push the posterior

base of tongue downwards in

the posterior oropharynx

Pulls the sides and back of the

tongue upwards and backwards

constricting the

posterior oral pharynx

Active during swallowing to bring

posterior tongue downwards to add

pressure to epiglottis to aid in

inversion and closing of the

vestibule

Helps to push the bolus backwards and

down the pharynx for swallowing

Squeezes the pharynx closed Active for swallowing to push the bolus

downwards in the pharynx towards

the upper esophageal sphincter







Closes to prevent regurgitation of

esophageal contents

Relaxes and opens at the end of

pharyngeal phase of swallowing to

allow the bolus to enter the

esophagus and then closes to

prevent regurgitation of esophageal

contents

Hypoglossal nerve

Hypoglossal nerve

Pharyngeal plexus of the

vagus, and external

branch of the superior

laryngeal nerve


vagus


vagus


vagus, external branch

of the superior

laryngeal nerve and a

branch of the recurrent

laryngeal nerve


175

Other muscles that dilate the upper pharynx include the levator veli palatini

and the hyoid muscles (mylohyoid, thyrohyoid, hyoglossus, and geniohyoid)

(Table 10.2 ). The levator veli palatini elevates the velum, closing off the velopharyngeal

port to prevent entry of the bolus into the nasal cavity during swallowing

and air fl ow during all speech sounds except the nasal sounds (/m/,/n/,/ng/). Elevating

the velum also serves as an upper airway dilator as it opens the hypopharynx, allowing

an increased opening for air fl ow into the hypopharynx.

During swallowing, changes in upper airway shape and pressures assure rapid

and complete passage of the bolus (food or liquid) through the oral cavity, hypopharynx,

and upper esophageal sphincter into the esophagus. Oral transit starts with

closure of the lips and jaw to prevent spillage, collection of the bolus into one mass,

and a stripping motion of the tongue blade against the roof of the mouth to move the

bolus backwards into the posterior pharynx. Prior to passage of the bolus through

the pharynx, the hyoid moves forwards and upwards to dilate the hypopharynx to

allow entry of the bolus while closing the upper airway by tucking the larynx forwards

and upwards under the epiglottis. The epiglottis becomes inverted over the

entry to the laryngeal vestibule by posterior action of the tongue over the hyolaryngeal

complex as it elevates under the tongue, squeezing the epiglottis downwards

(Fig. 10.1a ). Elevation of the hyo-laryngeal complex involves contraction of

the suprahyoid muscles pulling the hyoid forward and upward (geniohyoid,

mylohyoid, hyoglossus). Simultaneous contraction of the thyrohyoid is required to

elevate the thyroid cartilage to the hyoid as the hyoid is raising to close the laryngeal

vestibule reducing the risk of bolus entry into the airway (Fig. 10.1a ). Passage of the

bolus through the pharynx begins with pressure of the posterior tongue towards the

posterior pharyngeal wall while dilating the anterior pharynx though anterior elevation

of the hyo-laryngeal complex. Subsequent sequential squeezing actions of the

pharyngeal constrictors from superior to middle and inferior push the bolus downwards.

Opening of the upper pharyngeal sphincter is achieved through two actions,

anterior–superior movement of the larynx stretching the cricopharyngeus (Fig. 10.1b )

and re fl exive relaxation of the cricopharyngeus.

10.5 Pharyngeal Innervation

The human pharyngeal constrictor muscles have two distinct layers, an outer fast

layer innervated by the vagus and a slow acting inner layer innervated by the

glossopharyngeal nerve (Mu and Sanders 2007 ) . Mu and Sanders hypothesized that

the slow acting inner layer maintains stiffness in the pharyngeal wall for dilation for

respiration while the fast outer wall is essential for rapid and forceful contraction to

increase pressure on the bolus and push it downwards in the hypopharynx towards

the upper esophageal sphincter during swallowing. The inferior pharyngeal constrictor

also has a two layered structure but has rostral and caudal compartments

with the caudal portion having immunohistological characteristics similar to the

cricopharyngeus muscle. For that reason, it has been proposed that the inferior

176 C.L. Ludlow

a

MH

HG

Bolus

aspiration

GH

Effects of hyo-laryngeal elevation

on Airway protection

HG

b

MH

GH

UES

UES

Effects of hyo-laryngeal elevation

on opening the UES

Fig. 10.1 ( a ) Schematic illustration of the muscle vectors to raise the hyo-laryngeal complex to

close the laryngeal vestibule and protect the airway from bolus entry. ( b ) A schematic illustration

of how hyo-laryngeal elevation can stretch the cricopharyngeus to assist with the movement of the

bolus through the upper esophageal sphincter. The muscles are mylohyoid (MH), geniohyoid

(GH), hyoglossus (HG), and thyrohyoid (TH). The upper esophageal sphincter is labeled UES

pharyngeal constrictor functions as part of the upper esophageal sphincter along

with the cricopharyngeus (Mu and Sanders 2001 ) .

The upper esophageal sphincter is a complex structure. First, Mu and Sanders

have recently described the cricothyropharyngeus muscle found only in human specimens

(Mu and Sanders 2008 ) . This muscle originates from the anterior arch of the

cricoid cartilage, courses between the inferior pharyngeal constrictor and cricopharyngeus

muscles to insert into the median raphe at the posterior midline of the pharynx

with separate innervation of two compartments; a laryngeal portion innervated

by the external superior laryngeal nerve, and a pharyngeal portion innervated by the

pharyngeal plexus. The cricopharyngeus forms the major part of the upper esophageal

sphincter and is of great importance to swallowing—this muscle is normally

tonically active keeping the sphincter closed to prevent spillage of the contents of the

upper esophagus into the hypopharynx and the upper airway. Relaxation is essential

to allow the bolus to be cleared out of the hypopharynx and into the esophagus.

Without relaxation and bolus clearance there is the collection of residual of the bolus

which will collect in the pyriform sinuses, and spillage back into the glottis and

through the vocal folds places the person at risk of aspiration of food or liquid into


177

the lungs. Innervation of the cricopharyngeus is controversial and may include the

pharyngeal plexus, the glossopharyngeal nerve, the cervical sympathetic ganglion or

the RLN or a combination of these (Brok et al. 1999 ) . Clinical studies in humans

have investigated the relationship between RLN and the cricopharyngeus muscle with

some suggesting that the RLN may contribute innervation (Brok et al. 1999 ) while

others have found no relationship (Halum et al. 2006 ) . As Mu and Sanders (1998 )

suggested, several muscles are involved in this upper esophageal sphincter with different

innervation patterns; the inferior pharyngeal constrictor is innervated by the

pharyngeal plexus, while the cricopharyngeus may receive innervation from both the

pharyngeal plexus and the RLN. The more recently identi fi ed cricothyropharyngeus

is innervated by the eSLN and the pharyngeal plexus (Mu and Sanders 2008 ) .

10.6 Sensory-Motor Interactions Controlling

the Laryngeal and Pharyngeal Muscles

For airway protection and swallowing, sensory inputs to mechanoreceptors in the

laryngeal mucosa elicit brainstem re fl exes that produce vocal fold closure (Sasaki

and Suzuki 1976 ; Andreatta et al. 2002 ) referred to as the glottic closure re fl ex or

laryngeal adductor response (LAR) (Ludlow et al. 1992 ) , while pharyngeal stimulation

with water elicits a pharyngoglottal closure re fl ex and re fl exive swallow (Shaker

et al. 1998, 2003 ) . The importance of sensory triggers for the elicitation and motor

production of swallowing was demonstrated in healthy young volunteers when

anesthesia in the region of the iSLN not only interfered with the initiation of swallowing

but produced both penetration and aspiration during swallowing in normal

persons (Jafari et al. 2003 ) . Aviv and his colleagues measured laryngeal sensation in

patient with strokes who were with and without dysphagia and suggested that many

patients with aspiration had disruption of the LAR (Aviv et al. 1996 ) . However, this

has been controversial with some investigators supporting this association (Flaksman

et al. 2006 ) while others have questioned this association (Widdicombe and

Addington 2006 ) . Stimulation of the laryngeal mucosa for testing whether or not

upper airway re fl exes are intact for laryngeal closure is used clinically (Aviv et al.

1998 ) but needs further study to determine the role of this re fl ex in airway protection

during swallowing. One study demonstrated that this re fl ex was actually suppressed

during swallowing (Barkmeier et al. 2000 ) , although it remained intact

during voice and speech (Henriquez et al. 2007 ) .

The powerful effects of sensory stimulation to the glossopharyngeal and superior

laryngeal nerve for eliciting re fl ex swallowing has recently received attention as a

method for inducing swallowing in patients with swallowing disorders secondary to

neurological diseases or disorders. Using air pulse stimulation to the faucial pillars,

Martin and colleagues have shown that this can increase the frequency of swallowing

both in healthy persons as well as in the aged (Theurer et al. 2005, 2009 ) .

Both mechanical and electrical stimulation to the pharyngeal branch of the

glossopharyngeal nerve and to the iSLN, and electrical stimulation to the pharynx

178 C.L. Ludlow

wall are powerful stimuli for inducing fi ctive swallowing in the rat (Kitagawa et al.

2002, 2009 ) . This has recently been used clinically for inducing the return of swallowing

in stroke patients by use of electrical stimulation to the pharyngeal wall

(Jayasekeran et al. 2010 ) . The powerful effects of sensory triggers to the brainstem

centers controlling the laryngeal and pharyngeal muscles for swallowing are an

attractive mechanism for enhancing re fl exogenic swallowing in patients who have

lost volitional control.

10.7 Central Neural Control of the Laryngeal


Some neural substrates controlling this automatic motor patterning for voice and

speech are located in the cortex. Brain lesions or disease affecting the basal ganglia,

cerebellum, and thalamus often produce a slowing or a loss of the normal rhythm of

speech, producing disorders referred to as dysarthrias but the pattern of muscle

activation for the production of speech sounds is retained. Only when damage

involves cortical regions or interactions of other brain regions with the cortex is the

motor pattern for speech articulation disturbed, resulting in the loss, distortion, or

errors in speech articulation programming accuracy resulting in a disorder referred

to as apraxia of speech (Kent 2000 ) .

Vocalization which is not based on speech or singing is present at birth (the birth cry)

and depends upon mammalian vocalization systems which are contained in the brain

stem, pons, and periaqueductal gray and have a similar bases in humans as in other

mammals (Jurgens 2000 ) . In contrast, voice production for speech is cortically based

and unique to human species (Jurgens 2002 ) . As a result, studies of the neural control

of voice and speech in humans are limited to the study of the effects of brain lesions

or more recently to functional brain imaging and transcranial magnetic stimulation.

The neural substrates for swallowing involve subcortical brain mechanisms that

are similar in humans and other mammals and involve patterning of the laryngeal

and pharyngeal muscles. Cortical control for the volitional elicitation of swallowing

on command is also present in the human and has more recently been studied using

functional brain imaging showing cortical control is present similarly for volitional

and automatic swallowing (Martin et al. 2001, 2007 ) while brainstem control centers

are also active (Komisaruk et al. 2002 ) .

10.8 Effects of Neurological Diseases on Laryngeal

and Pharyngeal Muscle Control

Motor control for speech and swallowing are affected by a multitude of neurological

diseases. Peripheral neuropathies that are length dependent and impacted by the

RLN, the longest nerve innervating craniofacial muscles, are often affected by


179

genetic mutations resulting in neural transport abnormalities (Benson et al. 2010 ;

Landoure et al. 2010 ) . Brain stem strokes in the lateral medullary region, referred to

as Wallenberg syndrome, disrupt pre-synaptic input to the laryngeal motor neurons

in the nucleus ambiguus, resulting in a unilateral vocal fold paralysis for voice and

swallowing. In addition, lateral medullary lesions often result in a serious disturbance

in swallowing patterning as the integrity of the brainstem central pattern

generator for swallowing is affected on one side (Kim et al. 2000 ; Aydogdu et al.

2001 ) . Disorders and diseases of the basal ganglia can interfere with the timing of

muscle patterning and level of muscle activation. Most prominent are those that

accompany Parkinson’s disease particularly as the disease progresses (Dickson and

Grunewald 2004 ) to involve regions well beyond the substantia nigra (Braak et al.

2003 ) impacting the precision of recruitment of laryngeal muscles for rapid voice

onset and offset during speech (Gallena et al. 2001 ) .

Given the important contribution of cortical mechanisms in the left hemisphere

for speech and voice production, mechanisms of enhancing left hemisphere cortical

control while suppressing interfering brain mechanisms in the right hemisphere

have recently received a great deal of attention. Using transcranial magnetic stimulation

at slow rates which are inhibitory to motor function over the right hemisphere

has been found to induce recovery in a few patients with motor speech disorders

(Martin et al. 2009a, b ; Hamilton et al. 2010 ) .

For the elicitation of swallowing, sensory stimulation seems to enhance the elicitation

of re fl exogenic swallowing, perhaps at the brain stem level. However, recent

studies using functional magnetic resonance imaging now suggest that the application

of sensory stimulation in the oropharynx can enhance cortical activation not

only in the somatosensory regions but also in regions of the cortex that are active for

the volitional control of swallowing in normal humans (Lowell et al. 2008 ; Soros

et al. 2008 ) , indicating that sensory stimulation may be useful in up-regulating cortical

motor control mechanisms involved in the control of both the laryngeal and

pharyngeal muscles for automatic and volitional swallowing.

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Chapter 11

Laryngeal Muscle Response to Neuromuscular

Diseases and Speci fi c Pathologies

J. C. Stemple , L. Fry, and R. D. Andreatta

Musculature of the craniofacial region represents a diverse group of skeletal muscles

responsible for processes underlying respiration, deglutition, speech production,

vision, hearing, and the display of emotions. Together, these muscles demonstrate a

remarkable degree of anatomical specialization that permits their successful engagement

in behavioral functions. Because the functional demands placed upon craniofacial

muscles differ substantially from those imposed upon other skeletal muscles, the

craniofacial muscles show marked anatomical, physiological, and biological deviations

from typical limb skeletal muscles. The uniqueness of the craniofacial muscle

phenotype has led to their being described by some as “paradoxical” members of the

skeletal muscle group (Noden and Francis-West 2006 ) .

It is increasingly recognized that the anatomical and physiological differences

that exist between craniofacial and limb skeletal muscles are vast. Architectural differences

related to muscle insertion patterns, fascicle orientation, muscle fi ber size,

and sarcomeric structure have been noted (Porter and Baker 1996 ; Andrade et al.

2003, 2004, 2005 ; Porter et al. 2003 ; Sadeh et al. 1981 ) . Additionally, differences in

contractile protein expression, mitochondrial content, neuromotor innervation, and

contraction-related proprioceptive mechanisms have recently been documented.

These latter specializations produce functional differences in contractile times, force

generation, fatigability, and motor unit recruitment patterns (Porter and Baker 1996 ;

Zemlin 1988 ; Bendiksen et al. 1981 ; Brandon et al. 2003a, b ; Perie et al. 1997,

2000 ; Rossi and Cortesina 1965 ; Sciote et al. 2002 ; Shiotani and Flint 1998 ; Shiotani

et al. 1999 ; Konig and von Leden 1961 ; Close and Luff 1974 ; Luff 1981 ; Lynch

et al. 1994 ) . The exact nature of the distinctive phenotype of craniofacial muscle has

yet to be elucidated; however, it has been suggested that phenotypic diversity is

J. C. Stemple (*) • L. Fry • R. D. Andreatta

Division of Communication Sciences and Disorders , University of Kentucky ,

900 South Limestone Street , Lexington , KY 40536 , USA

e-mail: joseph.stemple@uky.edu




185

186 J.C. Stemple et al.

established during morphogenesis and is later regulated and in fl uenced by musclegroup

speci fi c patterns of gene expression (Noden and Francis-West 2006 ; Spencer

and Porter 2006 ; Cheng et al. 2004 ; Fischer et al. 2005 ) .

The consequences of the biological and functional diversity between craniofacial

and limb skeletal muscle are signi fi cant. Specialized phenotypes of craniofacial

muscles likely underlie and permit these muscles to (1) engage in extremely rapid

yet prolonged contraction, (2) contribute to highly re fi ned patterns of movement,

(3) recover consequently from mechanical and neurological insult, (4) resist the

in fl uence of aging and lastly, (5) escape the pathological cascade of select neuromuscular

diseases (Porter and Baker 1996 ; Zemlin 1988 ; Spencer and Porter 2006 ;

Cheng et al. 2004 ; Marques et al. 2007 ; McLoon et al. 2004, 2007 ; Muller et al.

2001 ; Norton et al. 2001 ; Thomas et al. 2008 ; Pavlath et al. 1998 ) . One subset of the

craniofacial muscles emerging as highly specialized in the mammal is the intrinsic

laryngeal muscles (ILMs). The ILMs are intricately involved in the life-sustaining

functions of respiration, airway protection, and swallowing, with critical secondary

functions in vocalization and communication behaviors (i.e., human speech).

11.1 Differences in Limb vs. Craniofacial Muscles

Point to the Existence of Unique Phenotypes

It has been well established that limb skeletal muscle has the capacity to regenerate

in the face of injury via the action of satellite cells. After myo fi ber injury for example,

satellite cells progress from a quiescent state to an active state. Once active,

these cells move to the site of injury, fuse with one another, and differentiate into

new myo fi bers (Mauro 1961 ) . However, recent work in the extraocular muscles

(EOM) and laryngeal muscles of rabbits suggests that myo fi ber remodeling is an

ongoing event in these select muscle groups, occurring in the absence of any apparent

fi ber injury (McLoon et al. 2004 ; Goding et al. 2005 ; Shinners et al. 2006 ) .

Seminal work in this area by McLoon et al. ( 2004 ) found evidence of continual

myonuclear removal and addition in uninjured single fi bers of rabbit EOM.

Remodeling was noted to proceed at a rate of one myonuclear addition per 1,000

myo fi bers in cross section every 12 h. Subsequent work by Goding et al. ( 2005 )

identi fi ed similar patterns of uninjured fi ber remodeling in rabbit thyroarytenoid

(TA) and posterior cricoarytenoid (PCA) muscles, estimating that myonuclear addition

in the laryngeal muscles occurred at a rate of 2 myonuclei per 1,000 myo fi bers

in cross section per 24 h. Together, these fi ndings suggested that muscle precursor

cells, generally quiescent in limb skeletal muscle, are continuously active in subsets

of craniofacial muscles, and that this enhanced remodeling capacity may be related

to the great potential of these muscles to recover after insult (Goding et al. 2005 ;

McLoon et al. 2004 ) .

Along this same vein, the laryngeal muscles have long been recognized for their

ability to survive and reinnervate following neurological insult (Gardner and

Benninger 2006 ; Nomoto et al. 1993 ; Shindo et al. 1992 ) . Following denervation of

11 Laryngeal Muscle Response to Neuromuscular Diseases and Speci fi c Pathologies

187

a vocal fold, reinnervation ensues in a portion of cases, even after extended periods

of time (Shindo et al. 1992 ) . This marked ability to reinnervate has not been fully

explained; however, it has been suggested that regenerating axons from the damaged

nerve or supplemental innervation from the superior laryngeal nerve (SLN)

may play a role (Nomoto et al. 1993 ; Shindo et al. 1992 ) . Such patterns of reinnervation

and muscle maintenance post-insult are not observed in limb skeletal muscle,

where reinnervation is less common and denervation atrophy can be marked (Engel

and Banker 1994 ; Watras 2004 ; Kobayashi et al. 1997 ) .

11.2 Differences in Limb and Craniofacial Muscle

Response to Neuromuscular Disease and Injury

Most neuromuscular diseases exert their pathological cascade universally across

skeletal muscles. However, some craniofacial muscles respond uniquely to neuromuscular

disease challenges that target typical skeletal muscle. For example,

differential response of the extraocular and laryngeal muscles in Duchenne muscular

dystrophy (DMD), amyotrophic lateral sclerosis (ALS), myasthenia gravis, and

mitochondrial myopathy have been recently documented (Porter and Baker 1996 ;

Spencer and Porter 2006 ; Fischer et al. 2005 ; Marques et al. 2007 ; Thomas et al.

2008 ; Kaminski et al. 1992 ; Andrade et al. 2000 ) . Generally, the neuromuscular and

cell biological underpinnings for the EOM and ILM’s unique responsiveness to

these select disorders have not been fully explained, and the mechanism of the

group’s differential response in these diseases has not yet been determined. Current

hypotheses suggest that constitutive features of the laryngeal muscles (e.g., exquisite

remodeling capabilities, fi ber types, re fi ned calcium sequestration mechanisms,

and/or lower levels of mechanical force generation during contraction) may play a role

(Andrade et al. 2000 ; Karpati et al. 1988 ; Kjellgren et al. 2003 ; Lexell et al. 1986 ) .

The following section highlights the cell biology response of ILM to select neuromuscular

diseases and speci fi c pathologies for which any empirical data exist.

11.3 Laryngeal Muscle Response to Muscular Dystrophy

DMD is a recessive X-linked form of muscular dystrophy characterized by rapid

progression of muscle degeneration, eventually leading to loss of ambulation and

death. The disease is a result of a spontaneous mutation of the Xp21 gene, which

results in the absence of the cytoskeletal protein dystrophin (Lansman and Franco

1991 ; Lapidos et al. 2004 ) . In the absence of this pivotal support protein, the muscle

cell membrane is subject to the mechanical forces of muscle contraction (Lapidos

et al. 2004 ) . Sarcolemmal tearing often results, permitting the entry of extracellular

calcium into the muscle fi ber. High levels of intracellular calcium trigger the activity


of protein destroying enzymes and the subsequent destruction of the muscle fi ber.

Over time, the disease results in widespread necrosis and fi brosis throughout the

muscle (Lapidos et al. 2004 ; Menache and Darris 2001 ) . The main symptom of

DMD is muscle weakness and marked wasting of musculature of the hips, pelvic

area, thighs, shoulders, and calf. Muscle weakness also occurs in the arms, neck,

and other areas, but not as early as in the lower half of the body. Symptoms usually

appear before age 6 and may appear as early as infancy. Curiously, the laryngeal

muscles do not appear to be affected in the same manner as appendicular and axial

muscle groups.

Marques et al. ( 2007 ) examined the effects of dystrophin de fi ciency on the medial

& lateral thyroarytenoid (TA), lateral cricoarytenoid (LCA), PCA, and the cricothyroid

(CT) muscles in 4 month (adult) and 18-month-old (aged) dystrophin de fi cient

mdx and C57Bl/10 (control) mice. No evidence of myo fi ber degeneration or regeneration

was observed in the medial TA, lateral TA, LCA, and PCA muscles.

Interestingly, mild markers of disease (e.g., central nucleation) were evidenced in

the CT muscle of the mdx mice. While percentages of central nuclei in the mdx CT

(adult mean (M) = 9.3, standard deviation (SD) 4.0; aged M = 18.0, SD = 1.5) did not

approach those of the typically affected tibialis anterior (adult M = 50.0, SD 1.0;

aged M = 96.0, SD = 2.0), they were signi fi cantly higher ( p < 0.05) than those

observed in other mdx ILMs (range 1.0–2.5) and in control CT muscles (adult

M = 4.8, SD 1.1; aged M = 5.3, SD 1.1). The authors proposed that mild disease

effects in the CT in the face of otherwise widespread laryngeal muscle sparing may

have been secondary to the CT’s biochemical and/or structural differences from

other ILM.

Findings by Fry et al. ( 2010 ) also suggested that the CT and superior cricoarytenoid

(SCA), the murine analog to the human interarytenoids (IA), are spared

from the pathological consequences of dystrophin de fi ciency in the mdx mouse.

These results parallel to those of earlier studies using the mdx mouse that showed

sparing of the TA, PCA, and LCA muscles (Marques et al. 2007 ; Thomas et al.

2008 ) (Fig. 11.1 ).

While subtle morphologic changes were found in the mdx CT (i.e., percentages of

central nuclei that were twice that of control muscles), these changes did not reach

statistical significance (p = 0.058), and there was no corresponding evidence of sarcolemmal

disruption or other classic dystrophin de fi ciency markers, suggesting that

CT was spared. These fi ndings regarding the CT are in contrast to those of the 2007

study by Marques et al. ( 2007 ) . In that study, small increases in central nucleation

were accompanied by mild markers of myo fi ber degeneration (i.e., in fl ammation,

sarcolemmal disruption). The combination of these factors led the authors to conclude

a mild disease effect for the CT, a disease response falling between that of the

fully spared ILM and that of classically affected limb skeletal muscle. A similar pattern

of slightly increased central nucleation in the absence of marked myo fi ber

degeneration has been previously described in other craniofacial muscles known to

be marginally affected by dystrophin de fi ciency (Muller et al. 2001 ; Andrade et al.

2000 ) . Fry et al. (2010 ) also demonstrated that utrophin was not up-regulated or

relocalized in the laryngeal muscles, indicating that utrophin regulation alone cannot


189

Fig. 11.1 Hematoxylin and eosin staining of hindlimb muscles ( upper frames ) and laryngeal

muscles ( lower frames ). Control gastrocnemius shows normal gastrocnemius morphology with

rectangular muscle fi bers and peripheral nuclei; mdx gastrocnemius evidences fi brosis, pleomorphic

fi bers, and central nuclei. Control and mdx laryngeal fi bers demonstrate peripheral nuclei and

consistent fi ber size and shape. TA thyroarytenoid; PCA posterior cricoarytenoid (Thomas et al.

2008 . Reproduced by permission of the American Speech-Language-Hearing Association,

Rockville, MD.)

explain muscle sparing. These fi ndings point to the continued need to search for a

mechanism of laryngeal muscle sparing in dystrophin de fi ciency.

At present, investigators are considering a number of such mechanisms, including

the over-expression of other associated proteins (e.g., integrins), the mechanical

advantage offered by a smaller muscle fi ber size, the presence of a superior mechanism

of calcium ion handling, and the advanced regenerative capacity inherent in the

muscles (Fischer et al. 2005 ; Andrade et al. 2000 ; Karpati et al. 1988 ; Khurana et al.

1995 ; McLoon et al. 2004 ; Porter et al. 2004 ) . The results of the Fry et al. ( 2010 ) study

demonstrate that the IA, like the TA, PCA, and LCA possess unique cellular features

that appear to imbue a resistance to the effects of dystrophin de fi ciency. When such

fi ndings are considered in light of previous work by Tellis et al. ( 2004 ) showing the IA

to be phenotypically similar to limb muscle, it is possible that the IA may represent a

phenotypic variant or “blended” muscle type, sharing properties of specialized craniofacial

muscles and properties of typical limb muscle.

With regard to the CT, these results suggest that like other ILMs, this muscle may

be highly specialized with features that offer protection from disease processes. Yet,

the results of other studies showing the CT’s phenotype (e.g., metabolic pro fi le,

general morphology, response to disease) as falling between that of specialized

laryngeal muscle and that of prototypical limb muscle, point away from this conclusion.

Considering the full body of research on the CT, Fry et al. ( 2010 ) supported


the depiction of the CT as a “blended” or phenotypically variant form of skeletal

muscle and suggest that additional work is necessary to further characterize this

critical laryngeal muscle. Given the collective results to date, it is suggested that

phenotypical variation of ILMs may exist on a continuum, with some muscles (such

as the TA and PCA) expressing a highly distinct nature that is clearly different from

typical limb muscle and other related muscles (such as the IA and CT) demonstrating

a more transitional form.

11.4 Laryngeal Muscle Response to Amyotrophic

Lateral Sclerosis

ALS is a neurodegenerative disorder of the motor cortex and ventral horn cells of

the spinal cord and brainstem motor nuclei. It is the most common motor neuron

disease affecting muscles that control voluntary movement. In approximately

5–10% of cases, ALS is genetically familial and caused by mutations of Cu–Zn

superoxide dismutase type 1. The mechanism underlying the characteristic selective

degeneration and death of motor neurons in ALS is unknown in the remaining 90%.

Typical onset of ALS is between the fi fth and seventh decade of life, with diagnosis

typically based on neurological examination con fi rming the presence of progressive

symptoms: upper and lower motor neuron degeneration, progressive muscle weakness,

atrophy, fasciculations, spasticity, and speech and swallowing disturbances. Tests

often added to the clinical diagnosis of ALS include electromyography (EMG) and

neuroimaging through MRI (Hardiman et al. 2011 ; Ropper and Samuels 2009 ) .

The presentation of ALS is of two distinct types, limb and bulbar. Seventy- fi ve

percent of individuals present with a combination of upper and lower motor neuron

degeneration localized to the extremities with noted atrophy, weakness, and fasciculations.

In the remaining 25% of individuals with ALS, the presentation is that of

bulbar symptoms of the oropharyngeal muscles including dif fi culty with speech

(articulation, dysphonia, hypernasality, breathiness) and swallowing (oral control of

saliva and aspiration). These speech and swallowing symptoms are recognized as

possible early signs of bulbar onset of ALS (Langmore and Lehman 1994 ) . The

early laryngeal manifestation of ALS appears to be a function of the preferential

involvement of the cranial nerve nuclei responsible for laryngeal function (DePaul

and Brooks 1993 ) .

Tomik et al. ( 2007 ) pro fi led the gross laryngologic abnormalities in patients with

both limb and bulbar onset ALS. In their study, 35 ALS patients were recruited for

laryngeal examination, with participants divided into limb ( n = 11) and bulbar

( n = 24) groups. The bulbar group was further subdivided into predominantly lower

motor neuron presentation ( n = 10), and those with predominantly upper motor neuron

presentation ( n = 14). The larynx and vocal folds were assessed for vocal fold

vibration dynamics, mobility, and phonatory closure by a combination of mirror

examination, fl exible endoscopy, and videostroboscopy. All visual examinations

were augmented by audio-perceptual judgments of voice quality.


191

In the ALS limb group, vocal fold mobility demonstrated a slight deviation from

normal in nine out of 11 patients. Sluggish movement of both vocal folds and lack

of complete closure during phonation were detected in three participants. There was

a unilateral decrease in tension and mobility of the vocal fold in four cases and vocal

fold bowing in two others. However, audio-perceptual assessment of the voice

qualities of the limb onset patients revealed no disturbances to vocal pitch.

Bulbar onset participants with predominantly lower motor neuron involvement

presented with smooth vocal fold edges and decreased vocal fold mobility and

adduction during the respiratory phase. During phonation, some patients showed

lack of complete vocal fold closure, with an hourglass shaped glottis closure pattern.

In these cases, voice quality was described as husky and low. For bulbar onset

participants classi fi ed as predominantly upper motor neuron, their presentation

demonstrated slight disturbances with mobility, hypoadduction of the vocal folds,

and hyperadduction of the ventricular folds. The vocal folds were described as

thicker, and voice production was characterized by increased tension in the cervical

musculature causing a harsh, strain-strangled voice quality, similar to that heard in

spasmodic dysphonia (Tomik et al. 2007 ; Lundy et al. 2004 ) . In addition, this group

demonstrated a hypernasal quality.

These distinct laryngeal and voice quality fi ndings may be used to supplement

other clinical diagnostic tools especially with individuals suspected of presenting

with bulbar onset ALS. Indeed, it has been suggested that early bulbar signs such as

reduced voice frequency range and phonatory instability may be present in patients

with ALS before the occurrence of perceptually aberrant vocal characteristics

(Silbergleit et al. 1997 ; Watts and Vanryckeghem 2001 ) . Another frequent laryngeal

symptom of ALS that occurs when the respiratory muscles become weak is dyspnea.

Dyspnea may also result from a narrowing of the glottis due to paresis of the PCA

muscles, the vocal fold abductors. This paresis may lead to laryngeal symptoms

including hoarseness, hypophonia, and short phonation time to nocturnal nonproductive

cough and attacks of inspiratory stridor and shortness of breath (van der

Graaff et al. 2009 ) .

Beyond the laryngeal function of voice quality is the vegetative function of swallowing.

The laryngeal musculature is responsible for the protection of the airway

during this life-sustaining event. Laryngeal muscle paresis leading to reduced glottal

closure may lead to swallowing problems. Indeed, mortality in the ALS population is

often associated with aspiration pneumonia. Although typically considered only as a

motor neuron disease, Amin et al. ( 2006 ) studied the contribution of sensory dysfunction

as a contributor to this disease process. The sensation of the larynx was

studied in 22 patients with ALS with abnormal sensation found in 54.5% of the tested

population. The authors concluded that in addition to muscle weakness, decreased

sensation may also contribute to the swallowing dif fi culties of individuals with ALS.

Very little is known of the exact laryngeal muscle biological response to ALS,

although a handful of quantitative studies examining motor end plates and other

histological and physiological studies have been conducted in selected ILM (Gambino

et al. 1985 ; Kanda et al. 1983 ; Yoshihara et al. 1984, 1991 ; Nomoto et al. 1991 ) .

Yoshihara et al. ( 1998 ) examined the TA and PCA muscles in four patients with ALS


Fig. 11.2 Ultrastructure of the NMJ in ALS. ( a ) NMJ of the TA muscle retaining almost normal

nerve terminals, synaptic clefts and synaptic contact (bar 1.0 m m, ×6,400). ( b ) Small nerve terminal

( arrow ) on the fl attened primary synaptic clefts ( arrowheads ) and well-preserved secondary synaptic

clefts (PCA muscle). Inset : higher magni fi cation of the nerve terminal (bar 1.0 m m, ×7,600).

( c ) Schwann cell ( arrowheads ) covering the degenerating nerve terminal (PCA muscle) (bar 1.0 mm,

×10,000). ( d ) Distorted primary and secondary synaptic clefts and aggregation of myo fi brils (PCA

muscle) (bar 1.0 m m, ×10,000) (Ultrastructural Pathology by Taylor & Francis Inc. Reproduced with

permission of Taylor & Francis Inc. in the format Journal via Copyright Clearance Center.)

following total laryngectomy due to severe dysphagia and dysphonia. Control specimens

were obtained from non-affected muscles of three individuals who had total

laryngectomy secondary to laryngeal cancer. The TA and PCA muscles were examined

histochemically and with electron microscopy. Results demonstrated that the

affected specimens from participants with ALS exhibited typical neurogenic changes

such as small angulated fi bers and grouped atrophy. Acetylcholinesterase (AchE)

activities of the neuromuscular junctions (NMJs) of many fi bers in the ALS group

were decreased as compared to controls. In addition, some motor end plate areas on

each fi ber detected by AchE histochemistry were larger than those of the controls.

The ultrastructure of the ALS muscle fi ber specimens showed an increased number

of lipofuscin granules and/or nuclei, numerous mitochondria, and the disappearance

of myo fi laments. The NMJ also demonstrated varying degrees of structural change

ranging from almost normal to the absence of nerve terminals and Schwann cells

covering the junctional sites. In addition, primary synaptic clefts were fl attened while

the secondary synaptic clefts appeared relatively well-preserved. The authors also

described several small nerve terminals that were occasionally seen on the severely

distorted postsynaptic folds, suggesting regenerative efforts. In severely degenerated

muscle fi bers, the NMJ was generally absent (Fig. 11.2 ) .


193

11.5 Laryngeal Muscle Response to Myasthenia Gravis

Myasthenia gravis (MG) is an autoimmune neuromuscular disease that causes

fl uctuating muscle weakness and fatigue. The muscle weakness is caused by failure of

neuromuscular transmission, resulting from the binding of autoantibodies to proteins

involved in signaling at the NMJ. Antibodies bind to postsynaptic acetylcholine (ACh)

receptors, resulting in a reduction in the number of available ligand binding sites.

Normal repetitive nerve stimulation also leads to a successive decrease in the amount

of acetylcholine released presynaptically. The combination of fewer available binding

sites and reduced acetylcholine release at the motor end plate gives rise to the induced

muscle fatigue observed in patients with MG (Patel and Forsen 2001 ) .

Although any skeletal muscles can be affected by MG, the ocular, facial, oral, pharyngeal,

laryngeal, and respiratory muscles seem to be the most susceptible. The laryngeal

musculature was implicated in MG as early as 1914, when Edward Davis reported

to the Royal Society of Medicine a case of a 25-year-old woman who presented with

aphonia, dysphagia (Kluin et al. 1996 ), and nasal regurgitation (Davis 1914 ) . Mao et al.

(2001 ) reported a series of 40 patients who presented with hoarseness as their primary

complaint. Voice diagnostic testing including laryngeal videostroboscopy, EMG with

repetitive stimulation and Tensilon testing; radiographic evaluations were also conducted.

Stroboscopic observations revealed a fl uctuating unilateral or bilateral impairment

of vocal fold mobility. EMG detected evidence of NMJ abnormalities in all

subjects. Only one patient had evidence of AChR antibodies, but the authors reported

that many other abnormalities suggestive of autoimmune dysfunction were present.

Pyridostigmine therapy was initiated in 34 patients but was not tolerated in 4. Of the

remaining 30 patients, 23 reported improvement of symptoms. The authors concluded

that myasthenia gravis can present with symptoms con fi ned primarily to the larynx and

should be included in the differential diagnosis of dysphonia.

Of primary concern in human populations is weakness of laryngeal and pharyngeal

musculature leading to ineffective swallowing with poor airway protection. This

situation may be further compounded by a poor cough as respiratory musculature is

also frequently involved in patients with MG. The combination of poor respiratory

effort and an ineffective swallow with the absence of protective mechanisms can

lead to aspiration and, potentially, pulmonary infection. Indeed, Higo et al. ( 2005 )

studied the swallowing function of 11 patients diagnosed with MG via

video fl uoroscopy. Aspiration was seen in 34.8%, with half of these cases involving

silent aspiration. Three of the four cases that showed silent aspiration went on to

experience aspiration pneumonia during the follow-up term.

Unfortunately, while descriptive reports on peripheral clinical features abound,

the pathophysiological effects of MG on laryngeal muscle cell biology are currently

unknown. While it is tempting to extrapolate fi ndings from studies conducted with

other skeletal muscle systems, our own experience with the differential effects of

Duchenne’s muscular dystrophy on ILM cell biology provides a cautionary note to

blanket application of muscle features across differing functional systems. Critical

basic and functional work is needed to further advance our understanding of MG

pathophysiology in the human.


11.6 Laryngeal Muscle Response to Peripheral Paralysis

Laryngeal muscle denervation is caused by peripheral involvement of the recurrent

laryngeal nerve (RLN) and less commonly of the SLN. Proximal involvement of the

vagus (cranial nerve X) affects both the recurrent and SLNs while more distal injury

may affect just one nerve. The location of the lesion along the nerve pathway will

determine the type of paralysis and the resulting voice quality. Etiologies of vocal

fold paralysis include surgical trauma (i.e., thyroid, anterior cervical fusion, carotid

surgeries), cardiovascular, neurologic, chest diseases, and accidental trauma (Rubin

et al. 2003 ; Wilatt and Stell 1991 ; Kelchner et al. 1999 ; Benninger et al. 1998 ) with

idiopathic unilateral vocal fold paralysis accounting for 16.3–23% of all cases.

11.7 Recurrent Laryngeal Nerve Paralysis: Unilateral

The RLN innervates all the ILM except the cricothyroid. Patients with unilateral

RLN paralysis present with varied vocal symptoms, ranging from mild to severe

dysphonia. Typically noted perceptual symptoms of paralysis are breathiness, low

vocal intensity, low pitch, and diplophonia, resulting from irregular and incomplete

glottal closure during vocalization. Inadequate valving of the laryngeal system will

also compromise airway protection during deglutition. Because the RLN mediates

both adductor and abductor functions, the positioning of the paralyzed fold, varying

from fully abducted, to paramedian, to a midline state will in fl uence the nature and

severity of the associated voice and swallowing disruption. The most common outcome

of unilateral RLN paralysis is a paralyzed fold in the paramedian position,

approximately 1–2 mm from midline. This aberrant positioning of the paralyzed

fold will in fl uence factors such as glottal gap size, phonation dynamics, and airway

protection. Voice quality is usually characterized by breathiness and diplophonia,

and the inability to develop adequate lung pressures that result in dramatically

decreased vocal intensity. Patients with paralysis describe physical fatigue resulting

from the greater effort that is required to produce a suf fi ciently clear and loud voice.

Current treatment strategies include a large range of behavioral, surgical, and combination

approaches (Stemple et al. 2009 ) .

11.8 Recurrent Laryngeal Nerve Paralysis: Bilateral

Bilateral vocal fold paralysis is by far more serious than unilateral forms of paralysis.

The underlying etiology is typically a higher vagal injury or progressive neuropathy.

When vocal folds are paralyzed in the adducted position (at midline), they

cannot abduct to create an airway opening suf fi cient to sustain respiration. This

critical condition is called bilateral abductor paralysis and requires a surgical


195

procedure to re-establish adequate airway patency, often through a tracheostomy.

Surgical manipulation of one arytenoid cartilage also will create a suf fi cient airway

by either removing the arytenoid entirely or suturing it laterally (Gardner and

Benninger 2006 ; Lawson et al. 1996 ; Feehery et al. 2003 ) . If an arytenoid lateralization

is performed, voice quality will be permanently weakened and aphonic. If

bilateral paralysis of the folds results in a paramedian or laterally abducted position,

ventilation is no longer a concern but airway protection becomes a much

larger threat because of the inability of the vocal folds to adequately close to prevent

aspiration. With bilateral adductor paralysis in the paramedian con fi guration,

neither voice production nor airway protection can be achieved, with patients

often requiring gastrostomy tube feedings because of poor airway protection.

Augmentative communication aids such as speech ampli fi ers and electrolarynx

devices have been used before to augment the “whispered” voice. In some cases,

vocal fold contracture and fi brosis may arise several months after injury. These

conditions result in a drawing of the folds closer to midline, allowing for harsh

and breathy phonation quality to emerge and improvements to airway management

during swallowing (Stemple et al. 2009 ) .

11.9 Superior Laryngeal Nerve Paralysis: Unilateral

or Bilateral

The external branch of the SLN innervates the CT while internal branches provide

for sensation to the inner lumen of the larynx. Unlike RLN trauma, SLN injury is

not readily observable and dif fi cult to ascertain, especially in unilateral cases

(Dursum et al. 1996 ; Robinson et al. 2005 ) . In a recent study, Roy et al. ( 2009 )

demonstrated a tilting of the epiglottal petiole toward the side of paralysis during

the production of a high-pitched/eee/sound. In addition, unilateral SLN paralysis

may also result in an oblique positioning or an overlap of the folds because of the

unequal rocking of the cricothyroid joint. The overlap creates a gap between the

folds that limits the midline closure pattern during vocal fold vibration and decreases

the ability to build subglottic air pressure, thus limiting vocal intensity. Often these

voice disturbances are not noticeable during connected speech production, but the

laxness of the affected fold creates an imbalance that reduces the pitch. Most patients

with unilateral SLN paralysis complain of vocal fatigue and the inability to sing

(Dursum et al. 1996 ; Robinson et al. 2005 ) . Bilateral paralysis of the cricothyroid

muscles is rare and must be con fi rmed through the use of LEMG studies (Heman-

Ackah and Barr 2006 ; Sataloff et al. 2004 ) . If paralysis should occur, the vocal folds

will lack their normal tone and will not lengthen suf fi ciently during attempts to

increase pitch. Voice quality is limited in frequency, intensity range, and stability.

Although there is no medical treatment for SLN paralysis, behavioral voice therapy

may help maximize vocal potential.


Neurapraxia, acute temporary laryngeal paralysis, results from a loss of signal

conduction as a result of demyelination without disruption of the axons.

Remyelination by Schwann cells results in full recovery. Axonotmesis (e.g., nerve

crush) is a more severe injury that disrupts the axons but leaves the investiture of the

nerve intact. Recovery begins when regenerating axons enter the native endoneurial

tubes leading back to the original target muscles (Zealear and Billante 2004 ) .

Reinnervation is often inappropriate as regenerating axons may randomly enter

endoneurial conduits of the wrong muscle leading to synkinetic reinnervation.

Synkinesis results in chronic dystonia or fi xation because of simultaneous contractions

of antagonistic muscles. In cases where the muscle connection is appropriate,

paralysis may be the result of partial muscle denervation and abnormalities in the

type, size, and number of reinnervating motor units (Zealear and Billante 2004 ) .

11.10 Morphological Cell Changes of the ILMs:

Denervation and Reinnervation Effects

Several recent studies have characterized the morphology of laryngeal muscles

following denervation (Miyamaru et al. 2008 ; Vega-Cordova et al. 2010 ; Romo and

Curtin 1999 ; Woodson et al. 2008 ; Xu et al. 2009 ) , yet our current appreciation of

laryngeal muscle fi ber typing and morphological changes as a function of denervation

remains incomplete. What literature does exist is suggestive of important

differences in fi ber type composition and plasticity of ILM following denervation

and repair in animal models. A report from Rhee et al. ( 2004 ) , demonstrated that

ILM myosin heavy chain (MyHC) expression differs across tested ILMs and that

fi ber type modi fi cation does occur after transection and subsequent repair of the

RLN in the rat model. Speci fi cally, Rhee et al. noted that MyHC is differentially

expressed in the CT and the TA muscles, with CT expressing limb MyHC isoforms

and the TA expressing MyHC variants typically found in the EOM. CT muscles

were noted to possess all recognized MyHC isoforms found in limb skeletal muscles.

The TA, in contrast, was found to have three primary isoforms (2B/EOM,

2X/2B, and 2X) with each isoform localized to distinct compartments within the

TA. The TA was described as having an external division consisting mostly of 2B/

EOM fi bers, and a vocalis division composed of 2X, 2B/EOM, and some 2X/2B

fi bers. Experimental transection of the RLN and subsequent surgical repair resulted

in random cross-reinnervation patterns across different compartments within the TA

muscle. De-innervated TA fi bers from the external compartment progressively

declined in their expression of EOM and 2B MyHC, and increased in their expression

of 2x MyHC. These fi ndings are consistent with other reports describing similar

proportional changes in the ratios of type 2B, type 2B/EOM, and 2X isoforms

following denervation of the TA, LCA, PCA, and CT in animal models (Shiotani

and Flint 1998 ; Wu et al. 2004 ) . Together, these data indicate that rodent ILMs may

re fl ect distinct allotypes, and that constituent contractile proteins can be modi fi ed

by changes in neural inputs.


197

In addition to changes of MyHC isoforms as a function of denervation in ILMs,

other immunohistochemically identi fi ed factors have been discovered that impart

upon selected ILMs the capacity to resist nerve input loss and support repair. For

example, a recent report by Vega-Cordova et al. ( 2010 ) described changes to three

neurotrophic factors in the TA and PCA muscle following experimental denervation

of the RLN. Using immunohistochemistry to track the expression of brain-derived

neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin 4 (NT-4)

the investigators noted that neurotrophin expression in the TA and PCA responded

differentially to denervation over time. For the TA, NGF levels were initially

decreased, but rebounded after 6 weeks post-injury (Vega-Cordova et al. 2010 ) .

Both BDNF and NT-4 expression were unchanged 3 days following denervation

and 6 weeks post-injury in the TA. In contrast, the PCA demonstrated lower BDNF

level post-injury that never returned to pre-injury values. The PCA did not show any

differences in NGF or NT-4 expression levels at any point during the experiment.

A handful of reports suggest that TA muscle biology may differ signi fi cantly

from other forms of skeletal muscle in its inherent capacity to support reinnervation.

In typical skeletal muscle, denervation leads to atrophy and fi brosis, diminishing the

potential of the tissue to support reinnervation efforts (Kobayashi et al. 1997 ) . In

contrast, reports suggest that most laryngeal muscles, with the exception of the

PCA, are functionally and morphologically resistant to long-term loss of nerve

inputs (Johns et al. 2001 ; Morledge et al. 1973 ) , suggesting a greater potential for

recovery. In fact, a recent report by Miyamaru and colleagues has demonstrated that

the TA’s capacity to survive prolonged denervation may be due in part to the preservation

of optimal ratios of ACh receptors to nerve terminals. Preservation of ACh

receptors is an important prerequisite for robust reinnervation in skeletal muscle

tissue, since regenerating axonal sprouts target ACh receptors to re-establish effective

neuromotor communication (Miyamaru et al. 2008 ) . Subsequent reinnervation

of the TA by the RLN also has been demonstrated to effectively reverse denervationrelated

MyHC expression changes (up-regulation of type 2X and down-regulation

of type 2B isoforms) at the level of the whole muscle (Wu et al. 2004 ) . Considering

that denervation of the TA leads to the transition of one fast isoform (type 2B) to

another (type 2X), as noted above, it is not surprising that minimal functional

changes are noted in shortening velocities and contraction force (Johns et al. 2001 ;

Wu et al. 2004 ) . Together, these data support the conclusion that the TA is amenable

to re-innervation procedures and that the outcome of such procedures would likely

be quite ef fi cacious. Current work by Zealear and colleagues is testing these suppositions

through the development and use of implantable stimulators and electrotherapy

in canine models (Nomura et al. 2010 ; Zealear and Billante 2004 ; Zealear

et al. 2009 ).

Work by Shinners et al. ( 2006 ) has related the survivability of laryngeal muscles

after neurological insult to the distinctive remodeling capacity discussed above. The

authors identi fi ed heightened levels of fi ber remodeling immediately following

RLN nerve section that was maintained for 24 weeks post-injury. The authors concluded

that the remarkable regenerative capacities of the muscles may have facilitated

their ability to survive and regenerate following neurological insult. Regardless


of the precise mechanism at play, spontaneous reinnervation of the laryngeal

musculature does not often restore normal vocal fold abduction and adduction. It

does, however, appear to offer suf fi cient nerve input to prevent or impede severe

muscle atrophy in a number of cases (Gardner and Benninger 2006 ; Nomoto et al.

1993 ; Shindo et al. 1992 ; Titze 1994 ; Kano et al. 1991 ) .

Reports describing human ILM biology after paralysis are exceptionally rare, yet

occasionally can be found in the literature. One such report by Brandon et al. ( 2003a )

analyzed normal functioning and immobilized PCA muscle sub-samples in a set of

patients who had undergone total laryngectomies. In this study, the PCA was determined

to consist of two bellies (horizontal and vertical) distinguished by the MyHC

isoform present. Horizontal bellies were primarily type 1 (slow) fi bers with only

20% of the remaining sample consisting of type 2a and 2x (fast) variants. In contrast,

the vertical bellies had a more uniform distribution of type 1 and type 2 fi bers. Upon

inspection, morphological indications related to immobilization vs. normally functioning

vocal folds were dif fi cult to determine. For example, neonatal MyHC, a

marker for regeneration, was present in both normal and immobilized PCA samples.

Additionally, fi ber type grouping was found to occur in both PCA sub-samples, and

no changes to fi ber diameter and morphology were noted in either group. The lack

of differences in the PCA of the normal functioning vs. immobilized group suggested

that immobilization may have resulted from a cause other than neuropathy.

11.11 Concluding Remarks

It is apparent from our brief review in this chapter that our appreciation of laryngeal

muscle biology in general, and its speci fi c response to neuromuscular disease or

injury, is poor when compared to limb muscle cell biology. The increasing recognition

of the unique nature and structural pro fi le of ILM compared to typical skeletal muscles

makes interpolation of data from limb muscle biology tenuous at best. Together,

these factors strongly argue for substantially greater study of laryngeal muscle biology.

By far, of the data that does exist, reports in animal models represent the bulk

of the literature on ILM cell biological changes as a function of neuromotor disease

and injury. Unlike human limb skeletal muscle investigations, cell biological studies

of the larynx in man are rare and exceptionally challenging given the inherent

inability to biopsy and extract sample tissue for histochemical and morphological

analyses without causing unacceptable damage to the same structure being examined.

While animal studies have critically added to our understanding of laryngeal muscle

biology, they are limited in their capacity to inform investigators with interest in

human behavior, speci fi cally human vocal behavior. The extent to which we understand

the nature of human laryngeal muscle biology and the role that muscle fi ber

changes have in the pathophysiology of voice and swallowing disorders is quite

small. To date, the vast majority of human laryngeal muscle studies have used

electrophysiological measures to document central neural perturbations, yet only a

limited number of studies could be identi fi ed describing cell biology changes in


199

human ILMs. Given the known cell biology changes that are manifest as a function

of denervation, we hypothesize that other forms of neurological insult and disease

produce different forms of histological changes in ILMs. The nature of these changes

remains to be discovered.

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Part VI

Tongue Musculature

Chapter 12

Tongue Structure and Function

Alan Sokoloff and Thomas Burkholder

Abbreviations

MyHC-emb

MyHCeom

MyHC-neo

MyHC-st

MyHCembryonic

MyHCextraocular

MyHCneonatal

MyHCslowtonic

12.1 Introduction: The Tongue in Neuromuscular Context

The mammalian tongue is essential for normal respiration, swallowing, oral

transport, emesis, coughing and, in humans, speech production. To achieve these

behaviors, tongue musculature produces myriad changes in tongue shape and in

concert with other head and neck structures a wide range of tongue movement

speeds. Head and neck muscles are often described as having unconventional

kinematic and mechanical demands. They may be required to apply prolonged,

continuous force, as the activation of genioglossus to maintain airway patency, and

they may be required to change force very rapidly, as the extraocular muscles during

saccades. In this chapter, we describe the neuromuscular specialization that facilitates

tongue behavior, and contrast this with typical limb function, in which the

muscles undergo cyclical motion during relatively infrequent behaviors.

A. Sokoloff (*)

Department of Physiology , Emory University ,

615 Michael Street , Atlanta , GA 30322 , USA

e-mail: Sokoloff@physio.emory.edu

T. Burkholder

School of Applied Physiology , Georgia Institute of Technology ,

Atlanta , GA , USA




207

208 A. Sokoloff and T. Burkholder

The most obvious contrast between conventional skeletal muscle systems and

the tongue is the lack of rigid structural elements. Tongue movement is a consequence

of deformation of the constant-volume soft-tissue tongue body, movement

of the tongue body relative to the head and neck by tongue muscles with extrinsic

attachment, and movement of attached head and neck structures (e.g., mandible or

hyoid bone). Changes in tongue shape are enabled by arrangement of tongue muscle

fi bers in multiple axes and innervation by hypoglossal nucleus motoneurons

(approximately 6,000 hypoglossal nucleus motoneurons in the rat; 15,000 in the

human; Arvidsson and Aldskogius 1982 ; O’Kusky and Norman 1995 ) . Tongue

movements are accompanied by spatially diverse tongue body deformations indicating

spatially complex patterns of muscle fi ber and motor unit activation (motor

unit, MU: a motoneuron and the muscle fi bers it innervates).

12.2 Tongue Muscular Anatomy

12.2.1 Muscle Anatomy and Innervation: Classical Description

In the appendicular musculature, muscles are de fi ned anatomically as discrete populations

of muscle fi bers which are substantially separate from other fi ber populations.

Activation of contractile material anywhere within many appendicular muscles

has a similar mechanical action due to the constraints imposed by discrete muscle

attachments and by skeletal and ligamentous structures. Although considered as

separate entities, muscles frequently share common tendons, such as the gastrocnemius

and the soleus, and are linked by intermuscular connective tissue that limits

their mechanical independence (Maas et al. 2001 ) . Some muscles with large distributed

attachments may have very divergent regional functions, however, and there

can even be some variability in mechanical action within fusiform muscles (Chanaud

et al. 1991 ; Carrasco and English 1999 ) .

Nonetheless, locomotion and other tasks of the appendicular musculature are well

described by rigid segments connected at discrete joints, and simplifying contractile

material into discrete units has greatly facilitated the analysis of locomotion and understanding

of the control structures involved. Treating appendicular muscles as functionally

discrete structures is an illustrative simpli fi cation that facilitates analysis.

The musculature of the tongue is classically divided into extrinsic muscles,

which have their origins on bony structures outside the tongue body, and intrinsic

muscles, whose fi bers exist entirely within the tongue body. 1 The extrinsic muscles,

genioglossus (GG), hyoglossus (HG), palatoglossus (PG), and styloglossus (SG)

1

Dissection, histological, and MRI investigations have produced detailed descriptions of tongue

muscle organization in relatively few mammal species (primarily cat, dog, human, and rat). Primary

descriptions in the human are those of Abd-El-Malek ( 1939 ) and Gaige et al. ( 2007 ) for the adult

and Barnwell ( 1977 and related) for the fetal tongue. For organization of tongue musculature in

non-mammals see Herrel et al. ( 2001 ) and Nishikawa et al. ( 1999 ) .

12 Tongue Structure and Function

209

Fig. 12.1 Muscle anatomy and fi ber architecture of the human tongue. ( a ) Fiber tracts of extrinsic

and human intrinsic tongue muscles near midline revealed by DTI tractography (Gaige et al. 2007 ;

used with permission). ( b ) Stylized diagram of the human tongue (Takemoto 2001 ; used with

permission). Note the fan-like radiation of the genioglossus and primarily vertical orientation of

the hyoglossus. PG palatoglossus; SG styloglossus (c) Arrangement of the superior longitudinal

muscle (SL)

bear super fi cial similarity to appendicular muscles. Outside the tongue body they

are discrete populations of muscle fi bers encased in an epimysium and separable

from surrounding tissue by gentle dissection. They have discrete origins, and one

can ascribe a displacement of the whole tongue to shortening of each: GG originates

from the anterior mandible and pulls the tongue forward and down; HG originates

from the hyoid bone and pulls the tongue back and down; PG originates in the soft

palate and pulls the posterior tongue up and back; SG originates from the styloid

process and retracts the tongue. The external portions of these muscles appear to act

on the tongue in the same way that limb muscles act on bones. Fibers of each of

these muscles continue within the body of the tongue, where the epimysium loses

its de fi nition and fi bers intermix with fi bers of intrinsic tongue muscles.

The intrinsic muscles, inferior longitudinalis (IL), superior longitudinalis (SL),

transversus (T), and verticalis (V), however, bear little similarity to the discrete

appendicular and axial muscles. These muscles are not physically separate, but

occupy overlapping volumes of space. The central body of the tongue comprises alternating

laminae of vertically and horizontally oriented fi bers, the former being the

verticalis “muscle” and the latter being the transversus (Figs. 12.1 – 12.3 ). Along the

dorsal and ventral surface of the tongue, fi bers that comprise the IL and SL are woven

among intrinsic fi bers of T and V and extrinsic tongue muscle fi bers. These intrinsic

muscles fail the fi rst criterion of muscles, which is to be a discrete structure. Functionally,

these fi bers modify local tongue body shape, which may include effects similar to protrusion,

retrusion and dorsal bending, but they lack the discrete mechanical function

that has made the muscle model so powerful in the appendicular system.

12.2.2 Theoretical Considerations: Tongue as Deformable Solid

The muscle fi bers of the tongue are not easily divided into discrete populations, and

motion of the tongue is not well described by rigid segments with discrete articulations.

The simpli fi cations that offer so much clarity in the appendicular musculature do not


Fig. 12.2 Stylized illustration of parasagittal section of the murine tongue with photomicrographs

in the mouse of boxed regions. Note alteration of Transversus (T) and Verticalis (V) fascicles (c),

super fi cial T fi bers (arrow in a , asterisk in e) interlacing of V and longitudinal fi bers ( b , e ), anterior-to-posterior

distribution of motor endplate (MEP) zones in intrinsic longitudinal muscles ( b ,

c , e ) and single MEP band in the oblique GG ( f ). MEPs stained for acetylcholinesterase in b – f .

Calibration bar = 200 m m

Fig. 12.3 Coronal sections of rat and mouse tongue. ( a ) Anterior rat tongue stained for glycogen.

Note intermixing of fi bers of different orientation, super fi cial continuation of transverse fi bers

adjacent to epithelium ( arrow ), lateral location of vertical fi bers and medial extent of longitudinal

fi bers. ( b ) Diagrammatic representation of rat anterior tongue body showing features discussed in

text. ( c ) Acetylcholinesterase stain for motor endplates (MEP) in the anterior-middle mouse

tongue. Note MEP bands in vertical and transverse fascicles but sporadic MEPs in longitudinal

fascicles indicative of in-series fi ber organization. Arrow points to lateral vertical fi bers. Calibration

bars = 200 m m


211

clarify control of the tongue, which is much better described as a deformable solid,

using the formalism of continuum mechanics or a muscular hydrostat model (Kier

and Smith 1989 ). Diffusion spectrum imaging (DSI) and tagged magnetization MRI

techniques reveal regional specialization of both fi ber orientation and deformation

that might be used to develop a 3D mesh appropriate for reconciling tongue structure

and function (Gilbert et al. 2007 ) .

Structural division of the tongue should re fl ect its functional properties,

speci fi cally the nature of its deformations. Conventional de fi nitions of tongue muscles

do not offer suf fi cient anatomical resolution to account for regionally diverse

deformations of the tongue body. Extrinsic and intrinsic tongue muscles have complex

and distributed muscle fi ber architecture and motor units localized within the

tongue body. These features suggest that tongue deformation may be determined by

the differential activation of motor units by orientation and region (and not by muscle

or compartment membership per se). Information on tongue motor unit anatomy,

the mechanical consequences of motor unit activation and the activation of motor

units with respect to location and orientation is, however, limited, and it is not currently

possible to correlate motor unit activation with tongue deformation.

12.2.3 Architecture of Tongue Muscles

One approach to simplifying the description of a complex deformable solid is to

divide it into smaller regions over which local material strains vary little. This suggests

that two functionally important criteria for describing tongue structure are the

organization of motor units, which speci fi es the spatial resolution of the nervous

system and the geometry of deformation. There is only limited information on motor

unit localization, but single motor units appear to innervate fi bers of only one orientation,

to be restricted to one side of the midline, to be localized with respect to the A/P

axis but to span multiple fascicles and multiple laminae. The nervous system appears

to distinguish fi bers strongly by orientation and weakly by position.

Although below we describe tongue architecture in terms of fi ber orientation,

one should bear in mind these caveats. (1) Tongue muscle fi bers of different orientations

are present in all regions of the tongue body. (2) Many fi bers are oriented

obliquely to conventional anatomical axes and a muscle fi ber may curve to assume

different orientations along different parts of its length. (3) Fibers of a classically

de fi ned muscle may have highly divergent orientations in different regions. (4) Within

the tongue body fi bers of extrinsic muscles interdigitate with intrinsic muscles so as

to be indistinguishable histologically. (5) Posterior intrinsic muscle fi bers of IL, SL,

and T can have attachments to the hyoid bone and associated fascia suggesting

direct consequence of contraction for movement of the tongue body relative to the

hyoid bone. (6) Most muscle fascicles have a single motor endplate (MEP) band and

most fi bers a single MEP, but dual MEPs are present in a subset of tongue muscle

fascicles and on some muscle fi bers.


12.2.3.1 Muscle Fibers with Primarily Vertical Orientation

Muscle Fiber Architecture

Fibers with primarily vertical orientation are present in all regions of the tongue

body and contributed mainly by GG and V with additional contributions from HG,

PG, SL, and T. 2 GG fi bers are absent in the anterior tongue of the rodent and cat but

are present in anterior human tongue (Abd-El-Malek 1938, 1939 ; Hellstrand 1980 ;

Gaige et al. 2007 ) . In most species the anterior-most GG fi bers ascend vertically to

the dorsum near the midline with fi bers with progressively posterior insertion radiating

obiquely in a fan shape such that the deepest fi bers travel horizontally to the

tongue root (Figs. 12.1 and 12.2 ). In some species, oblique (anterior-dorsal fi bers)

and horizontal (ventral fi bers) divisions of the GG are recognized. In the posterior

tongue, GG fi bers occupy the majority of the medial volume, displacing V fi bers to

the lateral periphery. Although nominally vertical, V fi bers often have a dorsomedial

to ventrolateral orientation which would tend to form an A/P trough upon contraction.

In rodents, V fi bers may originate and insert in the lateral epithelium

forming a lateral arc of fi bers (Fig. 12.3 ). V fi bers are organized into laminae orthogonal

to the A/P axis of the tongue body. V fascicles alternate with T fascicles and

course through dorsal and lateral-ventral longitudinal fi bers to insert in epithelium

or connective tissue (CT) investing fascicles of other muscles (Fig. 12.2 ). At the

tongue tip, fascicles of V are less coherent and alternation with T irregular.

Fibers with vertical orientation are additionally contributed by HG fi bers that

course dorsally or antero-dorsally to the dorsum, and by PG fi bers that descend in

the lateral body and mingle with fi bers of SG (Fig. 12.1 ). The posterior-most fi bers

of SL originate near the hyoid bone and also course vertically, deep to the posterior

dorsum. In some species, T fi bers originating from the dorsal and ventral limits of

the medial septum course vertically to the dorsal and ventral epithelium, respectively

(Fig. 12.3 ). Vertical fi ber components are thus contributed by extrinsic and

intrinsic muscles and muscles classically considered retrusors and protrusors.

Innervation

GG and V fi bers extend for much of muscle origin to insertion length. V and vertical/

oblique GG fascicles appear to have a single MEP in the middle third, indicative of

in-parallel fi ber organization (Fig. 12.2 ). However, more horizontal GG fascicles

may contain two or more MEP zones (Mu and Sanders 2010 ) . The extent to which

multiple MEPs along GG fascicle length re fl ect offset of muscle fi bers, branching

of a single terminal nerve to innervate multiple MEPs on a single fi ber or innervation

2

Most tongue muscles have complex architecture the details of which may differ substantially

between species (e.g., minimal lateral longitudinal muscle fi bers in the anterior cat tongue,

Hellstrand 1980 ) . Cross-species differences in tongue muscle organization have not been studied

in detail and can offer insights into neuromuscular bases of tongue movement.


213

a

75 mg

Anterior EMG 1v

Middle EMG 1v

Posterior EMG1v

Tetanus

Twitch

200 ms

b

NUMBER OF MOTOR UNITS

26

22

18

14

10

6

2

A

M

P

AM MP AMP

LOCATION OF INFERIOR LONGITUDINALIS

AND SUPERIOR LONGITUDINALIS MOTOR UNITS

26

22

18

14

10

6

2

A

M

P

AM MP AMP

LOCATION OF GENIOGLOSSUS, TRANSVERSUS

AND VERTICALIS MOTOR UNITS

Fig. 12.4 Anterior–posterior localization of tongue motor units (MU) in the rat. ( a ) Intra-axonal

stimulation of single MU with EMG signature in the middle tongue. ( b ) Localization of MUs to

anterior, middle, posterior, or multiple tongue regions. From Sokoloff ( 2000 , American

Physiological Society; used with permission) and unpublished data

of a single fi ber by multiple nerves is not known. Vertical fascicles of HG are

centrally innervated by a single MEP band (Mu and Sanders 2010 ) .

Retrograde axonal tracer studies reveal somatotopic organization of GG, T, and

V motoneurons such that anterior regions of these muscles are innervated by caudal

hypoglossal nucleus motoneurons whereas posterior regions are innervated by rostral

hypoglossal nucleus motoneurons (Sokoloff and Deacon 1992 ; Aldes 1995 ) .

These fi ndings are compatible with compartmental innervation of oblique vs. horizontal

regions of the GG. Stimulation of single axons projecting to GG, T, and V in

the medial hypoglossal nerve (CNXII) produces activation of fi bers primarily localized

to anterior, middle, or posterior regions of the tongue body (Fig. 12.4 ), also

indicating MU localization with respect to the A/P tongue axis. A/P localization of

GG motor units is supported by discrete anterior vs. posterior activation of GG

regions during speech (Miyawaki et al. 1975 ; Baer et al. 1988 ) . Thus motor unit

localization with respect to the A/P tongue axis appears to be a feature of extrinsic

and intrinsic muscles of vertical orientation.

12.2.3.2 Muscle Fibers with Primarily Transverse Orientation

Architecture

Fibers with transverse orientation are present in all regions of the tongue body and

are contributed primarily by SG and T. Fibers identi fi ed with the classical T originate

on the median septum and are grouped in laminae that alternate with more

vertically oriented fi bers of V and GG (Figs. 12.2 and 12.3 ). These fi bers insert on

epithelium or CT investing super fi cial muscles. Although nominally transverse, in

some species the radial array of T fi bers is so strong that the most dorsal and ventral

T fi bers attain a near-vertical orientation. In other species, transverse fi bers are not

radially arrayed but extend primarily medio-laterally (Hellstrand 1980 ) . In the anterior

tongue of the rat and mouse, T fi bers pierce longitudinal fascicles to form an


outer super fi cial fi ber layer just deep to the epithelium (Figs. 12.2 and 12.3 ).

Transversus fi bers may also have a longitudinal component, with anterior T fi bers

arcing anteriorly and posterior T fi bers arcing posteriorly to intermix with fi bers of

SG. Activation of T fi bers would primarily be expected to condense the tongue medially

with consequent midline raising. Fibers of transverse orientation in the tongue

are also contributed by the SG (DuBrul 1976 ; Gaige et al. 2007 ; Saito and Itoh 2007 )

and by inferior-lateral GG fi bers which may course laterally to the lateral epithelium

(Mu and Sanders 1999 ; Gaige et al. 2007 ) .

Innervation

T fascicles in the mouse and rat have a single MEP band (Fig. 12.3c ). T fascicles in

humans have two bands (Mu and Sanders 2010 ) but whether this re fl ects dual innervation

of fi bers is not known. Stimulation of single axons in the medial branch of the

rat CNXII evokes regional EMG signatures with respect to the A/P axis, suggesting

limited A/P distribution of at least some T motor units (Fig. 12.4 ). Whether T motor

units are restricted in the transverse dimension is not known, nor is it known whether

the different components of SG receive discrete innervation.

12.2.3.3 Muscle Fibers with Primarily Longitudinal Orientation

Architecture

Fibers with longitudinal orientation are present in all regions of the tongue body and

are contributed by GG, HG, IL, SG, SL, and T. Longitudinal fi bers contributed by

intrinsic and extrinsic muscles intermix extensively and make histological distinction

dif fi cult. However, from current descriptions two longitudinal fascicle morphologies

appear to be present which coincide with intrinsic and extrinsic identity.

In one, short, in-series fi bers are organized into multiple fascicles that overlap along

the A/P axis. These are associated with superior, lateral, and inferolateral intrinsic

muscle fi bers (Figs. 12.2 and 12.3 ). In the other, longer, in-parallel fascicles and

fi bers are contributed by SG, HG and, at least in some species horizontal GG. Fibers

of both morphologies coexist in most tongue regions, although in-parallel fi bers are

dominant in the posterior tongue.

Longitudinal fi bers of the classical IL form a distinct mass in its posterior extent,

de fi ned by intramuscular septa and bordered by the GG medially and HG laterally

(Abd-El-Malek 1939 ; Gaige et al. 2007 ; Fig. 12.1 ). IL fi bers blend anteriorly with

longitudinal fi bers of other extrinsic and intrinsic muscles. In some species, longitudinal

fi bers of the SL are most prominent along the dorsal midline and are partially

delimited laterally by dorsal T fi bers. However, longitudinal fi bers are also present in

lateral and ventrolateral tongue body regions, and in some species these fi bers may be

numerous especially anteriorly (Fig. 12.3 ). Because the consequences of longitudinal

fi ber activation on tongue body deformation will differ with respect to radial location,


215

we assign these radially arrayed intrinsic longitudinal fi bers (i.e., not classical IL) to

a super fi cial intrinsic longitudinal muscle system that includes superior (the classic SL),

lateral (LL), and inferolateral (ILL) components (Fig. 12.3 ).

Activated as a group, longitudinal fi bers will tend to reduce the A/P dimension of

the tongue, but regional activation will cause local bending in the sagittal or transverse

planes.

Innervation

MEPs of intrinsic longitudinal muscles are scattered along the A/P tongue length in

a pattern typical of muscles of in-series fi ber design (Slaughter et al. 2005 ; Fig. 12.2 ).

MEPs of HG and SG in contrast appear to be concentrated in single bands near the

tongue root in a pattern typical of muscles of in-parallel design (Mu and Sanders

2010 ) . Innervation of the horizontal GG differs with species and in the dog and

human some fascicles have two or more MEP bands (Mu and Sanders 1999, 2010 ) .

In the human SL, dual MEPs may be present on single fi bers in close proximity and

appear to be innervated by a single axon (Slaughter et al. 2005 ) . Single unit stimulation

of lateral CNXII axons that project to intrinsic longitudinal fi bers evokes regional

EMG, indicating limited A/P distribution of motor units (Fig. 12.4 ; Sokoloff 2000 ) .

12.3 Neuromuscular Basis of Tongue Movement

12.3.1 Theoretical Considerations

The relatively clear separation of limb contractile material into discrete muscles is

re fl ected in neural organization. Each motor unit is restricted to a single muscle, and

sometimes to an identi fi able compartment, set off by a thick connective tissue

boundary, within that muscle. Motor units within each muscle or compartment are

recruited in a rigid, size-based order that closely couples the motor unit physiological

and biochemical properties (Binder and Mendell 1990 ; Gordon et al. 2004 ) .

Kinematic diversity can be described by the relative activation of these discrete

muscles and compartments, which may simplify neural control by separating the

intensity of activation from the selection of speci fi c motor units.

Muscle-based and compartment-based descriptions of control presuppose that

the motor unit pools used by the nervous system are the muscle or compartment

pools. However, there is evidence that motor unit groups used by the CNS are not

solely de fi ned by muscle or compartment identity. On the one hand, orderly recruitment

of motor units occurs among motor units from different muscles (Henneman

et al. 1965 ; Sokoloff et al. 1999 ) , indicating that the nervous system can use motor

unit pools that span muscles. Reports of motor primitives in the frog spinal cord and

“synergies” in several senses in mammals also seem to indicate control structures

that span muscle and compartment boundaries. On the other hand, motor units can


be organized into multiple pools independent of muscle region or compartment

identity (Herrmann and Flanders 1998 ) .

In the human GG, grouping of tongue motor units appears to be related to motor

unit location in some tasks but independent of motor unit location in others. During

speech tasks, GG motor units are selectively activated in anterior vs. posterior

regions (Baer et al. 1988 ) which may represent selective motor unit activation by

virtue of compartment membership (for example in anatomically de fi ned oblique

vs. horizontal GG regions) or by virtue of the speci fi c effect of motor unit activation

on tongue deformation. During wakeful respiration however, multiple groups of GG

motor units can be de fi ned by activity patterns recorded from the same electrode

and thus the same muscle region (Saboisky et al. 2006 ) . Whether differing respiratory

GG motor unit pools are grouped by virtue of metabolic, contractile, or other

motor unit properties are not known.

Above we reviewed the muscle architecture that constrains the geometry of

tongue deformation. The capacity of the nervous system to use this geometry is

dependent on the organization of motor units and the ways in which the nervous

system can combine and regulate their activation. Although evidence is limited, we

next review contractile features of tongue motor units that re fl ect molecular composition

of constituent muscle fi bers and anatomical features that determine the speci fi c

effect of motor unit activation on tongue deformation.

12.3.2 Tongue Motor Unit Organization and Activation

12.3.2.1 MEP Morphology and Muscle Fiber Innervation

Synapses of head and neck muscles show some differences from conventional

appendicular muscles. Two MEP morphologies have been described in human

tongue muscles, plate-like “en plaque” MEPs typical of appendicular systems and

grape-cluster-like “en grappe” MEPs present in many head and neck muscle systems

(Oda 1986 ; Perie et al. 1997, 1999 ; Slaughter et al. 2005 ; Mu and Sanders

2010 ) . A third MEP pattern described in extraocular muscles, which consists of

small terminal boutons distributed along the muscle fi ber length (Oda 1986 ) is not

present in the tongue. Functional and molecular correlates of en grappe MEP morphology

in human tongue muscles are not known. In human tongue, laryngeal, and

suprahyoid muscles, the absence of appreciable slow/tonic myosin heavy chain

(MyHC) precludes a relationship between MyHCslow tonic and en grappe MEP

morphology (Sokoloff et al. 2007 ) .

As discussed above, some tongue muscle fi bers have two MEPs. In extraocular

muscles, multiple MEPs per muscle fi ber may re fl ect innervation of a single fi ber by

multiple nerves (Chiarandini and Stefani 1979 ; Oda 1986 ) . SL fi bers with dual

MEPs appear to be singly innervated (Slaughter et al. 2005 ) , an organization similar

to human laryngeal muscle fi bers (Perie et al. 1997 ) . It is not known whether other

tongue muscle fi bers with dual MEPs are multiply or singly innervated.


217

12.3.2.2 Motor Unit Physiology

Physiological investigations, primarily in the rat, demonstrate that tongue motor

units are predominantly nonfatiguing and are similar to appendicular motor units

with respect to speed of contraction (Gilliam and Goldberg 1995 ; Sokoloff 2000 ;

for similar fi ndings in cat see Hellstrand 1981 ) . These fi ndings correlate with muscle

biochemistry; most rat tongue muscle fi bers have a moderate-to-high oxidative

capacity and are composed of conventional “fast” MyHC isoforms. However, rat

tongue motor units produce 100–1,000-fold less force than rat appendicular motor

units (Gilliam and Goldberg 1995 ; Sokoloff 2000 ) . Motor unit force is determined

primarily by the number and cross-sectional area of constituent muscle fi bers

(Totosy de Zepetnek et al. 1992 ) . Although studies are limited, the cross-sectional

area of rat tongue muscle fi bers appears to be one to four times less than the crosssectional

area of equivalently typed fi bers in rat neck and appendicular muscles

(e.g., Oliven et al. 2001 ; Matsumoto et al. 2007 ) . This suggests that, compared to

most appendicular motor units, tongue motor units comprise many fewer fi bers.

12.3.2.3 Motor Unit Anatomy and Localization

Direct anatomical evidence of tongue motor unit location, fi ber architecture, and

fi ber number (i.e., innervation ratio, IR) is lacking. Independent activation of anterior

vs. posterior regions of the GG during speech indicates localization of at least

some tongue motor units with respect to the A/P tongue axis in humans (Baer et al.

1988 ) . Localization of motor units with respect to the A/P tongue axis has also been

demonstrated physiologically in the rat. Following intra-axonal activation of individual

motor units, 65/105 SL-IL motor units and 41/42 GG, T and V motor units

were localized by EMG to either anterior, middle, or posterior tongue body regions

(Fig. 12.4 ).

Studies have not described motor unit IR, the dorso-ventral and medio-lateral

extent of motor unit territories and whether motor unit territories respect muscle

architecture divisions. Estimated motor unit innervation ratios of less than 25 in the

rat SG and GG suggest that motor unit territories may be circumscribed in the coronal

plane as well (Sutlive et al. 2000 ) .

We saw above that muscle fi bers of all orientations are found in most regions of

the tongue and that traditional division of contractile material into discrete, anatomically

de fi ned volumes does not simplify description of tongue motion and does

not facilitate understanding. The ability to voluntarily change the local curvature of

the tongue indicates that the nervous system controls sub-volumes of contractile

material and our goal is to describe tongue structure in a way that clari fi es both the

deformations and their control. Although data on anatomical localization and distribution

of motor unit territories are limited, data reviewed above indicate that motor

units span more than one T/V laminae but are spatially restricted. Some inferences

can also be made from observed behavior. Imaging data indicate that the tongue

deformation gradient is relatively low frequency, and a high-resolution fi nite


element model (Mijailovich et al. 2010 ) also suggests that the tongue body might be

adequately described using a coarse spatial mesh, e.g., anterior/middle/posterior,

dorsal/ventral/root, and left/center/right, giving a total of 27 spatial regions. Further

determination of regional strain fi elds and further evaluation of motor unit distribution

have great potential for deciphering tongue control.

12.4 Gross Tongue Function During Respiration,

Mastication, and Speech

During open-mouth respiration, the tongue is pulled toward the fl oor of the mouth

to free the airway. This is accomplished primarily by activation of GG motor units,

but in some animals intrinsic muscles are also involved (Lu and Kubin 2009 ) . Phasic

activation of other muscles is also observed (e.g., Inoue et al. 2004 ) and the tongue

may undergo rhythmic protrusion and retrusion or elevation and depression (e.g.,

panting, lapping, feeding; Biewener et al. 1985 ; Thexton and Crompton 1989 ) .

During mastication, the tongue follows systematic movements during transport,

processing, bolus formation, and deglutition (Hiiemae and Palmer 2003 ; Felton

et al. 2008 ) . These movements may be asymmetric with respect to the left and right

side, but generally have low spatial frequency, i.e., between 0.5 and 1 wavelength

along the length of the tongue and 0.5 wavelength or less in the coronal plane. For

example, Abd-El-Malek ( 1955 ) describes four tongue shapes during processing,

two of which amount to formation of an anterior hollow composed of a 0.5 wavelength

cup in the transverse direction and a 1 wavelength A/P cup-and-hill. Other

tongue shapes are even less complex.

Even during speech production most vowel shapes can be accommodated by a

limited number of basic tongue postures, and speci fi c spatial control does not seem

critical (Stone and Lundberg 1996 ) . The spatial frequency of many tongue deformations

is thus quite low, compatible with data that suggest the neural structures that

organize tongue movement are larger and more diffuse than the lamina of T and V

fi bers, but smaller and more localized than the whole tongue. Localization of motor

unit territories may enable maximal diversity of tongue deformation for movements

that involve disparate and complex patterns of expansion and compression in different

tongue regions, for example, during oral transport when different tongue regions

may behave independently (e.g., Hiiemae et al. 1995 ) .

Current understanding of tongue motor unit territories is compatible with the

reported regional tongue deformations. To form a hollow or trough in the tongue, a

central depression bounded by raised lateral edges, the simplest deformation is uniform

transverse shortening of the dorsal surface without shortening of the ventral

surface. The largest transverse motor units to cause this motion could span the entire

dorsal surface, but should not cross the transverse mid-plane. Smaller motor unit

territories would allow a sharper corner between the fl oor of the hollow and the

walls. Vertical fi ber contribution to the motion could be uniform throughout the

tongue body. So formation of half-wavelength C shapes requires only one motor


219

unit, and formation of whole-wavelength S shapes requires two. As discussed,

motor unit territories have been localized only coarsely—to anterior, middle, or

posterior regions and to left/right sides, but this localization is all that is required to

achieve the many tongue shapes used during routine behavior. It is also possible that

motor unit territories are much smaller and could allow either sharper ( Z -like) or

more serpentine shapes.

12.5 Tongue Muscle Fiber Biochemistry

12.5.1 Background

Studies in appendicular and cranial muscles demonstrate a relationship between

MyHC isoform and muscle fi ber contractile properties. For example, among muscle

fi bers that uniformly express one of the four conventional MyHC, shortening velocity

progresses from slowest to fastest in the order: MyHCI, MyHCIIA, MyHCIIX,

MyHCIIB. Although shortening velocity is one of the most dramatic differences

among fi bers, MyHC isoform is highly correlated with a range of specializations

that include calcium kinetics, glycolytic capacity, and mitochondrial content.

Experimental models indicate that fi ber type is plastic and can be altered to meet

functional demands, most notably duty cycle, suggesting that muscle protein expression

is regulated to provide speci fi c contractile or metabolic properties. Muscle fi ber

contractile diversity can additionally be achieved by hybridization of multiple

MyHC in single fi bers, thereby creating fi bers with intermediate properties in proportion

to the prevalence of constituent MyHC.

In mammals, including human appendicular muscles, single extrafusal fi ber contractile

diversity is typically achieved by homogeneous expression of MyHCI,

MyHCIIA, MyHCIIB, or MyHCIIX and only limited hybridization of MyHC isoforms

(primarily MyHCII) (as opposed to single intrafusal fi bers found in muscle

spindles). Head and neck muscles diverge from this appendicular norm in two

respects. In addition to the four MyHC isoforms expressed in limb and body skeletal

muscle, some adult head and neck muscles express developmental isoforms

MyHCembryonic and MyHCneonatal and additional isoforms MyHCalpha-cardiac,

MyHCextraocular, MyHCmasticatory, and MyHCslow tonic, which are absent from

normal appendicular muscles. Further, some head and neck muscles contain many

hybrid fi bers, including fi bers with MyHCI-MyHCII hybridization and MyHC

hybridization where single fi bers contain mixtures from all three categories of

MyHC isoforms. MyHC hybridization is most extensive in masticatory and extraocular

muscles where single fi bers may contain fi ve MyHC (Yu et al. 2002 ; McLoon

et al. 2011 ) .

Many head and neck muscles, but not tongue muscles, undergo a different

developmental path than axial and appendicular musculature. Limb, body, and

tongue muscles originate from the embryonic somites and are dependent on

Pax3/7 for differentiation (Buckingham et al. 2003 ) . Head and neck muscles

largely originate from the branchial arches of the embryonic somitomeres and


Fig. 12.5 Myosin heavy chain (MyHC) mRNA pro fi les for anterior tongue body muscles in

human, rhesus macaque, and rat determined by quantitative PCR (Rahnert et al. 2010 ; S. Karger

AG, Basel; used with permission). ( a ) Conventional and prominently expressed isoforms.

( b ) Developmental and unconventional isoforms, eo: extraocular muscle speci fi c; beta: beta cardiac;

alpha: alpha cardiac; emb: embryonic; neo: neonatal; st: slow tonic

cranial mesoderm and undergo differentiation via a Tbx1 or Pitx2 pathway (Kelly et al.

2004 ; see Chap. 2 ). Expression of unconventional MyHC isoforms (MyHCalphacardiac,

MyHCextraocular, MyHCmasticatory and MyHCslow tonic) is largely

restricted to these branchial arch muscles and the extraocular muscles, and the Tbx1

and Pitx2 pathway may be less effective in silencing their expression .

12.5.2 MyHC Composition of Tongue Muscles

Quantitative PCR, separation SDS-polyacrylamide gel electrophoresis (SDS-PAGE),

western blot, and immunohistochemistry (IHC) demonstrate that adult tongue muscles

of the mouse, rat, macaque, and human consist almost entirely of MyHCI,

MyHCIIA, MyHCIIX, and MyHCIIB. By PCR, only limited mRNA (0.1–0.8% total

mRNA) of MyHCembryonic and MyHCneo is detected in anterior tongue body

muscles of the rat, macaque, and human with the exception of MyHCalpha-cardiac

in the human (5%) and MyHCeom in the macaque (3.7%) (Rahnert et al. 2010 )

(Fig. 12.5 ). The developmental and additional MyHC proteins are not visualized in

tongue muscles of the adult mouse, rat, and human by SDS-PAGE (d’Albis et al.

1990 ; Agbulut et al. 2003 ; Granberg et al. 2010 ; Daugherty et al. 2012 ) .

MyHC phenotype prevalence by IHC has been studied most extensively in

humans. In human extrinsic muscles, phenotype prevalence is generally ordered

MyHCIIA > MyHCI > MyHCI-IIX with limited MyHCI-IIA and minimal MyHCIIX

(Sokoloff et al. 2010 ) . Predominance of MyHCIIA and MyHCI with minimal

MyHCIIX has also been reported in human intrinsic tongue muscles (Granberg

et al. 2010 ) . These studies however, suggest differences between extrinsic and

intrinsic muscles with respect to the presence of phenotype MyHCI-IIX (in human

extrinsic but not intrinsic muscles) and phenotype MyHCIIA-IIX (in human intrinsic

muscles but not GG (Daugherty et al. 2012 ) . MyHC expression is related to the

pattern of nerve activation (Ausoni et al. 1990 ; Pette 2001 ; Schiaf fi no et al. 2007 ),


221

and MyHC phenotype disparity might re fl ect differential patterns of MU recruitment

between intrinsic and GG tongue muscles. Further studies with equivalent IHC

methods are required to con fi rm MyHC phenotype differences between intrinsic

and extrinsic muscles.

Few studies have investigated MyHC phenotype or fi ber type with respect to

extrinsic muscle architecture. By ATPase, a greater prevalence of Type II vs. Type I

fi bers was reported in dog anterior-oblique compared to horizontal GG regions (Mu

and Sanders 1999 ) . In the human, the oblique GG contains relatively more MyHCIIA

and less MyHCI than the horizontal GG (Daugherty et al. 2012 ) . In contrast, greater

prevalence of faster isoforms was reported in the posterior vs. anterior GG of the rat

(Volz et al. 2007 ) . Greater prevalence of “faster” myosin isoforms in anterior vs.

posterior intrinsic tongue muscles of the human and macaque is demonstrated by

ATPase and separation SDS-PAGE, with speci fi c type/MyHC prevalence varying

by region and muscle (dePaul and Abbs 1996 ; Stal et al. 2003 ; Granberg et al. 2010 ) .

A general anteroposterior disparity in “fast” (anterior) vs. “slow” (posterior) fi ber

composition might re fl ect relatively greater participation of anterior tongue regions

for feeding and oral transport tasks and of posterior tongue regions for respiration

and maintenance of airway patency.

By IHC only occasional fi bers are positive for the developmental MyHC isoforms,

MyHCalpha-cardiac, and MyHCslow tonic in macaque and human tongue muscles

(0–3% of total fi bers in any individual; Sokoloff et al. 2010 ; Granberg et al. 2010 ) .

Thus, mammalian tongue muscles studied to date differ from some head and neck

muscles, which have appreciable expression of developmental and additional MyHC

isoforms.

The bases for the limited expression of the developmental and additional nonlimb

skeletal muscle MyHC in the human tongue are not known. IHC studies of the

human HG and SG suggest that MyHCneonatal is primarily localized to fi ber endings,

possibly re fl ecting fi ber remodeling at the myotendinous junction (Sokoloff

et al. 2010 ) . Appendicular muscles may also express MyHCneonatal at fi ber terminations

(Rosser et al. 1995 ) , and expression of MyHCneonatal at fi ber terminations

may account for low levels of MyHCneonatal reported in many head and neck muscles

by PCR and IHC (see also Tellis et al. 2004 ) . The absence of signi fi cant levels

of developmental MyHC suggests however that persistent muscle fi ber remodeling

is not a feature of human tongue muscles, even in very old age.

12.5.3 Capillarization and Oxidative Metabolism

of Tongue Muscles

In appendicular muscles, there is a general relationship between fi ber type/MyHC

phenotype, capillarization (capillary number/mm 2 fi ber), and oxidative metabolism

such that type I fi bers tend to have a higher capillarization and higher oxidative

capacity than type II fi bers. However, capillarization, mitochondrial density, and

oxidative capacity of muscle fi bers are highly plastic and change with age and use.


Compared to appendicular muscles, many cranial muscles have relatively high

capillarization and mitochondrial content (Stal and Lindman 2000 ; Kjellgren et al.

2004 ) . Human intrinsic tongue muscle fi bers also have relatively high capillarization

with values similar to extraocular and jaw-closing muscles but two times greater

than appendicular muscles (Granberg et al. 2010 ) . Human intrinsic tongue muscles

also have a moderate to high mitochondrial enzyme activity as do most tongue

muscle fi bers in the cat and rat (Hellstrand 1980 ; Sato et al. 1990 ) .

Interestingly, high capillarization and high mitochondrial enzyme activity in

human tongue muscles are present in fi bers of slow and fast MyHC, suggesting that

tongue muscle fi bers generally are refractive to fatigue. These characteristics accord

with measures of high resistance to fatigue following CNXII branch and hypoglossal

nucleus motoneuron stimulation in the rat (Gilliam and Goldberg 1995 ) . The

high oxidative capacity of human tongue muscle fi bers may support two features of

the tongue motor system that differ from the appendicular system, the constitutive

activity of some tongue motor units (Tsuiki et al. 2000 ; Saboisky et al. 2006 ; Bailey

et al. 2007a ) and the relatively high fi ring rates of motor units activated during

respiration or voluntary tasks (Bailey et al. 2007b ) .

12.6 Aging of Tongue Muscle

Age-related loss of muscle mass and muscle function (i.e., sarcopenia, Cruz-Jentoft

et al. 2010 ) occurs in many motor systems. Features of sarcopenia vary extensively

by muscle but often include decrease in muscle fi ber number and size (especially of

“fast” fi bers). Aging is also associated with changes in MyHC prevalence, increased

hybridization of different MyHC in single fi bers, and increased expression of developmental

MyHC (Andersen 2003 ; Snow et al. 2005 ) . Most motor systems lose

motoneurons with age, and the resultant denervation/reinnervation remodeling of

muscle fi bers may account for some of the above-mentioned anatomical and molecular

changes (Delbono 2003 ; Snow et al. 2005 ) .

Tongue muscles appear spared from many age-related changes typical of motor systems.

Although studies of aging of mammal tongue musculature are few, there is little

evidence of fi ber atrophy, expression of developmental MyHC, change in fi ber type

prevalence/MyHC composition (Connor et al. 2009 ; Sokoloff et al. 2010 ; Rother et al.

2002 ; but see Nakayama 1991 ) , and evidence for only minimal change in neuromuscular

junction morphology (Hodges et al. 2004 ) . Interestingly, hypoglossal nucleus

motoneuron number is preserved with age (Sturrock 1991 ; Gai et al. 1992 ) , which protects

tongue muscles from cell-loss-induced denervation/reinnervation remodeling.

The bases for the apparent protection of tongue muscles from typical age-related

neuromuscular pathology are not known. As noted, some GG motor units are constitutively

active indicating a high duty cycle of some tongue motor units. Tongue

motor units typically have high rates of activation. During swallowing high tongue

pressures are generated in normal swallows, although this can be increased in effortful

swallows (Hind et al. 2001 ) . In appendicular muscles, resistance exercise can delay


223

age-related muscle decline, although it does not mitigate motoneuron loss or prevent

sarcopenia. Hypoglossal motoneurons also receive inputs from numerous central and

peripheral sources, and it is possible that this rich synaptic milieu supports hypoglossal

nucleus motoneurons during dysfunction in any one projection system.

12.7 Conclusions

The architectural and neural specialization of the tongue re fl ects its unique lack of

skeletal constraints. Deformations of the tongue during oromotor behaviors are varied

and are not well described by activation of classically de fi ned muscles. Tongue

muscle architecture is complex and tongue motor units occupy limited territories,

enabling localized contraction of fi bers with different orientation that is needed to

achieve the dimensional control required by the muscular hydrostat model. The

extent to which the nervous system actually uses the fi ne-grained control structure

during routine behavior is not yet clear.

The tongue appears to be composed of conventional skeletal muscle fi bers with

speci fi c structural and control adaptations that re fl ect an unusually high degree of

daily activity and the absence of skeletal constraints on motion. In many species

tongue muscles are comprised principally of two conventional MHC isoforms. In

the rat, tongue motor unit contraction times are similar to those of other fast appendicular

motor units but produce much less force likely re fl ecting a low number of

muscle fi bers per motor unit.

Compared to appendicular muscles, tongue motor units have high duty cycles,

whether constitutively active to maintain airway patency or phasically active during

respiration or swallowing. Highly localized and small motor units may require high

fi ring rates for meaningful force production. Persistent activation of many motor

units may require high mitochondrial content and capillarization and protect tongue

muscles from typical aging dysfunction.

Acknowledgements We thank Audrey Jernigan for illustrations. This work was supported by

grant DC005017 from the National Institute on Deafness and Other Communication Disorders .

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Tissues Organs 181(1):51–64

Snow LM, McLoon LK et al (2005) Adult and developmental myosin heavy chain isoforms in

soleus muscle of aging Fischer Brown Norway rat. Anat Rec A Discov Mol Cell Evol Biol

286(1):866–873

Sokoloff AJ (2000) Localization and contractile properties of intrinsic longitudinal motor units of

the rat tongue. J Neurophysiol 84(2):827–835

Sokoloff AJ, Deacon TW (1992) Musculotopic organization of the hypoglossal nucleus in the

cynomolgus monkey, Macaca fascicularis. J Comp Neurol 324(1):81–93

Sokoloff AJ, Siegel SG et al (1999) Recruitment order among motoneurons from different motor

nuclei. J Neurophysiol 81(5):2485–2492

Sokoloff AJ, Li H et al (2007) Limited expression of slow tonic myosin heavy chain in human

cranial muscles. Muscle Nerve 36(2):183–189

Sokoloff AJ, Daugherty M et al (2010) Myosin heavy-chain composition of the human hyoglossus

muscle. Dysphagia 25(2):81–93

Stal PS, Lindman R (2000) Characterisation of human soft palate muscles with respect to fi bre

types, myosins and capillary supply. J Anat 197(pt 2):275–290

Stal P, Marklund S et al (2003) Fibre composition of human intrinsic tongue muscles. Cells Tissues

Organs 173(3):147–161

Stone M, Lundberg A (1996) Three-dimensional tongue surface shapes of English consonants and

vowels. J Acoust Soc Am 99(6):3728–3737

Sturrock RR (1991) Stability of motor neuron and interneuron number in the hypoglossal nucleus

of the ageing mouse brain. Anat Anz 173(2):113–116

Sutlive TG, Shall MS et al (2000) Contractile properties of the tongue’s genioglossus muscle and

motor units in the rat. Muscle Nerve 23(3):416–425

Takemoto H (2001) Morphological analyses of the human tongue musculature for three-dimensional

modeling. J Speech Lang Hear Res 44(1):95–107

Tellis CM, Rosen C et al (2004) Anatomy and fi ber type composition of human interarytenoid

muscle. Ann Otol Rhinol Laryngol 113(2):97–107

Thexton AJ, Crompton AW (1989) Effect of sensory input from the tongue on jaw movement in

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227

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Chapter 13

Tongue Biomechanics and Motor Control

Mary Snyder Shall

13.1 Introduction

The tongue is one of the most intriguing of the skeletal muscles, considering that it

consists of several muscles and as a group, takes many shapes. It plays a vital role

in respiration, suckling, acquiring and manipulating food, swallowing, and speech.

Obviously, not all species use the tongue in the same way, so the tongue has adapted

to deform into different shapes and mechanisms of movement to meet the needs of

the animal. Even when considering only mammalian tongues, two categories of

tongue have been proposed (Doran 1975 ) . The type II tongues in animals such as

marsupials, monotremes, and pholidota protrude at least 100% of their resting

length to gather food such as ants or fl ies. Many of these tongues reach their prodigious

lengths by a hydrostatic mechanism typically created by contraction of the

vertical and transverse lingual muscles, compressing the longitudinal muscles,

resulting in more elongation of the tongue (McClung and Goldberg 2000 ; Smith and

Kier 1989 ) . While intriguing, the type II tongues are not discussed further.

This chapter focuses on the higher order mammalian type I tongues that protrude

less than 50% and function more for intra-oral manipulation. In humans, the normal

tongue moves quickly and precisely to speak and enunciate clearly. Many patients

with central nervous system disorders must speak slowly due to the lack of coordination

of the tongue. We discuss the impact of anatomical and contractile characteristics

on the biomechanics and motor control of the tongue in higher mammals.

M. S. Shall (*)

Department of Physical Therapy , Virginia Commonwealth University ,

Richmond , VA 23298 , USA

e-mail: msshall@vcu.edu




229

230 M.S. Shall

13.2 Biomechanics

Dr. Sokoloff described the anatomy of the muscles in the previous chapter; Figure 1

in that chapter illustrates their orientation. The body of the tongue is composed of

three pairs of “intrinsic” muscles and four pair of “extrinsic” muscles. By de fi nition,

the vertical, transverse, and longitudinal intrinsic muscles originate on muscle fi bers

and insert on other muscle fi bers or the connective tissue within the body of the

tongue. The extrinsic genioglossus (GG), styloglossus (SG), hyoglossus (HG), and

palatoglossus (PG) muscles originate on bone (genial tubercle of the mandible, the

styloid process, the hyoid bone, and the lateral palate, respectively) and insert onto

the base of the body of the tongue. There has been debate on the intrinsic/extrinsic

terminology since muscles from both groups interdigitate and work together on

many actions.

The jaw and hyoid positions must be part of the pattern that strategically places

the entire tongue for the appropriate muscle movements for speech or mastication.

The masseter muscle is important to position the mandible and is examined thoroughly

in Chaps. 6 , 7 , and 8 . As the jaw opens to accept food, the mylohyoid and

geniohyoid contract to move the hyoid bone forward relative to the mandible to

elevate and close the larynx. Like the GG, the geniohyoid originates on the genial

tubercle of the mandible, but inserts on the hyoid bone rather than the tongue. The

mylohyoid forms the fl oor of the oral cavity from the mandible to the hyoid bone.

13.3 Motor Activation by the Hypoglossal Nerve

Hypoglossal (cranial nerve XII) motoneurons are dedicated to providing innervation

to all the tongue muscles except for the palatoglossus, which is innervated by

the vagus nerve (cranial nerve X). Most of the innervation details of the tongue

muscles have been discovered by retrograde labeling techniques from injections

into various regions of the tongue (McClung and Goldberg 1999, 2000, 2002 ;

Sokoloff 1993 ; Sokoloff and Deacon 1992 ) . The hypoglossal nucleus, located close

to the midline of the medulla is subdivided into two major compartments, which

have been most thoroughly studied in rats (Uemura-Sumi et al. 1988 ; Sokoloff

1993 ; Aldes 1995 ; McClung and Goldberg 1999, 2000 ) (Fig. 13.1 ).

The motoneuron projections from the ventral portion of the nucleus travel

through the medial branch of the hypoglossal nerve to supply the GG muscle, a

protrusor muscle. Aldes ( 1995 ) found that some hypoglossal motoneurons in the

ventral aspect of the hypoglossal nucleus innervate the vertical and transverse intrinsic

muscles, implying shared functions of intrinsic muscle fi bers with the GG muscle.

The motoneurons innervating the geniohyoid muscle mostly originate in the

lateral accessory subcompartment of the hypoglossal nucleus and travel in the

medial branch of the hypoglossal nerve. A small number of the motoneurons supplying

the geniohyoid arise from the medial subnucleus of the caudal hypoglossal

nucleus and pass through the upper root of the ansa cervicalis before jumping on

Fig. 13.1 Retrogradely labeled entire hypoglossal nucleus motoneurons on the left and only the

dorsal subdivision of the nerve intact on the right . Cells are seen 600 m m rostral to the internal

obex in ( a ), at the internal obex in ( b ), and 600 m m to the internal obex in ( c ). The dorsal subgroup

is surrounded by the thick line and includes motoneurons supplying the styloglossus (SG), hyoglossus

(HG), and the inferior (Inf) and superior (Sup) longitudinal (long) intrinsic tongue muscle

fi bers. The ventral subgroup is surrounded by a thin line and includes motoneurons supplying the

genioglossus (GG), and the vertical (vert) and transverse (trans) intrinsic tongue muscle fi bers. The

geniohyoid (GH) motoneurons are located in the lateral accessory subgroup. CC central canal.

Scale bar = 100 m m for ( a ), ( b ), and ( c )

232 M.S. Shall

the medial branch of the hypoglossal nerve (Aldes 1995 ; Kitamura et al. 1985 ;

Uemura-Sumi et al. 1988 ) . In the human, the hypoglossal cranial nerve receives a

contribution from the fi rst cervical nerve for its innervation of the geniohyoid muscle

(Curto et al. 1980 ) . The more dorsal compartment of the hypoglossal nucleus

contributes motoneurons to the lateral branch, which supplies the HG and SG.

McClung and Goldberg ( 1999 ) also found that the superior and inferior longitudinal

muscles are involved in tongue retrusion and are innervated by the motoneurons

located in the dorsal part of the hypoglossal nucleus.

13.4 Somatic Sensation

Tongue sensation is frequently associated only with taste, supplied by cranial nerves

VII, IX, and X. However, somatic sensation of the tongue surface plays a vital role

in both proprioception of the tongue and manipulation of food so that the food bolus

is of an appropriate size for the esophagus and in a position for swallowing. Steele

and Miller ( 2010 ) emphasize in their review that sensory feedback is important to

all phases of deglutination. Anterior tongue sensation triggers the subconscious

pharyngeal swallow. Sensory receptors continue to monitor the bolus as the sequential

motor activity of the tongue moves it along. The esophageal swallow intensity

is modi fi ed in response to the sensory evaluation of the bolus, and secondary peristalsis

is initiated.

The lingual nerve off the mandibular division of cranial nerve V is responsible

for the somatic sensation of the anterior 2/3 of the tongue surface, while branches of

the maxillary division provide input from the palate. The lingual branch of cranial

nerve IX supplies both surface sensation and taste of the posterior 1/3 of the tongue

(Goetz 2007 ) . The internal branch of the superior laryngeal nerve and other branches

of the vagus nerve provide the feedback in the pharyngeal region. Cortically, the

mammalian tongue homunculus is one the largest cortical areas dedicated to sensation,

even at birth, leading the infant to explore everything with its tongue. Sakamoto

et al. ( 2008 ) found that most of the somatosensory processing is located in the primary

somatosensory cortex (SI), Brodmann area 40 and the anterior cingulate cortex

(ACC). A fraction of the tongue SI is primarily activated by the anterolateral

tongue, implying its voluntary activity in speech as well as the initiation of feeding

and drinking. It is interesting that children show symmetric patterns of lingual twopoint

discrimination whereas adults develop an asymmetric pattern (McNutt 2009 ) .

This seems to indicate a maturing of language skills as the child learns to emphasize

particular patterns of speech that are speci fi c to the language and region.

Somatosensation of the posterior parts of the tongue is processed less by SI and

more by Brodmann Area 40 and ACC (Sakamoto et al. 2010a ) . It is known that the

ACC plays an important role in sensory, motor, cognitive, and emotional information

(Sakamoto et al. 2010b ) , and pain processing (Schnitzler and Ploner 2000 ; Vogt

2005 ; Qiu et al. 2006 ) . It follows that posterior tongue sensation is more involved in

the maintenance of the patent airway, vomiting and swallowing functions, and the

13 Tongue Biomechanics and Motor Control

233

connection with the limbic system. Choking, retching, etc., may be accompanied by

tears and a sense of panic and pain.

Masseter muscle spindle afferents synapse with cranial nerve XII premotor

neurons via the trigeminal mesencephalic nucleus (Luo et al. 2006 ) . These synaptic

connections provide some of the proprioceptive mediated jaw–tongue coordination.

Less is known about the proprioceptive feedback from the human tongue during

tongue movement. Anesthesia of the lingual nerve (carrying cranial nerve V afferents)

induces a delay in the corticomotor control of tongue muscle (Halkjaer et al.

2006 ) . It is common knowledge that there are neural network motoneurons, sensory

neurons, and interneurons known as “central pattern generators” that can generate

basic motor patterns for repetitive movement. These networks are particularly useful

for activities such as locomotion that are performed the same way, at the same

rate, many times in a day. Similarly, rhythmic movements of the tongue, driven by

the hypoglossal nuclei, receive inputs from the dorsal medullary reticular column

(DMRC) and the nucleus of the tractus solitarius (NTS). These interconnections are

helpful for repetitive functions such as respiration and chewing (see below) with

sensory feedback from cranial nerves V and IX.

13.5 Functions

13.5.1 Protrusion and Retrusion

The GG muscle originates on the genial tubercle on the inside of the anterior mandible

and inserts on the ventromedial base of the tongue (McClung and Goldberg

2000 ) to pull the tongue toward the mandible, i.e., protrude the tongue. The SG

muscle angles inferiorly from the styloid process of the temporal bone to the ventrolateral

base of the tongue to retract the tongue up and back. Synergistically, the

HG muscle originates on the hyoid bone and runs superiorly to insert on the superolateral

aspect of the base of the tongue (McClung and Goldberg 2000 ) . Downward

movement (depression) of the base of the tongue is performed by the combined

action of the GG and HG muscles. Conversely, the SG and PG lift (elevate) the base

of the tongue.

The functional organization of the intrinsic muscles has been more dif fi cult to

pin down. It is generally accepted that intrinsic muscles shape the tongue to execute

more fi nely controlled movements as well as contribute to protrusion and retrusion.

Protrusion is not a major function of the human tongue, though it is usually the

function tested to evaluate the status of the hypoglossal cranial nerve. A dysfunctional

nerve will result in the GG contracting only on the intact side so that the

tongue appears to “point” to the side of the lesion. It is interesting to study the

mechanics of protrusive activities such as licking and lapping in experimental animals

such as dogs, cats, and rats (Reis et al. 2010 ) . As expected by our own observation,

a dog’s tongue penetrates the water and quickly scoops the liquid into a ventral

“cup” and into the mouth as it closes. In contrast, the cat quickly touches the dorsal

234 M.S. Shall

tip of the tongue and pulls up a column of water to be partially captured by jaw

closure, only seen by high speed videography. These are two very different adaptations

of the tongue to perform the same function though lost as humans adapted to

drinking from a cup or sucking through a straw.

Contraction of the intrinsic muscles can thicken the body of the tongue or bend

the tongue’s tip downward or upward (Napadow et al. 1999 ) . Humans restrict their

movements to within or around the oral cavity, e.g., bending the tip to the side

would be activated by that side’s longitudinal intrinsic muscles.

13.5.2 Respiration

Rather than tongue protrusion, humans are much more concerned about the development

and maintenance of the ability to suck, chew, swallow, breathe, speak, and

coordinate all of those activities to avoid problems such as biting the tongue, aspirating

food, or losing nourishment.

Obviously respiration is the fi rst function recognized at birth, and the tongue plays

an important role in maintaining an open airway. At birth, the rat GG muscle expresses

only neonatal/embryonic isoforms (Brozanski et al. 1993 ) . The myosin heavy chain

(MyHC) isoforms rapidly mature to adult expression of 2A, 2X, and 2B but neonatal

MyHC still accounts for about 10% of the total MHC composition at postnatal day 25.

Considering that the neonatal rat is comparable to a human fetus in the third trimester

(Romijn et al. 1991 ) , it is understandable that the human tongue motor units would

to be ready for independent respiration but still have room for modi fi cation.

The GG co-contracts with the HG during inspiration to decrease pharyngeal collapsibility

in both animal and human subjects (Fregosi and Fuller 1997 ; Fuller et al.

1999 ) . If stressed to clear the airway, the superior longitudinal intrinsic muscle will

assist in opening the airway by helping to pull the tongue forward.

Human tongue movement has been most extensively studied in terms of its role

in respiration. Most of the single unit recordings of the tongue have focused on the

GG because of the ease of human access under the tongue or percutaneously with

fi ne wire electrodes (see Bailey 2011 for review). Some of the earliest recordings

described rhythmic activation of the GG during inspiration to pull the tongue forward

and open the airway when the subjects are sitting or standing upright (Sauerland

and Mitchell 1970 ) . The activity changed to continuous activity when supine, even

in stable non-REM sleep (Bailey et al. 2007a ) . The EMG activity decreases during

REM sleep (Sauerland and Harper 1976 ) . This data led to the hypothesis that

the GG was the vital key that modulated the oropharyngeal aperture that should

counterbalance the collapsing force exerted by inspiration (Remmers et al. 1978 ) .

Clinically, this seemed to indicate that a lazy GG might cause sleep apnea. However,

data from further research has reformulated the hypothesis to involve the co-activation

of multiple pharyngeal airway muscles along with the GG to maintain the airway

and prevent sleep apnea (Fregosi and Fuller 1997 ; Fuller et al. 1999 ) .

Indeed, it became important to de fi ne the type of breathing or types of recruitment

to determine the possible reasons for the muscles that are active and their


235

fi ring patterns. It is easy to understand that vestibular input (Tsuiki et al. 2000 ) , state

of wakefulness (Bailey et al. 2007a ) , hypoxia (Hwang et al. 1983 ) , or laryngeal

mechanoreceptor stimulation (Withington-Wray et al. 1988 ) will alter recruitment

and the respiratory pattern, considering that these are very different functions. The

vestibular system would provide information that the head is vertical or horizontal

in a gravity controlled environment before there is feedback of hypoxia. If the head

is horizontal, the tongue might collapse into the oro-pharyngeal space. As a result,

a greater number of GG motor units are recruited during sleep because of the recumbent

position (Tsuiki et al. 2000 ) . One might think that the recruitment of the GG

might be a simple train of potentials to pull the tongue forward during inspiration

when sleeping in the supine position. Instead, Bailey et al. ( 2007a ) found at least six

different fi ring patterns in non-REM sleep, which persist after arousal from sleep

(Wilkinson et al. 2010 ) and in quiet wakefulness (Saboisky et al. 2007 ) . Recognition

of insuf fi cient oxygen is a primitive re fl ex that attempts to maintain an open airway

at all times. Hypoxia is recognized in the blood by the chemoreceptors located in

the carotid sinuses and sensed by cranial nerve IX. The sensation is directly connected

to the breathing centers of the brainstem, which recruits the respiratory

muscles including the GG to open the airway and increase the rate of inspiration

(Hwang et al. 1983 ) . If there is food or liquid aspiration into the larynx, the recruitment

of motoneurons may shift from inspiratory to expiratory to expel the problem

(Withington-Wray et al. 1988 ) .

Recruitment of motor units and rate coding vary during respiration, depending

on how much is needed to meet the need for suf fi cient oxygen. It is suggested that

the modulation of force in the hypoglossal motoneuron pool is biased in favor of

recruitment rather than rate coding (Bailey 2011 ) . There seem to be some localized

areas of the posterior GG that are active during quiet breathing (Bailey et al. 2007b ) .

Magnetic resonance imaging (Cheng et al. 2008, 2011 ) and intramuscular stimulation

(Oliven et al. 2007 ) reveal the mechanical action of deeper transversely oriented

GG fi bers that particularly contribute to opening the pharyngeal airway. The intrinsic

motor units may be more involved in respiration than previously considered.

The documentation of respiratory-related co-activation of protrudor and retrusor

tongue muscles reinforced the hypothesis of a respiratory central pattern generator

(CPG) (Bailey and Fregosi 2004 ; Peever et al. 2002 ) . The motor units of the tongue

and chest wall fi re in synchrony at frequencies between ~1.5 and 8 Hz (Rice et al.

2011 ) . As the breathing becomes more rapid, the chest wall and diaphragm work

ef fi ciently together while leaving the tongue to other complex tasks.

13.5.3 Suckling, Acquiring and Manipulating Food,

and Swallowing

Fortunately, at birth, most animals are ready to voluntarily protrude the tongue on

the nipple using the GG, apply the upward pressure or stroking on the nipple, using

the SG and vertical intrinsic tongue muscle fi bers which causes the milk to be

expressed. The tongue intrinsic muscles and HG propel the bolus toward the back

236 M.S. Shall

Fig. 13.2 Contractile responses of the postnatal day 14 tongue retractor musculature in a damreared

( left ) and arti fi cially reared ( right ) rat pup. ( a ) Constant frequency stimulation with 200ms

duration trains at 20, 40, 60, and 80 Hz from bottom to top . The dam-reared rat pup’s fusion frequency

= 80 Hz and maximum tetanic tension = 25.91 g. The arti fi cially reared rat pup’s fusion

frequency = 60 Hz and maximum tetanic tension = 25.91 g. ( b ) Fatigue response to stimulation at

50 Hz for 500 ms, 1 train/s for 2 min. The fi rst response is the top trace (showing greater tension)

and the last response is the bottom trace . The fatigue index (ratio of the last response to the fi rst

trace) of the dam-reared pup = 0.81 and the arti fi cially reared rat pup’s fatigue index = 0.55

of the tongue, which triggers the swallow. If the baby is intubated because of other

health issues, and has no opportunity to “practice” nutritive suckling and swallowing,

then these are activities that require learning later, and the baby may develop

speech at a later developmental age or have a persistent speech disorder (Jennische

and Sedin 1998, 1999 ) .

Newborn rats transition from nutritive suckling to chewing in 30 days (Maeda

et al. 1987 ) , during which time the MyHC isoform composition shifts from developmental

to adult fast MyHC (Brozanski et al. 1993 ) . A rat model mimicking perinatal

infants with disrupted suckling was developed in the Goldberg/McClung lab

to study the neuromuscular development in the absence of suckling experience.

Arti fi cial feeding via a gastric cannula from day 4 to postnatal day 14, eliminating

nutritive suckling behavior during the initial postnatal period, caused at least a

short-term alteration of the contractile characteristics of the SG muscle. Relative to

dam-reared animals, the rats had a decrease in fusion frequency and a decrease in

fatigue resistance. A 1-month resumption of dam-rearing and transition to rat chow

was suf fi cient for recovery of the contractile speed and fatigue characteristics of the

SG (Fig. 13.2 ) .

However, in the long-term, there was an increase in MyHCIIA isoform expression

and a decrease in the MyHCIIB isoform expression (Kinirons et al. 2003 ) . This

subtle change in muscle fi ber MyHC isoform expression may partially explain the

subtle changes in the motor control of the tongue. The rat is not deprived of all sensory

sensation during this period but fails to gain the sensory experience of nutrition

in the mouth to fully develop tongue coordination.

Swallowing is a complex sensorimotor function involving the tongue (see Ertekin

and Aydogdu 2003 ) . The initial “oral phase” is accepted as mainly voluntary, though

the duration of the phase may vary depending on hunger, taste, motivation, etc.

Initially, while still in the oral phase, the food is acquired and chewed into small


237

enough sizes to fi t through the pharynx and esophagus. All of the tongue muscles

are active in manipulating the food into the correct position for the teeth. The SG

and the PG lifts the posterior tongue to close off the pharynx while the intrinsic

muscles manipulate the bolus. If the food moves too quickly to the pharynx or a

tongue depressor depresses the tongue and stimulates the oral pharynx, the gag

re fl ex is stimulated. The vagus nerve senses the stimulation and makes a monosynaptic

connection with the hypoglossal nerve.

The pharyngeal phase propels the bolus to the esophagus while coordinating

inhibition of respiration, closing the palatopharyngeal isthmus, and constricting the

larynx. The genioglossus and the anterior digastric may be active initially, followed

by the mylohyoid, stylohyoid, and geniohyoid, working to lift the hyoid anteriorly

(Ono et al. 2009 ) . Finally, the posterior tongue is depressed to form the anterior wall

of the pharynx as the pharyngeal muscles take over in the effort to propel the bolus

toward the esophagus.

It is also important to consider the role of the mandible during eating and speech.

Obviously, several of the muscles attach to the mandible and so need the stability of

the bone on which to move the tongue. The temporomandibular joint facilitates the

synchronicity of anteroposterior movement of the mandible and tongue but limits

horizontal movement. The hyoid, on the other hand, moves with the tongue to produce

large amplitude horizontal movements.

There has been a lot of exploration of a masticatory CPG focused on the medial

bulbar reticular formation, with most of the studies using in vitro isolated mammalian

brainstem preparations (Katakura et al. 1995 ; Nakamura et al. 1999 ) . It became

apparent that sucking rhythm generators coupled with cranial nerves V, VII, and XII

were initially necessary to coordinate suckling during late gestation and infancy

(see Barlow 2009 for review). At birth, the system has to develop an interaction

between the swallow and a protection of the airway. Once again, sensory experience

is important during this critical period to develop a brainstem pattern for swallowing

pro fi ciency. As the infant develops, the tongue begins to discern the size of

the food bolus and how to move it to the back of the tongue for swallowing. The

more mature patterns of mastication involve the rhythmic opening and closing of

the jaws but rhythmical bursts also occur in hypoglossal motoneurons (Dellow and

Lund 1971 ) .

13.5.4 Speech

Manipulation of the tongue during speech is highly variable depending on the language,

acoustic feedback, and learned pattern of speech. Therefore the movements

of the muscles are extremely complex and only somewhat follow a pattern. Models

of the tongue and vocal tract have been enhanced by computer power. Speci fi cally,

the models have tried to relate muscle recruitment and tongue shape (Perkell and

Zandipour 2002 ) . More recently 3D biomechanical models of the tongue and oral

cavity have provided a view of the activity of parts of muscles rather than whole

238 M.S. Shall

muscles (Buchaillard et al. 2009 ) . For example, the general activity of the GG is one

of lowering the tongue while pushing it forward. When the focus is on forming a

sound with the fi ne nuances of the muscle, one can see that the anterior GG enlarges

the tongue in a transverse direction while moving the tongue downward. The posterior

GG elevates the tongue while pushing it forward. The HG also lowers the tongue

but in a posterior direction. On the other hand, the SG pulls the tongue backward but

the action may be up or down depending on the synergist.

One assumes that synergies exist in the motor control of the tongue which is not

evident at birth. Human infants listen and watch and practice, with the result that the

word “mama” comes fi rst after watching the lips and the word “dada” is more

dif fi cult since the tongue’s contact with the palate is concealed. The three-dimensional

orientation of the intrinsic muscles is fi nely coordinated to position the tongue

relative to the palate and the teeth to form vowel and consonant sounds.

In summary, the tongue is a wonderful complex of muscle fi bers that have developed

to meet the needs of each species. The masseter and the hyoid muscles position

the mandibular platform for the four pairs of extrinsic muscles to move the tongue

forward and back. The three pairs of intrinsic muscles deform the body of the tongue

in three dimensions for its respiratory, nutritional, and speech functions.

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Chapter 14

Tongue Muscle Response

to Neuromuscular Diseases and Speci fi c

Pathologies

Zi-Jun Liu

14.1 Overview

The tongue is the only muscular organ in the craniofacial region and plays fundamental

roles in almost all oral motor functions, including drinking, ingestion, chewing,

swallowing, respiration, and speech. A number of neuromuscular diseases, such as

epilepsy, multiple sclerosis, cerebral palsy, muscular dystrophy, Parkinson’s and

Huntington’s diseases, and myasthenia gravis, signi fi cantly affect tongue motor

functions. These negative impacts include reduced or complete loss of control in

moving the tongue (tongue displacement) and/or changing the shape of the tongue

(tongue deformation), tongue spasm or convulsion, muscle dystonia, and ankyloglossia.

Several sensational disorders may also occur due to these neuromuscular

diseases, including burning tongue, loss of taste function (ageusia), decreased ability

to taste (hypogeusia), and changes in taste (dysgeusia). In recent decades, extensive

studies have demonstrated that tongue size, volume, position, and neuromuscular

activity, especially in the tongue base, are signi fi cantly implicated in obstructive

sleep apnea (OSA), a potential life-threatening disorder of breathing, which affects

2–4% of the adult population (Schwab 2003 ; Schwab et al . 2003 ) .

In addition to the complex network of interwoven fi bers and fi ber bundles from

four intrinsic and four extrinsic tongue muscles which facilitate complicated and

delicate tongue kinematics, the tongue also has a large network of subdividing nerve

branches and blood supply. Studies have shown that the hypoglossal nerve alone has

more than 50 primary branches innervating tongue musculature (Mu and Sanders

1999 ) . Unlike other body motor organs, the tongue is composed almost entirely of

Z.-J. Liu (*)

Department of Orthodontics , University of Washington , Seattle , WA 98195 , USA

e-mail: zjliu@uw.edu




241

242 Z.-J. Liu

skeletal muscular tissue and lacks an internal bony support for motor function. While

the extrinsic tongue muscles arise externally from bony structures, the intrinsic

tongue muscles originate and terminate within the tongue proper (see Sokoloff and

Burkholder, Chap. 9 ). By contracting these complex muscular structures, the tongue

performs motor function and exerts force through various shape changes (Mu and

Sanders 1999 ) . As a “muscular hydrostat,” the tongue kinematics and biomechanical

effects (displacement, deformation, and load production) are produced by complex

changes of its shape in various dimensions. For example, the tongue is capable

of simultaneously lengthening and shortening in different regions. These kinematic

features may produce a great variety of nonlinear movements and deformations

without altering its tissue volume (Kier and Smith 1985 ; Kier et al. 1989 ; Nishikawa

1999 ; Sokoloff 2004 ). It has been recently advocated that the tongue neuromuscular

organization and motor control are no longer entirely muscle-based but use grouped

motor unit- or segmented structure unit-based strategies (Slaughter et al. 2005 ;

Sokoloff 2004 ; Takemoto 2001 ) .

14.2 Tongue Kinematics

Because of anatomical complexity and inaccessibility, tissue attributes, and functional

precision and diversity, studying tongue kinematics and biomechanics by

examining its shape changes (deformation) or position changes (movement) during

manipulation and function has been an ongoing challenge (Napadow et al . 1999a, b ;

Takemoto 2001 ; Sawczuk and Mosier 2001 ) . In addition to various imaging techniques

including video fl uoroscopy, cineradiography, X-ray microbeam, and MRI,

ultrasonography has been extensively used to study tongue kinematics in feeding

and speech. However, even with the availability of 3D reconstruction, this technique

can only trace movements represented by surfaces of the tongue, and deformational

changes remain undetectable. Due to the incompressibility and complex

fi ber structure, studying tongue biomechanics from changes of its overall tissue

shape or displacements may not be appropriate. Rather, internal muscular deformation

should be examined and analyzed (Napadow et al . 1999a, b ) . Therefore, tongue

internal kinematics are a key component of tongue biomechanics.

For years, our group has developed an innovative approach of digital microsonometrics

to study real-time tongue kinematics by measuring the changes in tongue

shape in multiple dimensions as well as tongue regional volume during various

functions. By implanting 6 ultrasonic crystals in the anterior 2/3 of the tongue blade

and body (Fig. 14.1a ) or 8 in the posterior 1/3 tongue base (Fig. 14.1b ) in a minipig

model, together with other techniques such as high-speed jaw movement tracking,

wire electromyography (EMG), in vivo loading, and respiratory monitoring, the

normal kinematics of the tongue and ensuing biomechanical consequences have

been extensively investigated.

14 Tongue Muscle Response to Neuromuscular Diseases and Speci fi c Pathologies

243

Fig. 14.1 Con fi gurations of the two ultrasonic crystal arrays. ( a ) Six crystals in anterior 2/3 of the

tongue. ( b ) Eight crystals in posterior 1/3 of the tongue. Empty circles and numbers indicate

implanted crystals, and two dark dots indicate circumvallate papillae the border of anterior 2/3

(body and blade) and posterior 1/3 (base) of the tongue. Inset : ultrasonic crystals with B barbs

14.2.1 Tongue Kinematics During Manipulations

of the Hypoglossal Motor System

Investigation on the relationship between regional tongue deformation and manipulation

with the hypoglossal motor system is essential in understanding the role of

the tongue in maintaining upper airway patency and loading on its surrounding

bony structures. When the tongue is manually moved forward, the major changes

are a large increase in the length (~18–20%) and a small decrease in the width

(~5–6%) and thickness (~9–11%). The anterior width symmetrically decreases to

28–30% when the tongue is moved laterally. However, the changes in the posterior

widths are side-dependent, decreasing in the dorsal and increasing in the ventral for

the ipsilateral side and vice versa. This side dependence feature is also seen in the

changes in length and thickness, i.e., length decreases and thickness increases for

the ipsilateral side. When the tongue is bent, either dorsally or ventrally, it results in

a small decrease in the width and thickness, but considerable increase in the length

(~36–53%). Therefore, at least in pig, the tongue has more fl exibility of length

change in ventral bending compared with dorsal bending (Liu et al . 2006 ) .

The hypoglossal nerve is the somatomotor nerve that innervates all the intrinsic

and all but one (palatoglossus) of the extrinsic muscles of the tongue. The medial

branch supplies motor output to the tongue protrudor complex (genioglossal,

244 Z.-J. Liu

Fig. 14.2 Stimulation of hypoglossal motor system. Dots indicate the locations of hook electrodes

for stimulations. HG hypoglossal nerve trunk; LB hypoglossal nerve lateral branch; MB hypoglossal

nerve medial branch; GG genioglossus; SG styloglossus; LN lingual nerve, LF lingual frenum;

CP circumvallate papillae; FP follicle papillae

geniohyoid, and intrinsic tongue muscles) whereas the lateral branch supplies motor

output to the tongue retractor complex (styloglossal and hypoglossal muscles)

(McClung and Goldberg 2000 ; Fuller and Fregosi 2000 ; Yoo and Durand 2005 ) .

Electrical stimulations to its trunk, medial, and lateral branches (Fig. 14.2 ) widen

the posterior tongue body by increasing its dorsal and ventral width (~8–10%).

However, tongue body shortening and thickening (~4–9%) are evoked by the trunk

and lateral branch stimulations. In contrast, stimulation to the medial branch lengthens

the sagittal dimension of the tongue body (~7–9%) along with moderate tongue

protrusion. On the other hand, stimulation to the major tongue protrudor, the genioglossus,

results in the widening of the anterior tongue body and thinning of the

posterior tongue body, along with tongue body lengthening. All of these deformations

have the effect of dilating the upper airway in the ventral and lateral pharyngeal

wall, thereby maintaining upper airway patency. Because the stimulations to

the tongue protrudor (medial branch and genioglossus) and retractor (lateral branch

and styloglossus) show opposite directions in the tongue deformation, the notion

that coactivation of both complexes has an effect on maintaining upper airway patency

may not be true. While the tongue manipulations result in signi fi cantly larger

changes in width, length, and thickness than those by electrical stimulations to the

hypoglossal motor system, the changes by stimulations are surprisingly similar to

each other no matter which nerve trunk, branches, or muscles is stimulated. This

similarity may imply that at least in the hypoglossal motor system, the supramaximal

activation of a nerve branch could produce motor output strength analogous to

that caused by the tetanic contraction of its innervated muscle (Liu et al . 2006 ) .

14.2.2 Tongue Kinematics During Function

As illustrated in Fig. 14.1 , it has been veri fi ed that the implantation of a number of

crystals (2 mm in diameter) into the tongue has no signi fi cant functional impairment


245

Fig. 14.3 Deformational patterns in the anterior 2/3 of the tongue during chewing ( a ), ingestion

( b ), and drinking ( c ). RL and LL right and left lengths (#1–3# and #2–#4); AW anterior width

(#1–#2); PDW and PVW posterior dorsal and ventral widths (#3–#4 and #5–#6); RT and LT right

and left thicknesses (#3–#5 and #4–#6). Refer to Fig. 14.1a for the locations of crystal pairs

(modi fi ed from Shcherbatyy and Liu 2007 , with permission)

(Kayalioglu et al . 2007 ) . Accordingly, tongue kinematics during various functions

such as mastication, drinking, swallowing, and respiration could be examined using

such a method. Similar to humans, the mastication sequence of the pig is composed

of ingestion, chewing, and swallowing. Tongue dimensional changes during chewing

and ingestion cycles are stereotypical with considerable regularity, and the

frequency is about two times faster for ingestion than for chewing cycles (~240 ms

vs . ~450 ms). The ingestion cycles are dominated by length changes (sagittal plane),

whereas changes in width and thickness (transverse plane) are more prominent in

chewing cycles. The bilateral thickness changes are symmetrical during ingestion

but side-dependent during chewing, which clearly re fl ects the side difference of

alternating chewing in pigs (Fig. 14.3a , b) (Liu and Herring 2000 ) . Swallowing

occurs every 30–40 chewing cycles and lasts about 550–600 ms without the interruption

of mastication sequence. Widening and lengthening of the tongue base are

the major changes for bolus swallowing during feeding accompanied by activity

bursts of the middle pharyngeal constrictor and thyrohyoid muscles (Fig. 14.4a ).

Spontaneous salivary swallowing, on the other hand, is characterized by posterior

widening and anterior narrowing of the tongue base as well as activity bursts in the

middle pharyngeal constrictor, thyrohyoid, and styloglossal muscles (Fig. 14.4b )

(Herring et al . 2011 ) . The initial tongue shape alters signi fi cantly from mastication

to drinking, at which the tongue body elongates and the posterior part becomes thinner.

During drinking cycles, the overall dimensional changes reduce signi fi cantly as

compared to chewing and ingestion cycles (~10–20% vs. ~10–33%) and their

amplitudes are symmetrically distributed in all dimensions (Fig. 14.3c ). Water

swallowing occurs every 3–4 drinking cycles and is characterized by narrowing in

246 Z.-J. Liu

Fig. 14.4 Deformational pattern of tongue base and accompanying muscle activities during

voluntary bolus ( a ) and spontaneous salivary ( b ) swallowing. BWA and BWP base anterior (#1–#2)

and posterior (#3–#4) widths; BL base length (#1–#3); BT base thickness (#1–#5); MA masseter;

GG genioglossus; SG styloglossus; TH thyrohyoid; MC middle pharyngeal constrictor; Ppres palatal

pressure; Flow, Pres. and Vol respiratory air fl ow, pressure, and volume. Refer to Fig. 14.1b for

the locations of crystal pairs. Red arrows indicate swallowing episode

posterior width and shortening in length of the tongue body, along with the activity

bursts in styloglossus. The time analysis clearly indicated that the reversals of

expansion–contraction of various dimensions of the tongue body are not synchronous

but occur in a sequential manner as a function of performing tasks. Therefore,

we may conclude that: (1) tongue internal deformations are task-speci fi c in both

timing and amplitude; (2) these deformations are dominant in the transverse plane

(width and thickness) for chewing, sagittal plane (length) for ingestion, and symmetric

in both planes for drinking (Fig. 14.3 ) (Shcherbatyy and Liu 2007 ) .

Our group has also examined the internal deformations of the tongue base

(Fig. 14.1b ) in relation to respiration in the same pig model. During the inspiration


247

Fig. 14.5 Deformational pattern of the tongue base during respiration. BWA and BWP base

anterior (#1–#2) and posterior (#3–#4) widths; BL base length (#1–#3); BT base thickness (#1–#5);

GG genioglossus; SG styloglossus; TH thyrohyoid; MC middle pharyngeal constrictor; V/T transversus/verticalis;

SL superior longitudinalis; Flow, Pres. and Vol . respiratory fl ow, pressure, and

volume. Two dash lines de fi ne the phase of inspiration (ins.), and red arrows indicate tongue base

deformation during the inspiration phase. Refer to n for the locations of crystal pairs

phase, the tongue base becomes thinner, narrower, and longer, and the genioglossus

muscle is the most active. During the expiration phase, rhythmic activity bursts of

tongue muscles disappear except for sporadic activation of the styloglossus (Fig. 14.5 )

(Herring et al . 2011 ) .

14.2.3 Spatio-Temporal Coupling in Volumetric

and Dimensional Changes

According to the muscular hydrostat theory of tongue motor control, the constant

volume of the tongue is achieved by its deforming or displacing in various regions

and dimensions via contractions of highly de fi ned intrinsic and extrinsic tongue

muscles (Kier and Smith 1985 ) . Although the entire tongue is incompressible, a

volumetric change deriving from independent motor control of regions may occur

to allow its diverse functions to be accomplished (Slaughter et al . 2005 ; Hiiemae

and Palmer 2003 ) , as the tongue motor control is far beyond the whole muscle level

(Odeh et al . 1995 ) . Therefore, the changes in distance (elongation or shortening) in

248 Z.-J. Liu

various dimensions (width, length, and thickness) in a region of the tongue may not

be parallel or compensatory to each other, thus incompatible with the hydrostat

theory. Our 3D digital ultrasound recording demonstrated that rhythmic and stereotypical

regional volumetric changes do occur during mastication and drinking, and

these volumetric changes are signi fi cantly larger in chewing (~45.6%) than in ingestion

(~31.4%) and drinking (~30.4%). The regional volumetric expansion mainly

results from widening and shortening, and posterior thinning in the tongue body.

The data also suggest that the theory of region-independent motor control of the

tongue (Slaughter et al . 2005 ; Hiiemae and Palmer 2003 ) , i.e., one dimension of the

tongue compensates for the other dimension or the loss of one dimension is parallel

to the gain of other dimension, may not really occur. The time-series analyses

between the dimensional and volumetric changes further revealed that the volume

expansion is primarily due to the increase of widths while thickness and length actually

decrease. If the overall changes in amplitudes of various dimensions are

counted, decreases in thickness and length are the two biggest contributors to volumetric

expansion. Therefore, regional volumetric changes are coupled with changing

widths in the same direction and with changing thickness and length in the

opposite directions (Liu et al . 2008c ) .

14.2.4 Tongue Kinematics in Relation to Jaw Movement

and Muscle Activity

Tongue kinematics are restricted neither to the simple protrusion–retrusion and/or

descending–ascending axes, nor to vertical rotation like that seen for the jaw, but

involves complex shape and regional volumetric changes during function. These

changes are produced by sequential muscular activity and accompanied by jaw

movement (Hiiemae et al . 1995 ; Napadow et al . 1999a, b, 2002 ; Liu et al . 2008c ) .

A number of studies have indicated a strong linkage between tongue and jaw movements

during feeding (Liu et al . 1993 ; Thexton et al . 1982 ; Palmer et al . 1997 ) , but

the linkage between internal deformation of the tongue and jaw movement is largely

unknown. High-speed video with fl uorescent markers glued to the lips and the

tongue tip revealed that during mastication, the tongue tip retracts when jaw opening

begins, with a time delay of 16–24 ms (Fig. 14.6 ). This very rapid movement

most likely relates to the control of the bolus, and this observation contradicts the

widely accepted notion that tongue protrusion coincides with jaw opening during

rhythmic chewing (Thexton et al. 1982 ; Liu et al. 1993 ; Palmer et al. 1997 ) .

Conversely, during jaw closing it is the corner of the mouth which retracts suggesting

that the cheek is responsible for guiding the bolus at this stage. The realtime

and synchronized study on tongue internal deformation, jaw movement, and

EMG activities revealed that expansion of tongue widths mainly occurs in the

occlusal phase of jaw movement and is less coupled with the activity of tongue

muscles, but the expansions of length and thickness are seen in the opening and

closing phases of jaw movement and are better coupled with activities of tongue


249

Fig. 14.6 Fluorescent marks of jaw ( a ) and tongue tip ( b ), and tracings (digitized) of jaw and

tongue movement during chewing ( c )

muscles. Ingestion function is characterized by early expansion of anterior width

prior to the occlusal phase and strong associations between tongue deformation and

muscle activity. During drinking, the durations of tongue widening and lengthening

are signi fi cantly shortened whereas these are signi fi cantly prolonged during the

opening and closing phases of jaw movement. Anterior widening is predominant in

the opening whereas posterior thickening lasts from early jaw opening through late

closing. This speci fi c pattern of dimensional changes suggests that the tongue

stretches in width fi rst before jaw opening, then elongates and thickens to form a

central groove during drinking. This is an ideal shape to exert the mechanism of

suction, because no lapping and licking for liquid feeding is reported in pigs and

most of ungulates (Shcherbatyy and Liu 2007 ; Herring and Scapino 1973 ; Thexton

et al . 1998 ) . Interestingly, intrinsic tongue muscles do not have more or stronger

correlations with tongue deformation than do extrinsic tongue muscles. The time

and correlation analyses further found that the initiation of tongue dimensional

increase does not correspond with the activation of tongue muscles simultaneously.

A better coupling between tongue deformations and tongue muscle activations

exists in the sagittal (lengthening and thickening) than the transverse (widening)

planes of the tongue. Furthermore, expansion magnitudes of tongue deformation do

250 Z.-J. Liu

Fig. 14.7 The estimated overall tongue shape in relation to three phases of jaw movement during

chewing. Column A : dorsal view; Column B : sagittal ( right-side ) view. ( a ) Opening phase;

( b ) closing phase; ( c ) occlusal (power stroke) phase. Arrows indicate the direction of deformational

changes (modi fi ed from Liu et al. 2008c , with permission)

not show closer correlation with the amount of EMG activity in intrinsic than

extrinsic tongue or jaw muscles.

In summary, the estimated tongue shapes during three stages of chewing are

sketched in Fig. 14.7 . Compared to the overall shape during jaw opening phase

(Fig. 14.7a ), elongation in the body and narrowing and thickening in the posterior

body are the main deformations during the jaw closing phase (Fig. 14.7b ). During the

power stroke, the tongue extensively widens and shortens, along with its thinning in

the posterior body (Fig. 14.7c ). Taking all of these dimensional and volumetric

changes together, it can be concluded that increases in the widths are greater than

decreases in the length and thickness, and their combination is most likely responsible

for the volumetric expansion during the power stroke. On the other hand, decreases in

the widths and length are greater than the increase in the thickness, and their combination

is most likely responsible for the volumetric contraction during jaw closing.

14.3 Tongue Volumetric Reduction and Consequences

of Motor Function

14.3.1 Mass Reduction and Tongue Kinematics

Abnormalities in tongue size and morphology have been implicated in various clinical

diseases such as malocclusion, OSA, dysphagia, Beckwith-Wiedemann and

Down’s syndromes, and cerebral palsy. Tongue volume reduction is a valuable

approach for treating symptomatic macroglossia and some related functional disorders

(Deguchi 1993 ; Davalbhakta and Lamberty 2000 ; Wolford and Cottrell 1996 ;

Ruff 1985 ; Herren et al . 1981 ; Li et al . 2002 ; Stuck et al . 2005 ) . Given the fact that

the tongue is a volume-dependent muscular organ due to the nature of its hydrostat


251

Fig. 14.8 Schema of the

tongue surgery. Dark area

indicate the removed tongue

mass. ( a ) Dorsal view; ( b , c ):

anterior and posterior coronal

views. CP circumvallate

papillae. Empty dots indicate

the implanted ultrasonic

crystals

(Kier et al . 1989 ; Kier and Smith 1985 ; Bailey and Fregosi 2004 ) , this muscular

mass reduction is expected to alter the tongue motor function signi fi cantly.

Furthermore, some types of post-injury adaptations could be less appropriate for the

functional demands and even become a dysfunction rather than a positive adaptation,

which may lead to maladaptive motor function over time. By using digital

ultrasonic techniques in the same pig model receiving ~18–20% tongue volume

reduction through surgery (Fig. 14.8 ), our group examined these immediate and

longitudinal effects on tongue kinematics (Shcherbatyy et al . 2008a, b ) .

As to an immediate effect after surgical tongue volume reduction, the basic feature

of the tongue kinematics still remains but the regularity and amplitude of the

dimensional changes during chewing are diminished. While the major dimensional

losses of the tongue by the surgery are the anterior (66%) and posterior dorsal widths

(16%), the major decreases in tongue kinematics during chewing are found in the

length (~31%) and the anterior width (~44%). Conversely, changes in the posterior

widths and thickness are signi fi cantly enhanced by ~10–20% after the surgery, indicating

an immediate compensatory effect. Anatomically, the orthogonally oriented

intrinsic muscle fi bers are the major components of the anterior 2/3 of the tongue,

and extrinsic fi bers are mainly inserted laterally (hyoglossus and styloglossus) and

compose a large central region of the tongue base (genioglossus) (Napadow et al .

1999b ; Sicher 1960 ; Gray 2000 ; Peter 1995 ; Odeh et al . 1995 ) . Therefore, intrinsic

tongue musculature is the major component of the tongue tissue removed by the

surgery (Fig. 14.8 ), although muscle fi bers from extrinsic tongue musculature,

252 Z.-J. Liu

particularly genioglossus, might be also included. From this point of view, such a

compensatory effect by the posterior tongue may suggest that there is a mutual

interaction and adaptation between these two types of tongue musculature: intrinsic

and extrinsic. The previous notion that extrinsic muscles are to position the tongue

and the intrinsic muscles are to shape the tongue (Sutlive et al . 1999 ; Gray 2000 )

may not be correct. In fact, tongue kinematics are driven by both intrinsic and

extrinsic tongue muscles, and these two muscle groups are not only structurally

interwoven but also functionally interacting. It is expected that this compensatory

effect for the loss of tongue mass may not occur under neuromuscular stimulation

to the hypoglossal motor nerves due to the lack of interaction and coordination

between different groups and regions of the tongue muscles. However, this expectation

is not fully supported by our stimulation tests, in which the change in posterior

dorsal width (the second largest dimensional loss by the surgery) was adversely

enhanced under the stimulation to the medial branch of hypoglossal nerve. On the

contrary, the deformational change in the least surgically involved dimension, posterior

ventral width, was signi fi cantly reduced. This contradictory fi nding suggests

that the muscular mass reduction might not be the major factor causing the decrease

in deformational range in the surgically altered tongue.

To verify whether the above changes in tongue kinematics by muscular mass

reduction is a transient effect or a relatively permanent consequence, our group

further examined the longitudinal changes before and after the surgery. Signi fi cant

modi fi cations in the feeding function were observed during this 6-week time period.

Typically, the animal utilizes the mandible, instead of the anterior tongue, to shovel

food into the mouth for ingestion, and moves and shakes the head intentionally for

chewing and swallowing as a way to take an advantage of gravity (inertial pattern),

which results in making the feeding session signi fi cantly longer. The food leaking

from the mouth corners during mastication and more frequent and longer ingestion

episodes interposed in the masticatory sequence are often seen in the initial weeks

after the surgery. However, the amount of daily food consumption shows no change.

With regard to tongue kinematics, at week 1 after the surgery, masticatory deformations

decreased in the anterior width and body length, but increased in the posterior

widths and thickness signi fi cantly, as compared to the baselines (week 0). At week

2, the reduced deformational capacity in the anterior tongue (width and length) was

slightly restored with better regularity of stereotypical chewing cycles than those

seen at week 1. However, the increased deformation in the posterior tongue (widths

and thickness) diminished as compared to those seen at week 1. At week 4, the restoration

of anterior tongue deformation continued, but the deformational range in

the posterior tongue further decreased and almost returned to those seen at the baseline

(week 0). These time-course changes in tongue kinematics clearly indicated that

although there is a short-term loss of deformational capacity in the anterior tongue

and a compensatory enhanced deformation in the posterior tongue, these distorted

features diminished over time, featured by the restoration of reduced deformation in

the anterior tongue and the vanishing of enhanced deformation in the posterior

tongue over time. Nevertheless, the complete restoration of the deformational

capacity in the anterior tongue was not seen at the end point of week 4 (Fig. 14.9a, b ).

This type of functional modi fi cation in tongue kinematics most likely stems from


253

Fig. 14.9 Comparisons of masticatory tongue deformational ranges of each dimension over time

between reduction and sham (surgical incisions without mass reduction) animals. Asterisks above

the data points indicate signi fi cantly larger or smaller deformational ranges at each time point

between the reduction and sham animals. All values were converted to % of altered distance/initial

distance of each dimension. P0 : pre-surgery (baseline); P1 , P2 , and P3 : 1, 2, and 4 weeks after the

surgery; AW anterior width; LENG length; PDW and PVW posterior dorsal and ventral widths;

THICK posterior thickness

muscular plasticity and adaptation, and also can be attributed to the motor learning

process after the surgery. Apparently, this type of adaptation in tongue kinematics

does not result in as good a functional performance as in an intact tongue, evidenced

by behavior alterations during feeding as described above and potentially negative

effects on craniofacial growth (Shcherbatyy et al . 2008a ; Liu et al . 2008a ; Liu 2009 ) .

Thus, maladaptation in tongue kinematics may occur with muscular mass reduction

of the tongue, because the chance of full recovery through myogenic regeneration

is unlikely. Fibrosis would be the most likely outcome, which may be a permanent

consequence after tongue mass reduction (see below).

14.3.2 Morphological and Histologic Consequences

After Mass Reduction

The muscular mass reduction results in remarkable morphological changes in the

tongue. The tongue becomes much shorter and narrower in its body as compared to the

sham surgery, which leads to the entire lower dental arch becoming visible (Fig. 14.10 ).

254 Z.-J. Liu

Fig. 14.10 Comparison of tongue morphology and its relation to mandibular dentition 4 weeks

after the surgery. Top : Tongue received sham surgery; Bottom : Tongue received reduction surgery.

Note that the remarkable decreases in length and width ( double-arrowed red lines ) in the reduction

as compared to the sham tongues (from Perkins et al. 2008 , with permission)

The tongue cast and postmortem measurements further indicate that despite ongoing

growth (compare before and after in sham-surgery animals in Table 14.1 ), the reduction

surgery signi fi cantly reduces the length and width of tongue body, and results

in about 15% loss of both volume and weight of the tongue over a 4-week period

postoperatively (Perkins et al . 2008 ) .

Although complete healing of surgical incisions is seen from the tongue surface

(Fig. 14.10 ), muscle fi ber reconstitution does not occur histologically in the surgical

site. Instead, disorganized collagen fi bers are interwoven without any detectable

arrangement or orientation. A few atrophied myo fi bers with reduced perimysium

and endomysium are sporadically distributed in fi brous tissue (Fig. 14.11 ). These

features are typical signs of fi brosis. Therefore, the recovery of normal muscular

architecture and functionality is compromised (Perkins et al . 2008 ) . The formation

of fi brosis may cause further decreased muscle contractility and reduced range of

kinematics. A cell proliferation assessment study (Ye et al . 2010 ) further revealed

that like other skeletal muscles, myogenic regeneration in the tongue follows a centripetal

gradient that fl ows from outer to inner regions, showing most and least


255

Table 14.1 Comparisons of dimension and mass between reduction and sham tongues

Dimensions (mm) Mass

Length Width Thickness Volume (mL) Loss (%) Weight (g) Loss (%)

Sham Before 103.45 ± 4.90 60.15 ± 2.24 7.91 ± 0.33 n/a n/a n/a n/a

4 weeks after 113.05 ± 5.21* 67.76 ± 0.61* 9.16 ± 0.58* 71.45 ± 2.20 n/a 71.43 ± 1.52 n/a

Reduction Before 104.52 ± 3.68 57.88 ± 2.26 8.03 ± 0.33 n/a n/a n/a n/a

4 weeks after 82.99 ± 4.69* 50.66 ± 2.41* 10.49 ± 0.27* 60.62 ± 0.91 # 15.21 ± 0.78 59.42 ± 1.33 # 15.18 ± 0.19

Dimension measures on tongue casts (anterior 2/3), and mass measures on postmortem tongue specimens

% of loss calculated by specimen volume (weight)/removed part volume (weight) × 100%

* p < 0.05 before and 4 weeks after surgery in each group; # p < 0.05 between the two groups 4 weeks after surgery

256 Z.-J. Liu

Fig. 14.11 Muscular structures in the sham and reduction tongues (trichrome staining). ( a , b ): ×4

horizontal images showing muscular structure from sham ( a ) and reduction ( b ) tongues. The inset

area of image ( b ) shows disorganized collagen fi bers linked with a few intermittent muscle fi bers.

( c , d ): ×20 sagittal images showing the endomysium and perimysium from sham ( c ) and reduction

( d ) tongues (from Ye et al. 2010 , with permission)

Fig. 14.12 Pattern of muscular repair after the surgery (H&E staining). ( a ) A ×4 coronal image

from a reduction tongue, showing the scar tissue in the middle center area of the surgical site; the

centripetal repair is shown by small arrows. ( b ) A ×10 coronal image from the insert area of the

image ( a ), showing a number of intermeshed myo fi bers surrounding the scar tissue (from Ye et al.

2010 , with permission)

mature myo fi bers in the outer and inner regions, respectively (Fig. 14.12 ). All of the

regenerated myo fi bers have central nuclei, and their polygonal shape and organization

in fascicles are similar to normal myo fi bers (Charge and Rudnicki 2004 ;

Lefaucheur and Sebille 1995 ) . This immunohistochemical study further discovered


257

that despite the enhanced cellular proliferating activity in response to surgical injury

of the tongue, signi fi cantly more proliferating connective cell nuclei were found

than myonuclei in the surgical site. Therefore, the proliferation of connective tissue

prevails, while the capacity of myogenic regeneration is limited in the repair of

tongue injury. Because both muscle fi bers and connective tissues are oriented more

in the longitudinal than transverse and/or dorsal-ventral directions, sagittal views of

the tongue tissue usually contain the highest counts of proliferating cells. In conclusion,

the partial fi brosis without predominant myogenic regeneration is the major

histological consequence in the volume-reduced tongue, and the repair process does

not reconstitute the muscular structures of the tongue but rather is an adaption to a

new morphology, which in turn limits the functional recovery of an injured tongue

(Ye et al . 2010 ) .

14.3.3 In fl uences on Craniofacial Growth

and Dentition Formation

Even though the controversy of whether the tongue adapts to existing oral morphology,

or actively molds its surrounding tissues, is long-standing (Ingervall and

Schmoker 1990 ; Frohlich et al . 1991, 1993 ) , numerous clinical studies have claimed

that tongue size/volume/position may affect a number of elements of craniofacial

growth and dental/occlusal development (Lowe et al . 1985 ) . Prolonged low tongue

position from oral breathing in children may initiate a sequence of events resulting

in excessive molar eruption, which causes a clockwise rotation of the growing

mandible, a disproportional increase in anterior lower vertical face height, retrognathia,

and open bite. A low tongue position may also impede lateral expansion and

anterior maxillary development (Harvold 1968 ; Harvold et al . 1973 ; Principato

1991 ) . Therefore, examining the cause–effect relationship between modi fi cation of

tongue mass and alteration in craniofacial skeletal growth is imperative for understanding

the underlying mechanism.

To this end, our group performed a series of studies on a growing pig model, and

compared the effects on craniofacial skeletal components and dentition formation

longitudinally between the animals with and without tongue mass surgical reduction

(Liu 2009 ; Liu et al . 2008a ) . Our results indicated that tongue mass reduction

has an overall negative effect on the linear expansion of craniofacial skeletons, manifested

by signi fi cantly decreased amounts in premaxilla and anterior mandibular

lengths, mandibular ramus height, midface width, and anterior dental arch width

during the period of rapid growth (Fig. 14.13 ). A mass-reduced tongue also causes

a decrease of bone mineral density in premaxilla/maxilla and anterior mandible

examined by dual photon/energy X-ray absorptiometry (DEXA). It is worthwhile to

indicate that despite the growth effects occurring in all three dimensions (width,

height, and length) of both facial and mandibular bones, the two appearances are

distinctive. First, the majority of these in fl uences are around the anterior mouth

or anterior dental arch, particularly in the mandibular symphysis and premaxilla.

It should be noted that the mass reduction only involved the anterior 2/3 of the

258 Z.-J. Liu

Fig. 14.13 Effects of tongue mass reduction on craniofacial growth. ( a ) Sites of slowed skeletal

growth ( red lines ) detected by longitudinal tracking of cephalometric radiography. ( b ) Decreased

variables in elements of skeletons ( red double-headed arrows ) and dentition ( black double-headed

arrows ) detected by biometric measurements on the harvested skulls. Red and black dots indicate

measurement points in skeletons and dentitions, respectively (modi fi ed from Liu et al. 2008a , with

permission)


259

tongue which is thought to produce greater forces than does the tongue base

(Pouderoux and Kahrilas 1995 ) . Our in vivo loading study revealed that the tongue

produces more load in mandibular lingual surfaces than the premaxillary and maxillary

palatal surfaces, and these loads decrease in the anterior mouth (symphysis and

premaxilla) after the mass reduction. Loads in the posterior mouth (mandibular corpus

and posterior maxillary palatal surface) are less affected (Liu et al . 2008b ) .

Therefore, the observed slow growth in the skeletal components may in part contribute

to the decrease of functional loads in the anterior mouth by a mass-reduced

tongue. Second, among affected components of the craniofacial skeleton, the mandible

is affected more than the nasomaxillary skeleton in all dimensions: length,

width, and height. This striking difference between upper and lower jaws was also

con fi rmed by the examination of bone mineral density in which the only signi fi cant

decrease was found in the mandibular symphysis bloc of the mass-reduced animals

(Liu et al . 2008a ) . Anatomically, the tongue is directly attached to the mandible

through its musculature. Functionally, there is an inherent linkage between the

tongue and mandible (Palmer et al . 1997 ) . Furthermore, the mechanism of cranial/

nasomaxillary postnatal growth is mostly attributed to sutures, different from that of

the mandible which mainly depends on appositional deposition through intramembranous

ossi fi cation at the borders and alveolar ridges, and on secondary cartilage

through endochondrous ossi fi cation at the condyle (Sarnat 1997 ; Kantomaa and

Ronning 1997 ) . Based on these fi ndings, it is not surprising that the postnatal mandibular

growth would be suppressed more than the other elements of the craniofacial

skeletons by the tongue mass reduction.

14.4 Conclusions

Thus, compared to body skeletal muscles, the tongue musculature presents striking

differences with the following features: (1) myo fi bers of extrinsic (with bony attachment)

and intrinsic (without bony attachment) tongue muscles are aligned in both

parallel (longitudinal) and perpendicular (transverse, vertical, circumferential, or

radial) directions, and interweave with each other. This forms an intricate array and

provides the basis for multidirectional contraction and regional-dependent deformation;

(2) the unique architecture of the tongue musculature grants this organ an

enormous biomechanical versatility to ful fi ll various functional demands, and the

tongue motor control most likely uses grouped motor unit- or segmented structure

unit-based, rather than entirely muscle-based strategies. Thus, the tongue kinematics

in regions may not apply to the widely held theory of a muscular hydrostat;

(3) the extrinsic and intrinsic tongue muscles are not only structurally interwoven

but also functionally interacting. The reversals of expansion–contraction of various

dimensions of the tongue are not synchronous but occur in a sequential manner as a

function of performing tasks; (4) changes in the tongue mass not only signi fi cantly

alter the pattern of tongue kinematics, but manifest biomechanical effects on surrounding

hard tissue, which in turn affects the growth of the craniofacial skeleton

260 Z.-J. Liu

and the development of dentition, particularly in the mandible; (5) although the

healing of tongue musculature after injury follows the centripetal pattern seen in

other skeletal muscles, its capacity for myogenic regeneration is relatively weak.

Therefore, fi brosis becomes the major histological consequence after tongue injury,

which leads to compromised recovery of muscular architecture and functionality.

Acknowledgements I would like to thank the following persons for their important contributions

to the work described in this chapter: Drs. Volodymyr Shcherbatyy, Janathan Perskins, Mustafa

Kayalioglu, Gaoman Gu, Amir Sei fi , Wenmin Ye, and Mrs. Brandon Yamamura, Alfadhli Abu,

and Aaron Huang. Special thank goes to Dr. Sue Herring for her constructive discussions and critical

comments during the entire course of the study. This work was supported by the grant R01

DE15659 from NIDCR. The participation of Dr. Wenmin Ye was supported by China Government

Scholarship Program 2008–2010 (File No. 2008659018), and the participations of Mrs. Brandon

Yamamura, Alfadhli Abu, and Aaron Huang were supported by the grant T32 DE007132 from

NIDCR .

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Part VII

Facial Muscles

Chapter 15

Facial Nerve Innervation and Facial Palsies

Adriaan O. Grobbelaar and Alex C. S. Woollard

15.1 Introduction

There are a myriad of causes of facial palsy. Identifying the etiology in each case is

of vital importance to the choice of management pathway, either as an emergency

or in terms of long-term intervention. Most patients at the time of presentation are

convinced that they are suffering from either a stroke (50%), an intracranial tumor

(25%), or do not know but are nonetheless anxious (25%) (Peitersen 2002 ) . In a

review of the literature, Schaitkin and May identi fi ed over 100 possible diagnoses

but the overwhelming majority (50–66%) of cases were Bell’s palsies (Schaitkin

et al. 2000 ) . The dif fi culty of this diagnosis of idiopathic paralysis is that it is one of

exclusion. Any case of new onset palsy must be thoroughly examined, and the history,

as always, is vital in ascertaining the cause. The onset, progression, concurrent

symptoms, and localization all assist the physician in deciding what further investigations

are required.

Whatever the cause of the facial palsy, this is a devastating condition. The complete

or partial loss of function of the seventh cranial nerve results in a spectrum of

both functional and esthetic problems that plague the lives of sufferers. The

American Medical Association Guide to the Evaluation of Permanent Impairment,

which rates disabilities on a scale of “percentage of whole body impairment,” scores

unilateral facial palsy as 10–15% and bilateral as 30–45% (Cocchiarella and

Andersson 2001 ) . Communication, social interaction, vision, eating, and drinking

can all be affected. In children, it is a detrimental to their development and leaves

them introverted and shy. The lack of subcutaneous muscular tension exacerbates

the aging process such that the affected side of the face falls, causing long-term

problems with eye and mouth closure. Tears can run from the loose lower lid and

A. O. Grobbelaar (*) • A. C. S. Woollard

Institute for Plastic Surgery Research and Education , Royal Free Hospital ,

Pond Street , London NW3 2QG , UK

e-mail: aog@talk21.com




265

266 A.O. Grobbelaar and A.C.S. Woollard

the loss of oral continence results in dental caries and drooling. Alternatively the

patient may suffer from reduced lacrimal or salivary production and complain of a

dry eye and mouth. Corneal ulcers arise once the ocular sphincter is unable to effectively

protect the eye, especially where there is a loss of corneal sensation and the

normal blink re fl ex. The sense of taste can be diminished or absent and the lack of

oral tone can make it dif fi cult to keep dentures in place. A loss of stapedial re fl ex

can lead to hyperacusis, and any concurrent eighth nerve involvement leads to auditory

and balance disruption. A partial paralysis (or partial recovery) may not involve

all the branches of the nerve. Unilateral paralysis results in asymmetry, bilateral in

a completely static, expressionless affect.

15.2 Anatomy

The nucleus of the facial nerve lies in the lower third of the pons under the fourth

ventricle, just caudal to the trigeminal nerve nucleus. It receives input regarding

voluntary facial expression from the pre- and postcentral gyri of the cerebral cortex.

Here the homunculus is laid out with the forehead most superior. A cortical lesion

will often produce a facial palsy associated with weakness of the tongue, thumb, or

hand ipsilateral to the facial palsy.

Impulses are carried in the corticobulbar tract, through the internal capsule, the

upper mid-brain, and lower brainstem to synapse with the seventh nerve nucleus.

The upper face receives relatively little in the way of cortical input in comparison

with the lower face which may explain why the forehead and eyelid closure are not

as severely affected with focal central lesions (Jenny and Saper 1987 ) .

Resting tone, emotional, and involuntary movements are thought to arise in the

thalamus, globus pallidus, and basal ganglia of the extrapyramidal system.

Supranuclear lesions will tend to leave emotional movements and re fl exes intact.

The lack of facial movement in Parkinson’s and Meige’s syndromes is due to a dysfunction

of the extrapyramidal system. The seventh nerve also receives input from

the trigeminal and vestibulocochlear nerves as the basis of corneal and stapedial

re fl exes. A lower mid-brain lesion may result in a contralateral facial and extremity

paresis but an ipsilateral abducens defect due to the close association of the sixth

and seventh nerve nuclei.

The facial nerve (CNVII) exits the brain at the cerebropontine angle as a motor

and a sensory component (nerve of Wrisberg). It is in close proximity to the eighth

nerve (CNVIII, vestibulocochlear) and its fi bers pass around the nuclei of the sixth

nerve (CNVI, abducens) and the superior salivatory nerve. Pontine lesions can be

associated with a number of syndromes that are characterized by a spectrum of

involvement of these nerves (Jemec et al. 2000 ) . Examples include Moebius syndrome

(congenital VIth and VIIth cranial nerve palsies) and pseudobulbar palsy

(bilateral facial paralysis and other cranial nerve de fi cits, a hyperreactive gag re fl ex

and hyperre fl exia associated with hypertension). The sensory component of CNVII

carries the afferent taste fi bers from the chorda tympani nerve (taste to the anterior

15 Facial Nerve Innervation and Facial Palsies

267

two-thirds of the tongue), the taste fi bers from the soft palate via the palatine and

greater petrosal nerves, and the preganglionic parasympathetic innervation to the

lacrimal, submandibular, and sublingual glands. The lesser petrosal nerve carries

secretomotor fi bers to the parotid gland. There is also a small cutaneous sensory

component arising from the posterior auricular area.

The facial nerve has the longest bony course of any nerve as it traverses the

facial canal of the petrous temporal bone and then the lateral canal of the mastoid

bone, some 20–30 mm in all. This extended encased section is vulnerable to both

swelling through edema or in fl ammation, and fractures. The labyrinthine segment

in particular is especially narrow and lacks arterial cascades making it susceptible

to ischemia. Between the labyrinthine and tympanic segments lies the geniculate

ganglion where the petrosal branches are given off. Lesions prior to the geniculate ganglion

result in more severe ocular complications due to the lack of lacrimal

secretions (Mavrikakis 2008 ) . In the tympanic segment, the nerve passes behind the

cochleariform process against the medial wall of the cavum tympani, above and

posterior to the oval window. The bony wall is commonly thin or dehiscent here,

and the nerve may lie directly against the middle ear mucosa making it particularly

vulnerable to iatrogenic injury and middle ear infections. Between the external

auditory meatus and the horizontal semicircular canal the nerve makes a second

turn into the lateral canal of the mastoid bone. Three branches exit in this segment:

the chorda tympani, the nerve to stapedius, and the nerve from the auricular branch

of the vagus nerve (CNX).

Base of skull fractures can result in a facial palsy as a result of transection or

tension accompanied by entrapment of the nerve in its bony course. The presence of

a facial palsy in the setting of head and neck trauma is an indication that urgent

further assessment is essential with CT and MRI scans.

The facial nerve exits the skull through the stylomastoid foramen, supplies a

branch to the posterior auricular muscle, passes between and innervates the posterior

belly of digastric and the stylohyoid muscle before entering the parotid gland. In the

substance of the parotid, it divides into upper and lower trunks, which subdivide

into fi ve main branches: temporal, zygomatic, buccal, marginal mandibular, and

cervical.

The temporal branch innervates the upper eyelid and forehead. Paralysis results

in a ptosis of the brow and upper lid that in the elderly can be severe enough to

obscure vision. In addition, the upper eyelid is responsible for blinking and distributing

the watery tear fi lm that protects the cornea. Ulceration of an unprotected

cornea is a serious risk, and assessment of an adequate Bell’s re fl ex is an essential

part of any examination. Xeropthalmia (i.e., dry eye syndrome) is extremely uncomfortable

for patients and a dry eye can paradoxically elicit excessive tear production

that overwhelms the lacrimal duct resulting in epiphora.

The zygomatic and buccal branches innervate the muscles of the midface and

experience signi fi cant cross-innervation. Paralysis results in ptosis of the lower

eyelid and increased scleral show, exacerbating the eye problems alluded to above.

In combination with the two inferior branches, they control the movements of the

mouth and are responsible for oral continence, smiling, and speech.


Table 15.1 Distribution and function of the facial nerve (CNVII)

Branch of CN VII Muscle Action

Posterior auricular Posterior auricular Pulls ear back

Occipitofrontalis Moves scalp back

Direct branch Stylohyoid Retracts and elevates fl oor of mouth

Direct branch Posterior belly digastric Raises hyoid bone in swallowing

Temporal Anterior auricular Pulls ear forward

Superior auricular Raises ear

Frontalis

Raises brow

Corrugator supercilli Pulls eyebrows medially and down

Procerus

Pulls medial eyebrow down

Temporal and zygomatic Orbicularis oculi Closes eyelids

Zygomatic and buccal Zygomaticus major Elevates corners of mouth

Buccal Zygomaticus minor Elevates upper lip

Levator labii superioris Elevates upper lip and mid nasolabial fold

Levator labii superioris Elevates nasolabial fold and nasal ala

alaeque nasi

Risorius

Assists lateral vector of smile

Buccinator

De fl ates cheeks

Levator anguli oris Pulls corners of mouth up and medially

Orbicularis oris

Purses lips

Nasalis, dilator naris Flares nostrils

Nasalis, compressor naris Closes nostrils

Buccal and marginal Depressor anguli oris Depresses corner of mouth

mandibular

Depressor labii inferioris Depresses lower lip

Marginal mandibular Mentalis Pulls skin of chin up

Cervical Platysma Tightens skin of neck and depresses

corner of mouth

The marginal mandibular and cervical branches innervate the platysma and the

depressor anguli oris. Paralysis of the lower lip depressors impairs depression of the

lower lip on the affected, giving a snarl-like appearance especially during crying

(Tulley et al. 2000 ) . See Table 15.1 for a complete list of the muscles innervated by

each branch.

15.3 Etiology

Evidence for facial palsy dates back as far as 4000 BCE with an Egyptian statue

exhibiting a left-sided facial palsy (Resende and Weber 2008 ) . Avicenna (979–1037

CE) identi fi ed the difference between a central lesion affecting the body and face,

and an isolated nerve lesion affecting only the face (Kataye 1975 ) . Freidrich was the

fi rst to describe three cases of idiopathic facial palsy in 1797 in Germany (Bird and

Nicolaus 1979 ) . However, it was Charles Bell (later knighted) who demonstrated


269

Table 15.2 Possible causes of facial nerve palsy and related conditions

Cause Example

Congenital Moebius syndrome, myotonic dystrophy

Trauma Birth trauma, basal skull fracture, facial injuries, barotrauma, middle ear injury

Neurological Millard–Gubler syndrome, Wernicke–Korsakoff syndrome

Infectious Viral: Herpes simplex, herpes zoster, measles, mumps, cytomegalovirus,

infectious mononucleosis, HIV/AIDS

Bacterial/parasitic : Lyme disease, acute/chronic otitis media, osteomyelitis,

suppurative parotitis, scleroderma, botulism, tuberculosis, leprosy, malaria,

syphilis, aspergillosis, leptospirosis, cat scratch fever, trichinosis

Metabolic Diabetes mellitus, hyper- and hypothyroidism, hypertension, acute porphyria,

vitamin A de fi ciency

Neoplastic Cholesteatoma, leukemia, sarcoma, carcinoma, acoustic schwannoma,

fi brosarcoma, neural lesions (astrocytoma, glioma, etc.), parotid lesions,

facial nerve tumor

Toxic

Tetanus, diphtheria, arsenic, lead, alcohol, carbon monoxide

Iatrogenic Local anesthesia, surgery (parotid, temporal bone, carotid endartectomy,

temporomandibular joint)

Idiopathic Bell’s, Familial, Melkersson–Rosenthal syndrome, Charcot–Marie–Tooth

disease, temporal arteritis, Guillain–Barre syndrome, multiple sclerosis,

myasthenia gravis, Kawasaki disease, amyloidosis, sarcoidosis, Wegener’s

granulomatosis, scleroderma, Stevens–Johnson syndrome, osteogenesis

imperfecta, Paget’s disease, osteopetrosis

that the CNVII was responsible for movement of the facial muscles devoted to

expression. The eponymous Bell’s palsy bears his name despite the earlier description

by Bell ( 1821 ) .

As already alluded to, the number of possible causes of facial palsy can make a

de fi nitive diagnosis elusive. Pathology specimens are only available in the case of

neoplasms and to biopsy the nerve in most circumstances would violate primum

non nocere . “All that palsies is not Bell’s” and a thorough clinical assessment can

diagnose those cases where the underlying condition merits a more interventionist

approach (Cawthorne 1965 ) . In the series reported by May, over 300 of the 2,256

cases which had been referred as an acute Bell’s palsy turned out to have a treatable

progressive or life-threatening disorder (Schaitkin et al. 2000 ) . Table 15.2 gives

examples of etiologies taken from the comprehensive list given by Bonnet ( 2005 ) .

A systematic understanding of some of the key presenting features helps to guide

diagnosis. It is important to appreciate that very few features are explicit, and it is

an overall picture of the presentation that leads the clinician. Table 15.3 gives a list

of key diagnostic signs and symptoms to be evaluated.

Onset and completeness alone cannot determine the cause of the paralysis. In the

setting of trauma, a complete sudden palsy indicates a likely transection of the nerve

and warrants exploration. An incomplete palsy suggests that the nerve is likely to be

intact and deserves observation. An incomplete paralysis can progress for up to

10 days with a Bell’s palsy, after external blunt trauma or surgical trauma in the

parotid, temporal bone, or posterior cranial fossa. In herpes zoster, it may progress


Table 15.3 Diagnostic signs

Date of onset

Rate of onset

Incomplete vs. complete

Recurrence (ipsilateral or contralateral)

Family history

Pregnancy

Systemic illness (including any indications

of immunocompromise)

Malignancies

Medications

Trauma

Fasciculations

Mass lesion in head and neck

Recent viral episode or exposure

Pain or parasthesia

Otitis media or externa, tinnitus, ear surgery

Alteration in hearing or taste

Dizziness

Xerophthalmia or excessive tearing

Vesicles (and location)

for up to 21 days. An incomplete paralysis that is progressive for longer than 3 weeks

is almost certainly due to a tumor. In these cases, the nerve is slowly compressed by

the expanding mass resulting in progressive axonal destruction. Seventy six percent

of the tumors in May’s series presented in this fashion, 24% presented with sudden

onset complete palsy with approximately equal proportions of benign and malignant

disease in both groups.

Recurrence can occur with a Bell’s palsy (incidence 6.8–13%). In May’s series,

he describes the majority as contralateral (62%) and interestingly notes that whilst

it is a common fi nding with herpes simplex, it is very rare in herpes zoster infections.

Without explicitly attributing it to HSV, May believes recurrent contralateral

palsy to be virtually diagnostic of Bell’s palsy. A rare condition, Melkersson–

Rosenthal syndrome, is characterized by recurring, alternating facial palsy. This is

identi fi ed by having 2 of 4 features: recurrent alternating facial palsy, recurrent orofacial

edema, chelitis, fi ssuring of the tongue. Of the ipsilateral recurrences 30%

were associated with a tumor, and May advises a full tumor workup be carried out

in any case of ipsilateral recurrence (Schaitkin et al. 2000 ) .

Bilateral facial palsy , outside of the congenital presentations, can represent a

medical emergency. In cases of incomplete palsy, it can be dif fi cult to appreciate the

less-affected side. Guillain–Barre syndrome (GBS) and Lyme disease are probably

the commonest causes. GBS is an acute, in fl ammatory demyelinating polyradiculopathy

characterized by an ascending parasthesia, weakness, and are fl exia. It is

believed to be an autoimmune hypersensitivity reaction to peripheral myelin. The

evolution of symptoms occurs over 2–4 weeks and recovery takes 4–6 months in


271

85% of cases, though the majority of cases show some permanent loss of function.

The ascending motor paralysis can range from mild to total paralysis and may

progress rapidly to respiratory failure. The facial nerve is the most commonly

affected cranial nerve, occurring in approximately 50% of cases and is frequently

bilateral (Asbury and Cornblath 1990 ) . Urgent hospital admission for observation

and support of failing systems is essential. Lyme disease is caused by the spirochaete

Borrelia burgdorferei , which is transmitted via a tick host. It is characterized

by a localized erythematous rash that expands and lasts 3 weeks. This is associated

with generalized prodromal symptoms and occasionally neurological symptoms

including meningitis, cerebellar ataxia, and facial palsy, which can be bilateral

(Goldfarb and Sataloff 1994 ) . The disease occurs in three distinct stages: erythema

chronicum migrans, the development of neurological symptoms (when most patients

will present to a clinician), late onset arthritic changes and psychiatric disorders,

fatigue, and permanent paralysis. Treatment is with a long course of doxycycline,

(1 month), and inadequate duration can dampen the antibody response whilst still

allowing disease progression.

Bilateral facial palsy can rarely occur with Bell’s and with a number of other

conditions such as infectious mononucleosis, cytomegalovirus, sarcoidosis, acute

porphyria, amyloidosis, and botulism. Of the congenital conditions causing bilateral

palsy, Moebius is the commonest but still rare with approximately 1:500,000 live

births (Verzijl et al. 2003 ) . Most other cases fall into the spectrum of incomplete

Moebius-like syndromes.

15.4 Examination and Investigation

The history should be followed by a clinical examination. Cranial nerves V–XII

pass through or close to the temporal bone. Nerves VI and VIII both have their

nuclei adjacent to the nerve VII in the brainstem and deserve particular attention.

A full cranial nerve examination is vital as part of a facial palsy work up. Topognostic

testing relies on the sequential branching of the seventh nerve to identify the site of

the lesion. Anatomy can be variable, which reduces the validity of this method, but

does allow for complete assessment of the nerve and identi fi es speci fi c areas such as

eye function that may require prophylactic intervention.

Ear pain is a common complaint in Bell’s palsy. Pain, transmitted by the chorda

tympani, is likely to be associated with an in fl ammatory reaction and may be caused

by a viral infection. The chorda tympani also carries taste from the anterior twothirds

of the tongue. Papillae atrophy occurs with denervation, and this can be

observed under magni fi cation after 5–10 days.

Denervation of the greater petrosal nerve results in loss of tearing. Tearing is an

important aspect of corneal protection. It can be tested using Schirmer’s test with

the unaffected eye used as a control. A dry eye accompanied by loss of corneal

sensation and a poor Bell’s phenomenon places the eye at risk of ulceration and


long-term loss of visual acuity. Disordered reinnervation of the lacrimal gland can

lead to excessive tearing; however, this should not be confused with reactive

excessive tearing from incomplete eye closure.

Testing of salivation and the stapedial re fl ex are not reliable indicators of the

level of the lesion, but the stapedial re fl ex may have some role in prognosis if the

result is positive.

Clinical testing of auditory system and otoscopy is important particularly in the

presence of unilateral symptoms. These may suggest a mass lesion and warrant an

MRI. Dizziness is uncommon in facial palsy but can occur in Bell’s and with brainstem

lesions or herpes zoster cephalicus infection. Patients complaining of dizziness

should undergo vestibular testing and investigation of nystagmus.

There is some controversy over the value of electrophysiological testing in facial

palsy. There are three main tests that have been used: electromyography (EMG), the

maximal stimulation test (MST), and evoked electromyography (EEMG). In EMG,

a needle electrode is placed in the muscle and measurements taken of the electrical

activity due to the insertion of the needle itself, of the muscle at rest, and during

voluntary contraction. At insertion there is a normally a spike of activity. This is

characteristically increased in a denervated muscle, but decreased once fi brosis has

occurred due to atrophy. In the normal muscle, there is no signal at rest. Fibrillation

is indicative of denervation and occurs within 10–20 days after nerve injury (May

et al. 1983 ) . A normal voluntary contraction produces a reproducible bi- or triphasic

wave pattern. A polyphasic (>3 waves) signal is an indicator of regeneration or

myopathy; however, in reinnervation the signals tend to be prolonged.

The electrical signal in MST is measured in the muscles during maximal arti fi cial

stimulation of the entire facial nerve at the level of the parotid and at each subsequent

branch in the mid face. The response is compared with the normal “control”

side. Results are graded as equal, minimally decreased (less than half the normal

side) or markedly decreased (less than a quarter) and the test is repeated regularly

until there is return of function or no response. May believes this to have a strong

prognostic value in predicting recovery, with 92% of patients with an “equal” result

at 10 days having a complete recovery and 100% of those with no response at 10

days having an incomplete recovery (May et al. 1971 ) .

EEMG is similar to MST except that the muscle twitch is recorded on a graph

and the latency and amplitude of the response can be measured. Idiopathic palsies

show a progressive decrease in amplitude while tumors will display an increased

latency (Schaitkin et al. 2000 ) . A drawback of all these techniques is patient compliance,

especially in children. They can be painful and require the patient to remain

still during the course of the procedure. Also, in an ideal nerve stimulation test the

stimulus and the measurement should be either side of the nerve lesion. Due to

the anatomy of the facial nerve, it is not possible to stimulate the nerve cranial to the

stylomastoid foramen despite many of the lesions occurring proximal to this point.

Peitersen feels that the EEMG is useful in eliciting degeneration and that the EMG

has some use in demonstrating regeneration, but that the MST is not a reliable tool

in predicting recovery (Peitersen 2002 ) .


273

15.5 Bell’s Palsy

The natural history of Bell’s palsy is fascinating yet frustrating. It is the most

common cause of facial paralysis, and yet there is considerable uncertainty as to its

underlying pathology. Despite being a diagnosis of exclusion, it is a convenient

place to start to think about facial palsy as a whole. The theories to explain the cause

of idiopathic palsy began in the 1800s with the concept of “rheumatism” as the

condition seemed to be associated with fevers, chills, and localized pain and swelling

in the neck region. In fact, Freidrich initially published his account as the paralysis

musculorum faciei rheumatica . The idea of swelling, combined with the

anatomical knowledge that the nerve had a signi fi cant petrous course in the temporal

bone gave rise to the hypothesis that the nerve might become thickened and

edematous, resulting in compression around the stylomastoid foramen. This compression

was believed to have secondary ischemic effects due to disturbance of the

vasa nervorum accompanying the nerve. This gave rise in the 1930s to the school of

thought advocating mastoid decompression surgery, which was in vogue for some

30 or more years (Cawthorne 1951 ; Jonkees 1957 ) . In 1972, McGovern postulated

that an immunological source may be responsible for the in fl ammation and edema

causing the nerve damage; later that year McCormick suggested herpes simplex

(HSV-1) as a possible culprit (McGovern et al. 1972 ; McCormick 1972 ) . There is

still no conclusive evidence that HSV-1 is the de fi nitive cause, but polymerase chain

reaction techniques seem to be supportive (Murakami et al. 1996 ) .

Peitersen began a very thorough prospective study of the natural course of facial

palsy in the early 1970s, following over 2,500 patients around Copenhagen for 30

years (Peitersen 2002 ) . Emphasis was placed on the speci fi c details surrounding the

onset of the condition (e.g., time, other cranial nerve symptoms, pregnancy, comorbidities,

trauma, ocular, and auricular symptoms, etc.), any previous or familial episodes,

completeness vs. incomplete and the nature of branch involvement, as well

as the timing and completeness of remission. At the fi rst visit this was coupled to a

full ENT and cranial nerve examination, acoustic and vestibular tests, taste, nasolacrimal

and stapedial re fl ex examination, and baseline laboratory tests to rule out

diabetes, hypertension, serum antibodies to HSV, HZV, and borreliosis. Patients

were then seen weekly until function was observed to be returning. After 6 months,

this reduced to monthly and then discontinued after full recovery or after 1 year. If

patients suffered a second episode or had not recovered in 4 months, they underwent

further testing with CSF analysis and CT and MRI scanning. The Copenhagen

Facial Nerve Study is particularly useful in both its size and completeness of follow

up (98%). Of 2,570 cases, 1,701 were idiopathic or Bell’s palsies, an incidence of

32/100,000 per year. Seventy percent of these were complete paralyses. There was

a 6.8% recurrence rate and 4.1% represented familial cases. There was no indication

of a seasonal or decade variation, and there was no statistical connection with gender

or laterality. Bell’s palsy was uncommon under the age of 15 and above 60 years

with a maximum incidence between 15 and 45 years ( P < 0.001 in comparison with

the underlying population).


Eighty fi ve percent of patients recovered some movement within 3 weeks and the

remaining within 3–5 months. Complete remission occurred in week 1 for 6%,

week 2 for 33%, and week 3 for 16%. Interestingly, no patients achieved remission

between 3 weeks and 3–5 months, indicating that in the latter group there was total

degeneration of the nerve. Ten percent reached remission at 3–5 months and 5% at

5–6 months.

Overall, 71% of patients achieved a full recovery with 58% occurring within the

fi rst 2 months, though there was signi fi cant difference between those who initially

had an incomplete or complete paralysis (94% vs. 61%, P < 0.001). No patient who

still had abnormal movement 6 months after onset of paralysis regained full function.

The speed of onset of recovery was a critical prognostic indicator as was the

age of the patient. Ninety percent of children under 14 years achieved a full recovery,

84% of those 15–29, 75% of those 30–44, and less than 33% of those over 60.

Whilst Bell’s palsy was no more common in pregnant women, it did result in a

poorer prognosis (61% vs. 80% complete recovery, P < 0.001) (Peitersen 2002 ) .

Eight hundred and sixty nine patients had facial palsies with identi fi able causes

(i.e., not idiopathic/Bell’s palsies). It is worth expanding on cases in the context of

diabetes mellitus, those caused by HZV, and pediatric cases. Approximately 3% of

cases occurred in patients with diabetes mellitus (diabetes has an estimated incidence

of 3–4% in the Danish population). Two-thirds of these were incomplete

paralyses but did poorly, with only 25% achieving full recovery, in contrast to the

normal picture with incomplete palsy. It is thought that this is explained by the

underling diabetic neuropathy. Herpes zoster (HZV) oticus, or Ramsay-Hunt syndrome,

is associated with a very poor prognosis (Hunt 1908 ) and tends to af fl ict an

older subset of patients. Most of the time, it caused a complete paralysis (88%) and

was often associated with vestibular disturbances and irreversible hearing loss typically

of the higher tones. The diagnosis of HZV is based on clinical observations of

vesicles, which may not locate around the ear, necessitating a thorough examination

of the head, neck, and mucosal surfaces. The vesicles may appear before, with, or

after the palsy. Diagnosis can be con fi rmed by the detection of antibodies in serum

and CSF. Prognosis was also poor in this group with 46% achieving a fair recovery

and 54% a bad one. In addition, Peitersen feels that treatment with acyclovir does

not affect outcomes markedly (Peitersen 2002 ) .

The pediatric cases (349 cases, 13.5% overall) were dominated by neonatal cases

(169 cases) and Bell’s palsy (138 cases). The remaining cases were congenital bilateral

palsies, trauma, or infectious causes (Peitersen 2002 ) . There has been considerable

discussion over whether neonatal paralysis is congenital or due to birth trauma.

Congenital causes can be as a result of teratogenesis, aplasia of the facial nerve

nucleus or as part of a syndrome such as Treacher-Collins or Moebius. Of the neonatal

cases, the majority (80%) are due to birth trauma (Smith et al. 1981 ) .

One of the most dif fi cult aspects of evaluating facial palsy is the lack of a

common tool for measuring recovery that allows comparison between groups. The

complexity of normal facial movement and the variety of homeostatic functions that

the muscles of expression also encompass makes a succinct scale of total de fi cit

impossible. There have been several attempts to classify facial palsies according to


275

global, regional, or speci fi c de fi cits, and each has its advantages and disadvantages.

The ideal system needs to be simple to use, reproducible, and yet still manage to

usefully categorize a condition that is very complex in its manifestations. The

House–Brackmann system is probably the one most commonly used and provides

a global de fi cit measure that includes contraction and synkinesis (House 1983 ) .

Adour’s elegant regionally based system provides a facial paralysis recovery pro fi le

(FPRP) from which subtractions can be made for symptoms of contracture, synkinesis,

ptosis, etc., to generate a facial paralysis recovery index (FPRI) (Adour 2002 ) .

This gives a numeric score for each patient, but it is complicated and requires calculations

that make it unwieldy as a general tool for the clinician. The grading

system presented by Ross et al. is probably the most useful (Ross et al. 1996 ) .

It combines the regional approach with a simple numerical grading system and

includes synkinesis.

15.6 Management Approach

The importance of understanding both the possible etiology and the natural history

of a Bell’s palsy is demonstrated in the fi rst consultation with a patient suffering an

acute onset facial palsy. The history and examination systematically rules out any

treatable, traumatic, or possible neoplastic causes. The palsy is recorded as complete

or incomplete and given a Ross or House–Brackmann score. Further tests can be

ordered as required at this juncture. There is normally a slight delay in presentation,

which gives clues as to any progression or recovery. If the picture is compatible with

a Bell’s palsy, reassurance can be given that recovery is usually excellent and a

framework of the timing or return of function mapped out. Attention must be paid to

prophylactic measures with respect to sequelae, particularly eye care. Regular follow

up in this period aids accurate estimation of recovery and reassures the patient.

Opinion varies as to the value of electrophysiological testing during this time.

There is no indication that surgical decompression of the facial nerve in

in fl ammatory conditions improves outcome. If the palsy is as a result of an ongoing

process such as a cholesteatoma or suppurative otitis media then surgical intervention

to arrest the underlying condition is warranted. This is particularly important if

rapid progression of the severity of the palsy is noted. Grogan et al. performed a

meta-analysis of the evidence for early medical treatment. Oral steroids are thought

to “probably” have a bene fi cial effect on facial functional outcomes, acyclovir only

“possibly” (Grogan and Gronseth 2001 ) .

In all cases where progressive or life-threatening causes have been excluded,

patience is essential. Most patients with facial palsies will recover at least some

function, and the return of natural expression is more esthetic than any reconstruction.

Interventions to improve on any residual de fi cit should only be considered

12–18 months after there has been no further recovery of movement. At that stage

the original cause of the palsy has little impact on the reconstructive approach,

which will be guided by the residual de fi cit and the physiological assessment of the


patient. The fi nal plan must be tailored through detailed discussion between surgeon

and patient as to the desired end point. The overall aims focus on protection of the

cornea, resting symmetry and tone, and a dynamic symmetrical smile.

15.7 Nonsurgical Management

The nonsurgical approach really centers around prophylactic measures to reduce the

incidence of sequelae around the eye, predominantly corneal abrasions. Arti fi cial

tears such as hydroxypropyl methylcellulose can help to lubricate the eye. At night

a more viscous, petrolatum-based ointment in combination with taping down of the

upper lid can reduce the chances of a corneal ulcer.

Chemodenervation of the active facial muscles with botulinum A toxin can be

used to create a more symmetrical face. This must be administered 2–3 times per

year. It can help both with the static position and to reduce the twitching of synkinesis.

It is also possible to improve the symmetry of a smile in a partial paralysis

through careful denervation of small muscle groups around the mouth to in fl uence

the vector of the smile (Bulstrode and Harrison 2005 ) . Some physicians offer neuromuscular

retraining with specialist physiotherapists to improve dynamic motion,

but this is more usually in association with a functional muscle transfer.

15.8 Acute Surgical Management

Early repair of a nerve after transection improves the fi nal outcome. In a trauma scenario

with a grossly contaminated wound, the ends should be tagged and repaired as

soon as adequate debridement and infection control has been established, ideally

within 30 days. A nerve that has been accidentally divided during surgery should be

repaired immediately. If a segment of the nerve is invaded by a tumor, proximal and

distal ends can be sent for fresh frozen section and once con fi rmed clear can be

repaired or bridged with a cable graft (usually sural). A more distal division tends to

be compensated for by the cross-arborization of the buccal and zygomatic branches.

More proximal injuries also suffer from increased incidence of synkinesis as they

recover (Coker et al. 1987 ) . In cases where the proximal facial nerve is not suitable

for repair it is possible to perform an immediate mini-hypoglossal transfer to the

distal branches of the facial nerve at the same time as a cross-facial nerve graft that

can be coapted at a later date to augment the axonal load (Terzis and Tzafetta 2009 ) .

15.9 Chronic Surgical Management

As previously mentioned the goals of surgical reconstruction are tailored to the

needs of the individual patient. The procedures can be divided into static vs. dynamic

and by which area of the face they are trying to improve: the forehead; the upper and


277

lower eyelids; the midface and mouth; and lower lip. In general, we have found that

patients under 10 years get the best results with functional muscle transfer reconstructions.

They often achieve spontaneous smiles, and we believe this correlates

with their nerve regeneration capacity. In patients over the age of 55 years, the

bene fi t from a free-functioning muscle transplant procedure may be less predictable.

In these cases, we opt for either a simpler muscle transfer procedure or a static

sling that restores the ocular or oral continence and balances the face at rest but does

not provide movement.

15.9.1 The Forehead

The forehead undergoes a natural ptosis with age as it loses its natural elasticity.

In paralysis, this is more pronounced and more noticeable when unilateral. In extreme

cases, the brow can obscure vision. There are a number of procedures to correct

forehead ptosis, all of which are static. There is no option for recreating a useful

dynamic brow.

Brow lifts can be performed directly or endoscopically. Endoscopic lifts tend to

produce subtle adjustments as opposed to robust support and therefore produce disappointing

results in facial palsy patients. Direct lifts can be performed to address

either the eyebrow or the whole forehead. An eyebrow lift, or dermodesis, requires

the excision of an ellipse of superciliary skin and frontalis muscle and the pexy of

orbicularis oculi to the periosteum of the forehead (Ueda et al. 1994 ) . The main

risks of this procedure are scarring and damage to the supraorbital nerve which can

give rise to numbness on that side of the forehead.

In an open brow lift the forehead is usually approached via a bi-coronal incision

5 cm posterior to the hairline and the entire brow is elevated to the level of the

supraorbital ridge in the sub-galeal plane. The forehead is re-draped, and the excess

skin posterior is excised in an asymmetric fashion to compensate for the ptosis of

the paralyzed side. The scar is well hidden but can be problematic in male-pattern

baldness and in cases of incisional alopecia. Patients also often complain of parasthesia

posterior to the scar.

15.9.2 The Eyelids

The aim in eyelid surgery is to achieve adequate closure to protect the cornea whilst

minimizing ptosis. This can be achieved through both static and dynamic procedures

tailoring the management to the upper or lower lid depending on the nature of

the de fi cit. The upper eyelid is primarily responsible for eye closure. Gold weights

inserted under the skin of the upper lid to improve lid ptosis were originally described

in the 1960s (Smellie 1966 ) . Gold is an inert metal that triggers little in the way of

an in fl ammatory response. However, there can occasionally be problems with skin

erosion and extrusion of the weight. Test weights can be taped to the outside of the


lid in clinic to evaluate the required mass. The aim is to achieve approximation of

the lids to within 2–4 mm with the lightest possible weight which is then sutured in

a supratarsal position approximately 4 mm from the lid margin to reduce the possibility

of extrusion (Misra et al. 2000 ) . It is important to stress the need to avoid

inadvertent injury to the levator as this will result in ptosis. Sometimes the weights

have to be adjusted at a secondary procedure to fi ne tune lid approximation. More

recently, there has been some interest in platinum chains which allow better contouring

along the lid margin (Berghaus et al. 2003 ) . Lengthening of the levator has

a similar effect in lowering the upper lid but with the advantage of no arti fi cial prosthesis

or unaesthetic contour deformity that accompanies a gold weight. It is usually

performed by the interposition of a segment of temporalis fascia equal to the gap in

the orbital fi ssure during forced closure (Piggot et al. 1995 ) . It is possible to implant

a dynamic device to assist closure. A palpebral spring can be inserted between the

superior orbital rim and the upper lid margin. This is loaded by the opening action

of the levator and actively closes the eye as the muscle relaxes. Its advantage is that

it works even when the patient is lying down, but results are highly dependent on

the skill and experience of the surgeon (Levine and Shapiro 2000 ) .

The lower lid can be used to provide greater inferior support. Krastinova

described the insertion of an ellipse of conchal cartilage to improve the contour of a

paralyzed lower eyelid (Krastinova et al. 2002 ) . It is important to crush the cartilage

to reduce the incidence of extrusion through the subciliary incision. A McLaughlin’s

lateral tarsorrhaphy procedure provides static support by “double-breasting” the

lateral canthus through resection of the posterior lamella of the upper lid and a corresponding

portion of the anterior lamella of the lower lid (McLaughlin 1952 ) . This

raises the lower lid, narrowing the aperture of the eye and effectively lowering the

upper lid. It is a simple and effective procedure, especially useful in the elderly

where it also improves any ectropion of the lower lid. However, it can give the

appearance of a smaller eye and interfere with lateral gaze. The lower lid tension

can be augmented by a fascial or palmaris sling. This can be tunneled through the

lower lid and fi xed to the medial canthal ligament and the lateral supraorbital margin.

It is vital that the position of the sling relative to the lid margin does not exacerbate

or create ectropion (too low) or entropion (too high). A canthopexy alone

tends to loosen with time and therefore provides insuf fi cient support in facial palsy

cases. Where there is laxity of the medial canthal ligament and ectropion, it can be

addressed with a medial canthopexy or medial tarsal strip and suture fi xation to the

deep periosteum (McLaughlin 1951 ; Lee et al. 2004 ; Collin 1993 ) . This can also

help to address epiphora.

Gilles described a dynamic eyelid closure where by a pedicled transfer of a slip

of the temporalis muscle is turned over and extended across the upper and lower

eyelids via fascial strips to the medial canthal ligament (Gillies 1934 ) . The action of

chewing then causes blinking and lubrication of the cornea. Alternatively the muscle

can be used exclusively for the upper lid as it constitutes the main action of eye

closure, and the lower lid supported with a simple sling. Patients frequently complain

of a bulge at the lateral border of the orbit, a slit-like eye, and of the irritation

caused by eye closure whilst eating. More recently Terzis has reported a free


279

functional transfer of a segment of platysma with a cross-facial nerve graft

(CFNG) to restore the blink re fl ex, though the numbers are still small (Terzis and

Karypidis 2010 ) .

15.9.3 The Midface and Mouth

As with the forehead and the eye the reconstruction of the function of the midface

can also be approached through static and dynamic procedures. A loss of symmetry

and animation around the mouth is particularly noticeable and causes considerable

concern to patients with a facial paralysis. Young patients with facial palsy retain

good symmetry at rest due to the natural elasticity of the soft tissues. The aim of

reconstruction here is to restore the movement of the midface. These dynamic procedures

will provide additional static support as the new muscle is in effect also a

sling. In older patients with paralysis, the natural aging process gives a ptotic droop

to the cheeks and corner of the mouth, even in repose. These patients are bothered

by this static asymmetry and the appearance of instability in the face with contraction

of the non-paralyzed side. It causes drooling, dif fi culties with eye closure, and

affects their ability to mix comfortably in public situations. They tend to seek symmetry

at rest and a stable platform with which to use the expression of contralateral

mobile face, more than a broad smile. As a result of this, coupled with the reduced

capacity for nerve regeneration with increasing age, we have decided on an arti fi cial

cutoff of 55 years for dynamic transfers in our patients.

A static sling of autologous (palmaris longus, tensor fascia lata) or synthetic

(Goretex) material can address symmetry at rest and improve both the esthetic

appearance and functional aspects such as drooling. In our unit, we divide the medial

aspect into three slips that are fi rmly anchored to the ipsilateral philtral column and

commissure and the midline of the lower lip. In addition, resuspension of the suborbicularis

oculi fat pad (SOOF lift) can correct static ptosis of the midface (Horlock

et al. 2002 ) .

Early attempts at dynamic reanimation were based on a pedicled translation of

the temporalis muscle. Gilles in 1934 detached its posterior attachment and turned

it down over the zygomatic arch to insert into the corner of the mouth (Gillies 1934 ) .

There have been modi fi cations since then. MacLaughlin detached the temporalis

from the coronoid process and extended it to the corner of the mouth using fascial

grafts rather than folding it over the zygoma (McLaughlin 1952 ) . Labbé avoided the

need for the fascial grafts by partially detaching the origin of the temporalis allowing

the muscle to rotate and “slide” far enough to reach the mouth (Labbé 1997 ) .

Initially this was facilitated by an osteotomy of the zygomatic arch which was subsequently

plated, but modi fi cations mean it is no longer required. This procedure

reduces the main patient complaint of a bulge in the lateral cheek, but does require

intense physiotherapy to retrain the muscle to be used for smiling instead of mastication.

We use this procedure in older patients who are keen on a dynamic reconstruction

but where the results of a cross-facial nerve graft and free muscle prove


Fig. 15.1 First stage facial

reanimation: The cross-facial

nerve graft is coapted to a

buccal branch of the facial

nerve on the functioning side

and tunneled across the upper

lip to the paralyzed side of

the face. The regeneration of

the axons through the graft

can be traced by a positive

Tinel’s sign

unreliable. We also use a Blair type facelift incision to avoid the need for the

nasolabial inset incisions as described by Labbé.

CFNG were fi rst described by Scaramella in 1970. The arborization between the

zygomatic and buccal branches of the facial nerve is suf fi cient to allow minimal

donor de fi cit and provide synergistic nerve impulses to power the paralyzed side of

the face. Originally this was used to attempt reinnervation of native muscles

(Scaramella 1975 ; Anderl 1976 ) . In 1976, Harii performed the fi rst successful free

transfer of a gracilis into a paralyzed face. This was anastomosed to the deep temporal

vessels and coapted to the existing ipsilateral facial nerve stump. In 1979, he

described the two-stage procedure of a CNFG to contralateral facial nerve and subsequent

free muscle transfer (Harii et al. 1976 ) . This has become accepted as the

gold standard for dynamic reanimation (Figs. 15.1 and 15.2 ). Many muscles have

since been suggested as potential donors (gracilis, latissimus dorsi, extensor digitorum

brevis, pectoralis minor) in an attempt to improve the vector of the recreated

smile and to minimize the bulky contour that resides in the reconstructed cheek.

The two stages can be performed 9–12 months apart and in congenital palsy

cases results are better in children under 10 years. Long-term studies show a wide

variation in improvements with most authors claiming good to excellent results in

51–94% of patients (Terzis and Noah 1997 ; O’Brien et al. 1990 ; Harrison 2002 ;


281

Fig. 15.2 Second stage

facial reanimation: Once

there is adequate length of

functioning graft the donor

muscle is transferred. This is

anastomosed to the facial

artery and vein and a

neurorraphy performed

between the graft and the

muscle’s native nerve. The

muscle is secured to the

zygomatic fascia proximally

and divided into slips distally

to insert into the nasal alar

and the upper and lower lip

Kumar and Hassan 2002 ) . All centers declare that a signi fi cant minority of patients

required further revisional operations (Takushima et al. 2005 ) . We rely on the

pectoralis minor and a CFNG from the sural nerve. We feel that the fan shape of this

muscle conforms well to the dimensions of the cheek providing a good, complex

vector to the smile. In addition, the muscle does not have the bulk of gracilis, which

gives an unusual “hamster” appearance especially noticeable in a unilateral reconstruction.

The harvest of pectoralis minor is more technically demanding than gracilis

but the anatomy has been well described, and there is negligible donor site

morbidity (Scevola et al. 2003 ; MacQuillan et al. 2004 ) .

A one-stage reanimation has been described whereby the long pedicle of gracilis

can be coapted directly to the contralateral facial nerve at the time of free muscle

transfer (O’Brien et al. 1990 ; Kumar 1995 ) . This reduces the number of operations

and the recovery time by some 10 months since there is no need to wait for the

CFNG to grow across the face. However, results show that whilst the dynamic

results were comparable (93% vs. 90%), a good static appearance at rest is better in

the two-stage group (67% vs. 20%) (Kumar and Hassan 2002 ) . An experimental

rabbit model has con fi rmed that the axonal morphometry and tetanic force produced

by transferred muscles are comparable in one- and two-stage procedures (Urso-

Baiarda and Grobbelaar 2009 ) . Bae et al. described free gracilis transfer with direct

coaptation to the ipsilateral masseteric branch of the trigeminal nerve which provided

good excursion of the oral commissure but lacked the synchronous movement


achieved with a CFNG (Bae et al. 2006 ) . This option may be of bene fi t in older

patients or in recovery operations where a previous standard approach has failed.

15.9.4 Lower Lip

The lower lip depressors are innervated by the marginal branch of the facial nerve.

Paralysis is especially apparent during speech when the lower lip is retracted only

on the functioning side. The simplest treatment is aimed at reducing the movement

of the functioning side through regular Botulinum A toxin. A more permanent

approach is possible through surgical division of marginal branch or selective myectomy

of the unparalyzed side.

The main reconstructive option for the paralyzed lower lip is a transfer of the

anterior belly of the digastric muscle. This is innervated by the trigeminal nerve and

thus spared in most cases of facial palsy. It can be transferred on its pedicle and

inserted into the margin of the lower lip (Tulley et al. 2000 ) . Terzis advocates this in

conjunction with a CFNG to increase the synchronicity but this is a technically

dif fi cult procedure (Terzis and Kalantarian 2000 ) . We preoperatively image patients

to ensure the presence of the anterior belly since it can be absent, particularly in

congenital facial hypoplastic complexes (MacQuillan et al. 2010 ) . Alternatives

include the transfer of a segment of platysma or coapting the marginal branch in

an end-to-side fashion to the hypoglossal nerve (Terzis and Kalantarian 2000 ) .

A CFNG and free functioning muscle transfer may be suitable in severe cases.

15.10 Bilateral Facial Palsy

In cases of bilateral facial palsy there is no functioning contralateral facial nerve to

power the CFNG or new muscle. These patients require a full cranial nerve exam to

ascertain which other nerves are involved and therefore by extension which nerves

may be available to use as a donor (Terzis and Noah 2002, 2003 ) . Bilateral palsy is

usually caused by a congenital defect, such as Moebius syndrome where there is a

paralysis of CNVI and CNVII. It is part of a spectrum of disorders where there can

be involvement of other cranial nerves, the thorax, limbs, and face (Abramson et al.

1998 ) . Bilateral temporalis transfers can be performed, though these patients frequently

have problems with speech and mastication and removing the major muscle

for chewing can be debilitating. Potential nerve donors for a free muscle transfer are

the masseteric branch of the trigeminal nerve, the accessory nerve, and a proportion

of the hypoglossal (end-to-side anastomosis) allowing for preservation of tongue

function. Each has advantages and disadvantages. Provided there is good temporalis

function, mastication is not affected by the loss of some power in masseter.


283

As with unilateral reconstructions there is variation in the choice of donor muscle,

which can be in fl uenced further by any peripheral involvement of the patient’s

underlying syndrome.

We utilize the masseteric branch of the trigeminal nerve to power a segmental section

of latissimus dorsi. We alter the muscle donor from our unilateral reconstructions as

the length of nerve required to perform a neurorraphy within the muscle bulk of

masseter cannot be provided by pectoralis minor. Gracilis has a long enough pedicle

and in bilateral cases its excess bulk is less distracting due to its symmetry (Zuker

et al. 2000 ) . We prefer to operate in a single stage in children under 10 years of age

as this drastically reduces the overall recovery time, and we believe the plasticity of

the brain in this age group allows them to adapt and learn to smile spontaneously in

response to emotion (Woollard et al. 2010 ) .

15.11 Summary

The muscles innervated by the facial nerve have a very different function from

those of the axial skeleton. They facilitate the sophisticated and subtle ballet of

facial expression and communication, a vital part of human social interaction. They

provide protection to the eye and dentition. The movement and tone of the lips

allow for oral continence, clarity of speech, and of course smiling. These actions

comprise an interaction of many small muscles of variable strengths and vectors

acting in concert, perhaps rivaled only by the movements of the hand. Reconstruction

of a de fi cit in this nerve–muscle complex is still a crude science, and one in which

it is hard to remain faithful to Gilles maxim of replacing “like with like.” However,

its importance to a patient’s quality of life cannot be underestimated.

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Chapter 16

Spastic Facial Muscle Disorders

Juwan Park , Andrew R. Harrison , and Michael S. Lee

16.1 Introduction

Facial muscles are a group of striated muscles that, among other things, control

facial expression and are innervated by the facial nerve (CNVII). In contrast, the

nearby eyelid retractor muscles and masticator muscles are innervated by the oculomotor

(CNIII) and mandibular branch of trigeminal nerve (CNV), respectively.

Beside facial expression, facial muscles around the eyes are in charge of controlling

eye blink and eyelid closure. A blink is a temporary closure of both eyelids and

normally does not interfere with the continuity of vision. Physiologic blinking helps

keep the cornea moist to maintain a smooth refractive surface for clear vision. Re fl ex

closure of the eyelids is a spontaneous reaction to a corneal irritant. The normal

average spontaneous blink rate is 16 ± 9 times per minute.

Various dystonic or non-dystonic movement disorders, or dyskinesias, in the

facial region cause involuntary contractions of the facial muscles (Table 16.1 ),

which may be debilitating functionally and esthetically. In this chapter, we discuss

the more common facial muscle dystonias, including blepharospasm, hemifacial

spasm, and diverse conditions that cause facial spasms.

J. Park , M.D.

Department of Ophthalmology, University of Minnesota, Minneapolis, MN, USA

A. R. Harrison , M.D. (*) • M. S. Lee , M.D.

Department of Ophthalmology , University of Minnesota ,

420 Delaware Street SE , Minneapolis , MN 55455 , USA

e-mail: harri060@umn.edu




287

288 J. Park et al.

Table 16.1 Disorders of overactive facial muscles

Bilateral

Unilateral

Benign essential blepharospasm Hemifacial spasm ( rarely bilateral )

Re fl ex blepharospasm; ocular, eyelid disease,

foreign body

Apraxia of eyelid opening

Other idiopathic craniocervical dystonias

Meige syndrome (Brueghel syndrome)

Spasmodic dystonia

Torticollis

Drug induced

Acute dystonic reaction

Tardive dystonia

Tardive dyskinesia

Neurologic disorders

Parkinson’s disease

Progressive supranuclear palsy

Wilson’s disease

Huntington’s disease

Post-encephalitic syndrome

Midbrain infarction

Demyelination

Seizure

Psychogenic

Aberrant regeneration of facial nerve (Facial

synkinesis, facial nerve misdirection,

post-Bell’s palsy syndrome)

Ocular/facial myokymia

Focal motor seizure

Tics, Tourette’s syndrome ( can be bilateral )

Eyelid myokymia (only one eyelid involved)

16.2 Blepharospasm

Dystonia is a neurologic movement disorder (dyskinesia) characterized by involuntary

muscle contractions, which can vary from brief spasm to sustained contractions

and cause slow repetitive movements, twisting, or abnormal postures. There are

several different types of dystonia based upon the regions of the body which they

affect: most or all of the body (generalized dystonia), a speci fi c part of the body

(focal dystonia), two or more unrelated body parts (multifocal dystonia), two or

more adjacent parts of the body (segmental dystonia), or the arm and leg on the

same side of the body (hemidystonia) (Dystonia fact sheet).

Among its common forms, cranial dystonia involves eyelid, facial, mandibular,

oral, lingual, and laryngeal muscles. Blepharospasm , which is the most frequent feature

of cranial dystonia and the second most common focal dystonia after cervical

dystonia (spasmodic torticollis or torticollis), is the bilateral intermittent involuntary

forceful contraction of the protractor muscles of the eyelids. The protractor muscles

controlling eye blinks consist of the orbicularis oculi (main), procerus, and corrugator

supercilii muscles, which are all innervated by branches of the facial nerve

(CNVII). If blepharospasm is limited to the eyelids in the absence of other adnexal

16 Spastic Facial Muscle Disorders

289

disease, it is termed essential blepharospasm . Benign essential blepharospasm (BEB )

is de fi ned as an essential blepharospasm without a known underlying cause.

Blepharospasm is associated with additional abnormal dystonic movements of

the lower face, neck, or extremities in more than 50% of patients. Blepharospasm

accompanied by involuntary spasm of the lower face (oromandibular dystonia) is

termed Meige syndrome (idiopathic orofacial dystonia, idiopathic oromandibular

dystonia, or idiopathic cranial–cervical dystonia) named after the French neurologist

Henry Meige. In 1910, he described a condition characterized by blepharospasm

and facial, mandibular, oral, lingual, and laryngeal spasms and called it “ spasm

facial median .” Its alternative eponym is Brueghel syndrome named after a Flemish

artist in the sixteenth century. “De Gaper,” one of his paintings of a woman showing

apparent blepharospasm with face and neck involvement, is regarded as one of the

earliest suspected documentations of blepharospasm. The term, “Brueghel’s syndrome”

is used especially when extensive mandibular involvement is a major

component of the disease, and sometimes Meige syndrome and Brueghel syndrome

are differentiated as “idiopathic orofacial dystonia” and “idiopathic oromandibular

dystonia,” respectively.

16.2.1 Epidemiologic Features

BEB affects an estimated 20,000–50,000 people in the United States, with 2,000

new cases diagnosed annually and a prevalence of 1.2–5 per 100,000 compared to

the prevalence rate of overall cranial dystonia, which is estimated at 5–10 per

100,000 population (Patel and Anderson 1995 ; Hallett 2002 ; Bradley et al. 2003 ) .

Blepharospasm usually begins in the fourth to sixth decades, with its peak onset in

the sixth decade of life. Women are affected more frequently than men with the ratio

of 1.5–2:1 (Castelbuono and Miller 1998 ; Defazio and Livrea 2002 ) .

The disorder is usually sporadic, but there are a few reports of familial occurrence,

some of which suggest an autosomal dominant pattern with incomplete penetrance

(Defazio et al. 1993, 2003a, 2006b ) . Approximately one third of the patients

have at least one fi rst- or second-degree relative with a movement disorder, such as

blepharospasm, Meige syndrome, Parkinsonism, or essential tremor, suggesting a

genetic predisposition in some patients. Various medical problems, including

depression, thyroid disease, and autoimmune disorders, have been reported in

patients with cranial dystonia (Cavenar et al. 1978 ; Diamond et al. 1984 ; Wenzel

et al. 2000 ; Nishikiori et al. 2005 ; Grandas et al. 1990 ; Jankovic and Patten 1987 ) .

16.2.2 Clinical Features

Essential blepharospasm is typically a slowly progressive disorder. Symptoms may

stabilize in mild cases. Some patients have a fl uctuating course, with exacerbations

290 J. Park et al.

Table 16.2 Jankovic Rating Scale (JRS) severity score

Blepharospasm severity

0 = None

1 = Minimal, increased blinking present only with external stimuli (e.g., bright light, wind,

reading, driving, etc.)

2 = Mild, but spontaneous eyelid fl uttering (without actual spasm), de fi nitely noticeable, possibly

embarrassing, but not functionally disabling

3 = Moderate, very noticeable spasm of eyelids only, mildly incapacitating

4 = Severe, incapacitating spasm of eyelids and possibly other facial muscles

Blepharospasm frequency

0 = None

1 = Slightly increased frequency of blinking

2 = Eyelid fl uttering lasting less than 1 second (s) in duration

3 = Eyelid spasm lasting more than 1 s, but eyes open more than 50% of the waking time

4 = Functionally “blind” due to persistent eye closure (blepharospasm) more than 50% of the

waking time

and partial remissions. Remission rates of 1.2–11.4% have been reported (Castelbuono

and Miller 1998 ; Grandas et al. 1988 ) .

The involuntary movement ranges from increased blink frequency to severe,

sustained spasms of the protractor muscles causing the eyelids to clamp tightly shut.

It is very helpful in evaluating the effect of treatments for blepharospasm to grade

the symptoms based on the severity and frequency. The Jankovic Rating Scale (JRS)

is probably the most widely used current clinical scale which differentiates the

severity and frequency of blepharospasm into grades of 0–4 (Jankovic and Orman

1987 ) . As seen in Table 16.2 , the JRS primarily focuses on the objective signs of

blepharospasm but does incorporate subjective symptoms such as whether the

increased blinking and spasms affect quality of life.

Rarely, only one eyelid is affected in blepharospasm patients, but eventually in

almost all cases both eyelids are involved within weeks to months. However, the

degree of involvement may remain asymmetric. Most patients present with sensory

complaints of dry eye symptoms (ocular irritation, foreign body sensations, grittiness,

photophobia, and tearing) that may precede or occur simultaneously with the

development of the eyelid spasms (McCann et al. 1999 ) . The initial motor sign may

be an increased frequency in blinking, particularly in response to a variety of common

stimuli including wind, sunlight, and air pollution. Many blepharospasm

patients wear sunglasses, even inside and on cloudy days, and have dif fi culty with

reading and driving.

As the disease progresses, excessive blinking is seen early and late due to overaction

of the eyelid protractor muscles, particularly the orbital portion of the orbicularis

oculi and the corrugators. Once the contractions are well established they may

be tonic and sustained, brief and clonic, or regular and rhythmic. Patients frequently

complain of retro-orbital discomfort at the time of the spasms (Shorr et al. 1985 ) .

Spreading of the spasms to midfacial and lower facial muscles is often seen.


291

Additional dystonias are found in the body other than eyelids in 78% of patients

(Grandas et al. 1988 ) . For example, some patients progress to a more generalized

facial dystonia: Meige syndrome. Other muscle groups that may also be affected by

dystonic movements include muscles of the larynx and pharynx (“laryngealpharyngeal

dystonia”) (Alappan Spring 2008 ; Kahn 2001 ) . The voice may become

harsh, hoarse, and strained, a condition termed “spasmodic dysphonia.” (Zwirner

et al. 1997 ; Brin et al. 1998 ) . Cervical muscle involvement, typical of “spasmodic

torticollis,” may accompany cranial dystonia; less often distal muscles, such as of

the hand (as in “writer’s cramp”), may be affected (Gordon 2005 ) . A postural tremor

similar to benign essential tremor often accompanies cranial dystonia, and occasionally

Parkinsonian symptoms are present which should be differentiated from a

complication of levodopa therapy (Tolosa and Compta 2006 ) .

Symptoms vary during daily activities. Spasms are typically absent during sleep

and often for the fi rst 1 or 2 h after awakening in the morning. Patients may develop

and adopt sensory tricks to keep their eyes open. Reported conditions that might

relieve the spasms are sleep (75%), relaxation (55%), inferior gaze (27%), arti fi cial

tears (24%), traction on eyelids (22%), talking (22%), singing (20%), and humming

(19%) (Anderson et al. 1998a ). In addition, many patients adopt yawning, extending

the neck, whistling, coughing, walking, wearing dark glasses, or pressing the

supraorbital notch or temple in an attempt to reduce or hide the manifesting symptoms.

Increased attention or concentration, such as occurs in the physician’s of fi ce,

can temporarily reduce and mask the severity of blepharospasm. As a result, the

severity can be grossly underestimated even in a severely affected patient. Patients

who are severely affected may be rendered functionally blind even though their

vision is normal. Sudden involuntary eyelid closure can occur while a patient is

driving or crossing the street and thus can lead to serious injury. Many such patients

cannot keep their normal daily and social activities and become socially isolated

and often have psychiatric problems including depression (Patel and Anderson

1995 ; Hallett 2002 ; Grandas et al. 1988 ) .

There can be anatomic changes associated with long-standing blepharospasm.

Besides elevating their brows against contractions of the orbital part of orbicularis

oculi, patients with severe spasms have to manually pry their eyes open and keep

pressure on the upper eyelids to prevent the spontaneous closure. It may result in

elongation and dehiscence of the eyelid tissues and cause brow ptosis, blepharoptosis,

and dermatochalasis. Furthermore, entropion and ectropion may develop due to

medial and lateral canthal tendon laxity (Bodker et al. 1993 ) .

In blepharospasm, the most common ocular comorbidity is dry eye (49%), followed

by other neurologic diseases (8%) (Anderson et al. 1998 a). Usually the patient

has no apparent underlying cause for blepharospasm, but secondary blepharospasm

may occur in Parkinsonism (e.g., Parkinson’s disease, progressive supranuclear

palsy), (Golbe et al. 1989 ) months or years following an episode of Bell’s palsy,

(Baker et al. 1997 ) and in association with a lower pontine lesion (Aramideh 1996 ) .

292 J. Park et al.

16.2.3 Pathophysiologic Features

The etiology of blepharospasm is not clear but appears to be multifactorial, with a

genetic background factor (a predisposing factor such as reduced central nervous

system inhibition) and an environmental trigger factor (a precipitating factor such

as ocular irritation). Historically, patients with blepharospasm received the misdiagnoses

of a psychiatric illness, but today blepharospasm is considered to be a neuropathologic

disorder rather than a psychopathologic disorder. Given that 30% of

patients with essential blepharospasm have a family history, genetic predisposition

is thought be involved in the pathophysiology. It is believed to be related to

degenerative changes in the basal ganglia, diencephalon, corpus striatum–brainstem–

extrapyramidal system, and/or the cerebellum. A small number of patients with

lesions in the caudal diencephalon or rostral midbrain were reported to have abnormal

movements similar to those in cranial dystonia (Herrero et al. 2002 ; Kulisevsky

et al. 1988 ) . No consistent pathological features in the basal ganglia or brain stem

have been found in postmortem specimens. Enhanced blink re fl ex excitability, perhaps

due to supranuclear disinhibition of the facial nucleus and brain stem re fl exes,

denervation supersensitivity of the facial nuclear complex, sprouting of surviving

axons, or some combination of the three has been proposed as possible predisposing

factors for developing blepharospasm (Hasan et al. 1997 ) .

A relationship between blepharospasm and dopamine insuf fi ciency has been recognized

in animal models and suspected from clinical observations in patients with

dopamine-related disorders (Patel and Anderson 1995 ; Hotson and Boman 1991 ;

Schicatano et al. 1997 ) . Similar movements may be caused by levodopa therapy in

Parkinson’s disease and by dopamine receptor antagonists (e.g., neuroleptic, antipsychotic

drugs, and metoclopramide hydrochloride), both suddenly (acute dystonic

reactions) and after long-term therapy (tardive dystonia). This suggests that the

neurotransmitter dopamine may play an important role in the development of the

abnormal movements.

16.2.4 Diagnosis and Differential Diagnosis

There are no particular criteria for the diagnosis of essential blepharospasm.

Diagnosis is made based on the patient’s history and clinical fi ndings. A family

history of blepharospasm or dystonia further aids in the diagnosis.

It is helpful to divide the face into four quadrants and recognize the involved

areas to determine the diagnosis (Nerad et al. 2008 ) . Spasm in essential blepharospasm

involves both eyes although during a transient initial period it might present

unilaterally. If bilateral eyelid spasms are associated with twitches or spasms of the

lower face, then Meige syndrome is the diagnosis. If spasm is restricted to only one

side of the face, the proper diagnosis is likely to be hemifacial spasm. If spasm is

observed in only a single group of orbicularis oculi muscle fi bers on the unilateral

side, the patient probably has eyelid myokymia.


293

Essential blepharospasm can be divided into three categories depending on its

causes: BEB which is idiopathic; re fl ex blepharospasm associated with irritating

ocular or eyelid diseases; and atypical blepharospasm or apraxia of eyelid opening.

Many patients with blepharospasm often present with additional dystonic movement

abnormalities in other body parts beyond the eyelids, and thus rather than

BEB, Meige’s syndrome and/or apraxia of eyelid opening should be considered to

make the diagnosis. The diagnosis of BEB is one of exclusion. Several ocular and

non-ocular disorders which may lead to similar symptoms must be ruled out for the

diagnosis of BEB.

16.2.4.1 Re fl ex Blepharospasm

Re fl ex blepharospasm occurs in response to provocative, irritating mechanical or

light stimuli. Re fl ex blepharospasm may be misdiagnosed as BEB, resulting from

lack of recognition of a potentially treatable underlying disorder. Any cause of

re fl ex spasm must be ruled out before BEB is diagnosed. A thorough ophthalmologic

examination is indicated for various ocular or eyelid problems including dry

eye, ocular surface disease, blepharitis, eyelid or eyelash malposition, anterior

uveitis, and posterior subcapsular cataract, which render the patient abnormally sensitive

to light and cause ocular irritation. Foreign bodies on the internal surface of

the eyelids must be evaluated using magni fi cation and lid eversion. Once the underlying

causes of the excess blinking are eliminated, the spasms will be relieved in

patients with re fl ex blepharospasm.

16.2.4.2 Apraxia of Eyelid Opening (Atypical Blepharospasm)

Dif fi culty in opening the eyelids when the orbicularis oculi is not in forceful contracture

indicates that the patient is suffering from apraxia of eyelid opening

(Jankovic et al. 1982 ) . It is the inability to initiate voluntary opening of the eyes,

resulting from a combination of varying degrees of orbicularis oculi spasm and

inhibition of levator function. Patients with this condition have dif fi culty initiating

eyelid opening, resulting in prolonged periods of bilateral eyelid closure.

Some patients with blepharospasm often have a component of apraxia of eyelid

opening superimposed on top of the eyelid spasm; purely isolated apraxia of eyelid

opening can also occur. The estimated incidence of apraxia of eyelid opening among

patients with blepharospasm is 7% (Jordan et al. 1990 ) . It also occurs with neurodegenerative

diseases such as Parkinson’s disease, progressive supranuclear palsy,

and Shy-Drager syndrome (multiple system atrophy) (Vissenberg et al. 1993 ) .

One potential mechanism involves persistent contraction of the pretarsal orbicularis

oculi muscle with attempted lid opening. Electomyographic studies have shown

the inappropriate persistence of pretarsal orbicularis oculi activity during attempted

eyelid opening. This is often not clinically evident on examination. Patients with

apraxia of eyelid opening fail to open the eyelids even in the absence of clinically

294 J. Park et al.

evident eyelid squeezing (Tozlovanu et al. 2001 ) . The eyelids appear relaxed, and

the eyebrows are often raised as a result of prominent use of the frontalis to elevate

the upper eyelid (Krack and Marion 1994 ) . In contrast, the spasms in BEB usually

involve all the subparts of the orbicularis oculi muscles, causing characteristic lowering

of the eyebrows.

Injections of paralytic agents into the preseptal orbicularis oculi only are generally

unsuccessful in treating apraxia (Lepore et al. 1995 ) . Injection of 4–5 units of

botulinum toxin A into several sites around the pretarsal orbicularis oculi muscle

has been shown to elicit an improvement in eyelid opening, with the sites of most

effectiveness being between the preseptal and pretarsal portions of the orbicularis

oculi (Vissenberg et al. 1993 ; Forget et al. 2002 ) . On average, symptoms improve

for 2 months, with retreatment necessary after this time period to maintain improved

eyelid control. Limited myectomy with complete removal of the pretarsal orbicularis

and a frontalis sling operation should be considered for patients who are visually

disabled by the apraxia.

16.2.4.3 Meige Syndrome

Meige syndrome consists of blepharospasm plus oromandibular dystonia, characterized

by dystonic movements of the lower face, jaw, and neck. The most frequent

presenting complaint is blepharospasm, although it is not always present. The full

syndrome can take years to develop. It is estimated that as many as 50% of patients

with blepharospasm may have Meige syndrome (Bradley et al. 2003 ; Defazio

et al. 2001 ) . Eyelid involvement may predate or follow midfacial, oral, mandibular,

or pharyngeal involvement which includes facial grimacing, frowning, fl aring of the

nostrils, yawning, retraction and forced opening of the mouth, contractions of the

soft palate and fl oor of the mouth, pursing and tightening of the lips, jaw clenching,

tongue protrusion, head titubation, tensing of the platysma, torticollis, and spastic

dystonia.

Its earliest symptom is usually “action dystonia” with involuntary dystonic

movements appearing only when the involved muscles are used, such as in talking

or chewing. Typically one action may precipitate the dystonia; at the beginning

other actions may not be involved at all. As the disorder worsens, more and more

actions are affected, and the spasms become more intense. Eating, swallowing, and

speaking all may become impaired. Forced jaw closure may damage the lips, gums,

tongue, and teeth. Temporomandibular joint pain may occur, along with recurrent

jaw dislocation.

16.2.4.4 Eyelid Myokymia (Ocular or Orbicularis Myokymia)

Eyelid myokymia is a relatively common condition, and is a localized form of facial

myokymia characterized by benign episodes of continuous fi brillary twitching or

quivering of one or more fi bers or fascicles of the orbicularis oculi muscle lasting


295

seconds. It is unilateral, usually involving a single orbicularis oculi fi ber or small

fascicle of fi bers in lower eyelid. It does not close the eyelid fi ssure, even though it

is occasionally forceful enough to cause oscillopsia. Men and women are equally

affected. Its onset is acute and usually correlates with stress, fatigue, caffeine, or

alcohol consumption. Treatment is usually not necessary, since it is self-limiting

and usually lasts for less than a week. The longest reported case of eyelid myokymia

is 13 years.

16.3 Hemifacial Spasm

Hemifacial spasm affects the entire side of the face and neck unilaterally, and is

related to facial nerve irritation mainly at its exit from the brainstem. Hemifacial

spasm differs from blepharospasm and other features of cranial dystonia in that the

spasms remain unilateral in hemifacial spasm, whereas in blepharospasm there is

nearly always bilateral involvement. Rarely, hemifacial spasm is bilateral; in such

cases the movements on the two sides of the face are asynchronous, in contrast to

the simultaneous bilateral movements of cranial dystonia. In hemifacial spasm,

spontaneous contraction is often more of a spasm than a twitch. It may persist during

sleep unlike blepharospasm and, in general, cannot be altered by sensory tricks.

However, emotion and stress frequently aggravate the condition (Castelbuono and

Miller 1998 ; Defazio and Livrea 2002 ) .

16.4 Aberrant Regeneration of Facial Nerve (Facial

Synkinesia or Facial Nerve Misdirection

A history of facial paralysis or facial nerve injury as well as electrophysiologic studies,

might be helpful in revealing signs of synkinesis. As a simple test for aberrant

regeneration, patients can be asked to pucker their lips to see if the eyelid fi ssure

becomes narrow because of increased orbicularis muscle tone (Nerad et al. 2008 ) .

Like hemifacial spasm, these spasms persist during sleep.

16.5 Neurologic Disorders

Neurodegenerative disorders , especially those affecting the basal ganglia, such as

Parkinson’s disease, progressive supranuclear palsy, Huntington’s disease and

Wilson’s disease, can produce various combinations of spontaneous blepharospasm,

re fl ex blepharospasm, and apraxia of eyelid opening, in addition to involuntary

movements of the lower face. Patients with these lesions typically have additional

neurologic signs.

296 J. Park et al.

Focal motor seizures can include paroxysmal eyelid movements, such as

fl uttering, which occurs during the seizure. Unilateral facial movements or eyelid

closure which is repetitive, brief, and followed by weakness (Todd’s paralysis)

would suggest a focal motor seizure involving the face. Spread to the hands or

limbs, or generalization to involve the other side of the face or body with loss of

consciousness, would make this diagnosis obvious. Evaluation consists of an electroencephalogram

(EEG) and neuroimaging to detect a structural seizure focus,

followed by treatment with anticonvulsants.

16.6 Psychological Problems

Depression, anxiety, and personality disorder are often associated with

blepharospasm, but it is generally regarded that blepharospasm can cause or aggravate

the psychological problems. The variability in severity of symptoms, the

unusual aggravating and relieving factors, and the discrepancy between the history

of the disorder and objective signs seen by the physician have often resulted in the

condition being misdiagnosed as hysteria or other psychiatric disorders.

Blepharospasm used to be considered a psychological disorder but is now thought

only rarely to be due to psychogenic factors. However, sudden onset spasms in

young patients under 30 may represent psychological blepharospasm.

16.7 Drug-Induced Facial Dyskinesias (Tardive Dyskinesia)

The classic form of tardive dyskinesia, caused by long-term treatment with neuroleptics

(anti-dopaminergics), involves the buccal–lingual–masticatory area, most

frequently and usually spares the eyelids; tardive dyskinesia may consist of rapid,

continuous, stereotyped, writhing movements of the orofacial region, and may

involve either bilateral or unilateral blepharospasm.

Commonly used drugs that are implicated in tardive dyskinesia include antidopaminergics

or neuroleptics (e.g., haloperidol), dopaminergics or anti-Parkinson’s

agents (e.g., levodopa), antidepressant and anxiolytics (e.g., alprazolam), antiepileptics

(e.g., carbamazepine, phenytoin), antiemetics (e.g., metoclopramide), nasal

decongestants containing histamine, and anticholinergics (Levin and Reddy 2000 ) .

The reported duration of exposure that incites tardive dyskinesia ranges from 3 days

to 11 years, with an average of about 3.7 years, and onset of the dyskinesia can

occur up to 1 year after cessation of the offending drug (Jankovic 1985 ) .

The movements associated with this disorder differ from those of cranial dystonia

in that the movements are choreic rather than sustained or dystonic and are often

quite stereotypic (Tarsy 2000 ) . However, neuroleptics can also cause a chronic form

of dyskinesia that mimics cranial dystonia (tardive cranial dystonia) which is dif fi cult

to differentiate from essential blepharospasm. It is most important to check to see if


297

the drug history includes drugs which can cause tardive dystonia (Mauriello et al.

1998a ). Treatment consists of withdrawing the offending agent, sometimes combined

with the use of botulinum neurotoxin (BoNT) injections in refractory cases.

16.8 Treatment

Speci fi c treatment may be not necessary until patients with blepharospasm or other

cranial dystonia are disabled by the abnormal movements. Any potentially exacerbating

ocular disease such as dry eye or blepharitis must be treated fi rst. Dry eye

symptoms can be treated symptomatically with arti fi cial tears and punctal occlusion.

Tinted lenses also have been recommended to ameliorate photophobia in patients

with blepharospasm (Adams et al. 2006 ; Herz and Yen 2005 ) .

The treatment of choice in patients with debilitating blepharospasm, Meige’s

syndrome, and hemifacial spasm is localized injections of botulinum neurotoxin

type A ( BoNT / A ) around the eyelids to weaken the orbicularis oculi and other muscles

involved in eyelid closure and facial movements (Aramideh 1996 ; Aramideh

1995 ; Osako and Keltner 1991 ; Price and O’Day 1994 ; Defazio et al. 2002 ; Dutton

and Fowler 2007 ) . Greater than 90% of patients report a marked decrease in the

squeezing action of the eyelids and twitching in lower part of the face (Osako and

Keltner 1991 ; Elston 1987 ; Engstrom et al. 1987 ; Dutton and Buckley 1988 ;

Kennedy et al. 1989 ; Mauriello et al. 1996 ; Anderson et al. 1998b ). Some patients

with apraxia of eyelid opening bene fi t from BoNT injection depending on how

much of their eyelid closure is spastic. Most need higher doses of toxin and more

frequent injections.

16.8.1 BoNT Injection

BoNT injections were fi rst used to treat strabismus in 1977 by Alan Scott, a pediatric

ophthalmologist, (Dressler 2000 ) and subsequently used to treat blepharospasm in

the early 1980s by Frueh et al. ( 1984 ) and Scott et al. ( 1985 ) . Since then, BoNT has

been highly effective and well tolerated in the symptomatic treatment of a very

broad range of conditions involving either muscle hyperactivity such as blepharospasm

and hemifacial spasm, or cholinergic hyperactivity such as hyperhidrosis and

hypersalivation (Jankovic 2009 . Recently, BoNT has been approved for the treatment

of glabellar rhytids and chronic migraine headaches (Harrison 2003 ) .

The various strains of the anaerobic bacteria Clostridium botulinum produce

seven distinct serotypes of BoNT, of which fi ve are pharmacologically active in

humans (A, B, E, F, and G) and two are inactive (C and D) (Brin and Blitzer 1993 ) .

In all naturally occurring serotypes of BoNT (types A~G) and commercially available

BoNT preparations, the active neurotoxin (150 kDa; 100 kDa of a heavy chain;

and 50 kDa of a light chain) is noncovalently associated with a set of nontoxic and

298 J. Park et al.

Fig. 16.1 Contents of botulinum neurotoxin preparation

inactive complexing proteins (hemagglutinins (HA) and nonhemagglutinins (NHA))

and thus forms high molecular toxin complexes (Hasegawa et al. 2007 ; Hambleton

1992 ) (Fig. 16.1 ). The molecular weight of the toxin complex ranges between 230

and 900 kD, depending on the serotype (Daniele Ranoux 2007 ) .

Today, two serotypes are used in therapeutics, BoNT type A (BoNT/A) and type

B (BoNT/B). Among the seven distinct exotoxins, BoNT/A is the most powerful,

followed by type B and type F (Huang et al. 2000 ) . BoNT/A has been most commonly

used in the studies of eye movement disorders because this bacterial strain

retains its toxigenicity well, and it can be crystallized in a stable form. Compared

with BoNT/A, BoNT/B seems to have a quicker onset and greater diffusion in the

tissues. Also, its dosage is signi fi cantly different from that of type A, and its duration

of action is shorter. Patients treated with BoNT/B generally experience more

discomfort at injection, and their ultimate satisfaction rates are lower. Therefore,

BoNT/B is considered as an alternative only for patients who show decreased clinical

response or who fail to respond to initial treatment with BoNT/A (Baumann and

Black 2003 ; Alster and Lupton 2003 ) .

There are 3 type A and 1 type B brands of BoNT preparations currently available

in the United States (Table 16.3 ): Botox

®

(onabotulinum toxin A; Allergan Inc,

Irvine, CA, USA), Dysport ® (abobotulinum toxin A; Ipsen Ltd, Slough, Berks, UK),

Myobloc ® (rimabotulinum toxin B; Solstice Neurosciences Inc, Malvern, PA, USA),

and newly FDA approved Xeomin ® (incobotulinum toxin A; Merz Pharmaceuticals

GmbH, Frankfurt, Germany) (Albanese 2011 ; Frevert 2009 ) . The potency (toxicity)

of the BoNT preparations is expressed in units, but each preparation has its own

measurement. For example, 1 unit of Botox ® is de fi ned as the weight of intraperitoneally

injected toxin required to kill 50% of a group Swiss-Webster mice weighing

18–20 g (Harrison 2003 ; Schantz and Johnson 1990 ) . The mean lethal dose of


299

Table 16.3 Properties of different botulinum neurotoxin preparations

® ® ® ® ®a

Brand name Botox Dysport Xeomin Myobloc /Neurobloc

Generic name OnabotulinumtoxinA AbobotulinumtoxinA IncobotulinumtoxinA RimabotulinumtoxinB

Manufacturer Allergan Inc. (USA) Ipsen Ltd. (UK) Merz Pharmaceuticals GmbH Solstice Neurosciences Inc.

(Germany)

(USA)

Serotype A A A B

Target SNARE SNAP-25 SNAP-25 SNAP-25 VAMP (synaptobrevin)

Packaging (units/vial) 100 500 50, 100 2,500 (0.5 mL), 5,000 (1 mL),

Pharmaceutical

Preparation

10,000 (2 mL)

Powder Powder Powder Ready-to-use solution

(5,000 U/mL)

Stabilization Vacuum drying Freeze drying (lyophilization) Freeze drying (lyophilization) pH reduction

Complex size (kDa) 900 300–900 150 700

Complexing proteins O O X O

Excipients (per vial) HSA b 0.5 mg HSA 0.125 mg 100 units/vial; HSA 1 mg HSA 0.5 mg/mL

NaCl 0.1 M

Disodium succinate 0.01 M H O 2

NaCl 0.9 mg Lactose 2.5 mg Sucrose 4.7 mg Hydrochloric acid

Biological activity in 1 1/3 1 1/40

relation to Botox ®

Speci fi c activity (units/ng) 20 40 167 75–125

2–8°C 2–8°C Room temperature 2–8°C

Storage of packaged

product

Shelf life 36–48 months 24 months 36–48 months 24 months

pH of reconstituted 7.4 7.4 7.4 5.6

preparation

Storage once reconstituted 2–8°C for 24 h 2–8°C for several hours → 4 h if stored at room temperature

2–8°C for 24 h For a few hours

a ®

Myobloc is the brand name in Canada, the United States, and Korea. Neurobloc ® is the brand name in the European Union, Norway, and Iceland

b

HSA human serum albumin

300 J. Park et al.

Botox ® in humans is estimated as 39 units/kg and 2,500–3,000 units for a person

weighing 70 kg (Osako and Keltner 1991 ; Harrison 2003 ; Cather and Menter 2002 ) .

Based on several studies and our own personal experience, it seems that 100 units

of Botox ® or Xeomin ® are bioequivalent to 300 units of Dysport ® with a conversion

factor of 1 Botox ® or Xeomin ® unit to 3 Dysport ® unit and 50–100 Myobloc ® (Jost

et al. 2007 ; Odergren et al. 1998 ; Ranoux et al. 2002 ; Dressler 2009 ) .

BoNTs act on the peripheral nervous system where they interrupt calcium-mediated

exocytosis of acetylcholine-containing vesicles at the motor endplate within

the neuromuscular junction. It is mediated by inhibition of the proteolytic cleavage

of different proteins of the acetylcholine transport protein cascade (soluble

N -ethylmaleimide-sensitive fusion attachment protein receptor (SNARE) proteins).

BoNT/A hydrolyses synaptosomal-associated protein 25 (SNAP-25), which is

located on the presynaptic cell membrane, whereas BoNT/B acts on synaptobrevin

or vesicle-associated membrane protein (VAMP), which is embedded in the

membrane of the acetylcholine vesicles. By cleaving these target proteins, BoNT

prevents the fusion of the synaptic vesicle with the presynaptic membrane, thereby

blocking the release of acetylcholine into the synaptic cleft (chemodenervation).

BoNT/A consists of a heavy chain (100 kDa) and a light chain (50 kDa) of neurotoxin,

but only the light chain is responsible for the pharmacological action of BoNT

(Daniele Ranoux 2007 ; Dressler 2010 ) .

The neurotoxin acts on individual motor neuron terminals, and its effects occur

within hours of binding to the nerve cell membrane. The onset of action is gradual

and continues until the end-plate potential is reduced to an extremely low level.

Muscle weakness might become clinically evident in 2–7 days after the injection

because of the continued release of acetylcholine from vesicles that have not been

blocked by the toxin. Some reports indicate that Dysport ® has a quicker onset of

action, and can be as short as 1 day.

The local weakening effect is dose related and with a peak effect at 1–2 weeks

after injection, and the symptom-free duration lasts for 2–3 months in 90% of

patients (Dutton and Buckley 1988 ) . More than 5% of treated patients experience

relief for longer than 6 months, whereas some patients require injections as often as

monthly. Restoration of muscle activity is usually complete by 3–4 months after the

injection, and results from sprouting of the axon and the formation of additional

motor endplates de novo (Harrison 2003 ) . Histopathologically, the nerve terminals

show a mild degree of demyelinating changes after toxin. Subsequent regeneration

is seen at the neuromuscular junctions in the form of “onion bulb” formations and

nerve sprouting (Osako and Keltner 1991 ) . Patients should be aware that the aim of

treatment is to control rather than cure their symptoms, and the injection must be

repeated inde fi nitely because of its transient effect.

BoNT/A preparations should be rehydrated with preservative-free physiologically

normal saline, which should be introduced slowly into the wall of the vacuumsealed

vial to prevent frothing. Most physicians reconstitute Botox ® (100 units/vial)

in 2 mL of non-preserved saline so as that 0.1 mL solution contains 5 units of

Botox ® . The manufacturers recommend discarding the BoNT solutions after 4–24 h

of reconstitution, but many studies have shown clinical activity that persists for

several weeks after reconstitution.


301

The sites of injection for blepharospasm treatment include upper and lower eyelids,

brow and, in some cases, forehead. The exact sites of the injections vary from

patient to patient depending on the areas where the patient has spasms. In general,

the central portion of both upper and lower eyelids is avoided because of the risk of

upper lid ptosis, lower lid entropion, and diplopia. It is said that Dysport ® has a

greater dispersion area compared with Botox ® .

The effectiveness and side effects of BoNT injection using four different treatment

site applications (standard, brow, inner orbital, or outer orbital treatment

group) were evaluated. Standard injection sites were compared to injection sites

further from the eyelid margin and in the brow (Price et al. 1997 ) . This study found

that the further the treatment is away from the eyelid margin, the lower the risk of

ocular side effects and that in patients with blepharospasm, standard injections produced

the longest duration of effect but were associated with the most transient

ocular side effects such as irritation and epiphora. In patients with hemifacial spasm,

the brow treatment has an equally long duration of effect as that of the standard

treatment and has fewer side effects.

BoNT should be injected subcutaneously over the orbicularis oculi, without

being intradermal, to allow diffusion in a subcutaneous plane and to decrease deeper

penetration; the thicker corrugator and procerus muscles require intramuscular

injections.

The dosing of BoNT preparation also should be individualized based on previous

BoNT treatment. If the patient has no history of BoNT treatment or the previous

information is not available, the starting dose for blepharospasm treatment is 2.5–

5.0 units/injection site usually resulting in injection of 12.5–25 units/eye. Few

patients with blepharospasm received a total dose of greater than 75 units in the controlled

clinical trials and less than 70 units (35 units/eye) is recommended for the

initial total dose by the manufacturer (Xeomin ® (incobotulinumA) injection package

insert. It is necessary to adjust the dose, position, and/or number of injection sites for

the next treatment, depending on the therapeutic ef fi cacy and side effects.

There is some debate regarding the proper dosing of BoNT. Some authors reported

a dose–response relationship for ef fi cacy and its duration, in which the greatest

bene fi ts for BoNT were observed with the highest dose and maximum therapeutic

dose up to 840 units of both Botox ® and Xeomin ® in a variety of muscle hyperactivity

disorders without producing clinically detectable systemic adverse effects

(Dressler and Mander 2008 ) . It was also reported that in BEB patients undergoing an

upper eyelid surgical procedure that includes limited myectomy, upper blepharoplasty,

or levator advancement, the duration of the effect of botulinum toxin injections

might be increased. In 14 patients, the average duration of the effect increased

from 122 days preoperatively to 210 days after orbicularis oculi myectomy (Mauriello

et al. 1999 b). Although various authors have reported increased duration of effect

with larger doses as well as increased ef fi cacy of BoNT injection in patients previously

operated on for blepharospasm, these fi ndings are inconsistent and still controversial

(Osako and Keltner 1991 ; Dutton and Buckley 1988 ; Kraft and Lang 1988 ; Ainsworth

and Kraft 1995 ; Perman et al. 1986 ; Garland et al. 1987 ) .

302 J. Park et al.

Long-term effect and loss of ef fi cacy with repeated injections is also debated in

the literature. Although some studies have failed to demonstrate a reduced effectiveness

or shorter duration of treatment with time, (Ainsworth and Kraft 1995 ; Jankovic

and Schwartz 1993 ) it is sometimes clinically observed that initial treatments are the

most successful and, with time, the effect of each injection may be less or tends to

last for a shorter period.

Reduced ef fi cacy may be the result of antitoxin antibody development and binding

of the nonactive large protein chain. Careful consideration should be given

before labeling a patient as a failure due to antibody induction. Immunity to BoNT

is uncommon, and some authors reported that despite the observed development of

antibodies to BoNT/A in the serum of some patients receiving repeated multiple

injections; their presence did not appear to weaken its therapeutic effect (Ainsworth

and Kraft 1995 ; Siatkowski et al. 1993 ; Choi et al. 2007 ) .

The loss of ef fi cacy might be a result of disease progression rather than a true

resistance to the toxin. To differentiate a loss of pharmacological effect of the BoNT

from disease progression, affected patients should be evaluated 2 weeks after a

larger amount of BoNT treatment and should be tested for objective weakness of the

orbicularis oculi muscle. If they fail to develop weakness after injection, such immunized

patients are good candidates for myectomy.

Failure of treatments including BoNT and myectomy is often due to apraxia of

eyelid opening. These patients still struggle to open their eyes after BoNT or myectomy

but have little or no spasm. Jordan et al. estimated that almost 50% of patients

in whom BoNT treatment is considered a failure suffer from apraxia of eyelid

opening (Jordan et al. 1990 ) .

Reduced ef fi cacy after repeated BoNT injection may be the result of a nerve

sprouting and the formation of new motor end plates on the paralyzed muscle fi bers

(Holds et al. 1990 ; Alderson et al. 1991 , Harrison et al. 2011 ) . Paralysis of the neuromuscular

junction is irreversible, so repeated injections cause the development of

collateral nerve fi bers, with a resulting increase in the number of axon terminals.

This may explain the development of tolerance after repeated BoNT injections.

Some microscopic pathology studies show that long-term exposure to the BoNT

can cause denervation atrophy of some skeletal muscles, which might reduce the

frequency and amount of BoNT treatment needed. Others observed only mild

degenerative muscle changes including changes in myo fi bril size and increased distribution

of anticholinesterase. These studies imply that repeated BoNT injection

does not appear to result in irreversible changes such as fi brosis or scar formation

that is secondary to neurogenic muscle atrophy (Borodic and Ferrante 1992 ; Horn

et al. 1993 ) .

The most common side effect of BoNT injections is erythema or swelling of the

eyelid, sometimes accompanied with bruising. It is known that signi fi cant systemic

complications do not occur, since clinical doses of BoNT in cranial dystonia or

hemifacial spasm are relatively small in amount, and moreover, it is injected locally

into the muscle or subcutaneous plane and very little enters the systemic circulation

(Siatkowski et al. 1993 ) . Local complications related to BoNT treatment for

blepharospasm include transient blepharoptosis (7–11%), exposure keratopathy or


303

lagophthalmos (5–12%), dry eye (7–10%), entropion, ectropion, epiphora, photophobia

(2.5%), and, less likely, diplopia (<1%) (Osako and Keltner 1991 ; Dutton

and Buckley 1988 ; Wutthiphan et al. 1997 ; Kalra and Magoon 1990 ) . These are all

due to the paralytic effects of the toxin and its deep penetration. They resolve spontaneously

as the effects of the BoNT wear off.

Contraindications for BoNT injections include pregnancy and lactation, allergies

to the drug, human serum albumin, or cow milk (due to lactose in Dysport ® ), uncooperative

patients, neuromuscular diseases, coagulopathies, infection in the injection

site, and use of medications such as quinine, calcium channel blockers, and

penicillamine or aminoglycoside antibiotics (Dutton and Buckley 1988 ; Hexsel and

Dal’forno 2003 ) .

16.8.1.1 Complications During Injection

(a) Pain : Slow injection with a fi ne, 30-gauge needle on a tuberculin syringe and

injection volume less than 0.1 mL per site are fairly helpful in reducing the

discomfort associated with injections. Some physicians prefer using a topically

applied anesthetic, such as Betacaine ® gel or EMLA ® cream before injection, or

ice compress before and after injection, while others do not use any sedatives or

local anesthesia (Soylev et al. 2002 ; Linder et al. 2002 ) .

Some patients feel more pain with injections around the corrugator supercilii

muscle because the skin at this location is thicker, and the supratrochlear nerve

is compressed by drug in fi ltration. Patients with a previous history of eyelid

surgery including myectomy tend to complain of more pain since the fi brotic

scar tissue is more dif fi cult to penetrate with a needle and is less expandable

compared to normal tissue. Slow injection of less volume with a higher concentration

is helpful in this situation.

(b) Ecchymosis / Hematoma : Any visible vessels underneath thin eyelid skin must

be avoided to reduce hematoma formation. If a hematoma occurs, compression

at the injection site should be applied for several minutes.

(c) Eyeball Perforation : Injection into the eyelids of controlled patients who move

their head vigorously and uncontrollably risk eyeball perforation. It is always

necessary to stabilize and hold the patient’s head still during the procedure.

16.8.1.2 Complications After Injection

(a) Erythema , Swelling : Erythema and swelling typically last for several days after

injection and slowly resolve.

(b) Blepharoptosis : Injections spreading from the upper eyelid injection sites to the

levator muscle can cause one of the most concerning complications, blepharoptosis.

In patients treated more than four times, the reported incidence of ptosis

304 J. Park et al.

is as high as 50%. It is recommended to inject the toxin into orbicularis oculi

muscles in a super fi cial, subcutaneous plane and spare the central portion of

upper eyelid to prevent blepharoptosis. The tip of the needle should be directed

outwards, not towards the median portion of upper lid. This complication also

can be avoided by using a lower concentration and/or a lower volume, which

reduces the risk of spreading to adjacent areas.

The use of less toxin (<25 units/eye) might be helpful, but there is controversy

about the relationship between volume and dose of each set of injections

and the incidence of blepharoptosis. Dutton and Buckley (Dutton and Buckley

1988 ) reported that the incidence of blepharoptosis will be more than double if

more than 25 units of BoNT are injected per eye. On the other hand, Osako and

Keltner (Osako and Keltner 1991 ) reported no signi fi cant difference in dosage

of BoNT or volume of injections between the patients who developed ptosis

and those who did not.

The blepharoptosis is transient as is the effect of toxin, but if needed, the a 2-

adrenergic agonist Iopidine ® (apraclonidine 0.5%) eye drops can be applied to

correct the ptosis temporarily. This causes Müller’s muscles to contract and

temporarily elevate the upper eyelid up to 2 mm.

(c) Dry eye , Lagophthalmos , Exposure keratopathy : Patients with blepharospasm

often have dry eye. BoNT injection also may induce dry eye secondary to either

exposure keratopathy with lagophthalmos or meibomian gland dysfunction.

This generally lasts several days to weeks and can be treated with lubricants,

taping, and punctal occlusion. Rarely, a temporary tarsorrhaphy may be necessary

in severe patients.

(d) Diplopia : Diplopia secondary to BoNT injections is rare, and the inferior

oblique is the most commonly affected muscle due to the anterior site of its

origin (Wutthiphan et al. 1997 ) . As the toxin may spread deep into the orbit,

thus reaching the inferior oblique muscle, Frueh et al. ( 1988 ) recommended

avoiding injecting into the medial portion of the lower eyelid. Once diplopia

occurs, an eye patch or prism lens can be applied to reduce the discomfort until

the effects of the toxin wear off. In patients with puffy lower eyelids, the dose

injected into the lower lid should be reduced, as the risk of diffusion of BoNT

is greater increasing the risk of diplopia due to inadvertent treatment of the

inferior oblique muscles.

(e) Antibody Formation : One of the main potential long-term side effects of BoNT

use is the development of an immunologic resistance due to the production of

neutralizing antibody to the neurotoxin after repeated injections. This, however,

is still controversial (Jankovic and Schwartz 1993 ; Kalra and Magoon 1990 ) .

Antibody formation is more likely to occur in patients with torticollis than in

those with blepharospasm or hemifacial spasm because the amount of toxin

used is much higher in torticollis patients. The reported incidence of this sensitization

is 3–10% (Greene et al. 1994 ) .

Several risk factors for sensitization to BoNT have been identi fi ed: (Greene

et al. 1994 ; Dressler and Benecke 2007 ) injection of over 100 units of Botox ®


305

or 300 units of Dysport ® per session; an interval of less than 3 months between

two injections; using the “Booster” technique where another dose is injected

2–3 weeks after the fi rst injection; and use of a BoNT drug with a low intrinsic

activity. Cumulative dose, treatment time, and patient age have been excluded

as risk factors. Antibody-induced therapy failure usually develops within the

fi rst 2–3 years of BoNT therapy (Dressler 2002 ).

The intrinsic activity of BoNT drugs is de fi ned as the number of toxin units

per amount (nanograms) of clostridial proteins (i.e., toxin complex). At each

injection of toxin, the administered protein mass will be greater when using a

toxin with a low intrinsic activity. The toxin’s antigenic potential is probably

related to the total protein concentration injected (protein load). This may be a

much more relevant parameter in the development of resistance than the number

of units injected (Borodic et al. 1996 ). In patients with cervical dystonia, the

original formulation of Botox ® (100 units/25 ng protein) was six times more

likely to elicit the production of neutralizing antibodies than the newer formulation

of Botox ® (100 units/5 ng protein). The authors conclude that the low risk

of antibody formation after newer Botox ® treatment is related to lower protein

load (Jankovic et al. 2003 ).

The newly FDA approved BoNT/A drug Xeomin ® may reduce antibodyinduced

therapy failure, since it contains only the pure neurotoxin (150 kDa)

produced by a manufacturing process that separates it from complexing proteins

such as hemagglutinins and other proteins in the neurotoxin complex

(Frevert 2009 ; Park et al. 2011 ). Long-term comparative trials in naïve patients

between Xeomin ® and conventional BoNT/A drugs are required to con fi rm the

lower immunogenicity of Xeomin ® (Park et al. 2011 ).

(f) Systemic Toxic Effects : The LD in humans is approximately 390,000 unit/kg,

50

and single injection of more than 500 units may cause acute systemic toxicity.

Systemic toxic effects have not been reported in the treatment of cranial dystonia

because the amount for each treatment is relatively small.

(g) Excessive Facial Weakness : In the patients with Meige’s syndrome or hemifacial

spasm, injections in the mid- and lower facial muscles may induce excessive

facial weakness. Careful toxin injection of appropriate drug levels can

reduce this side effect.

16.8.2 Psychotherapy

Psychotherapy such as behavior modi fi cation and biofeedback has been used to

decrease the frequency and amplitude of spasm. The principle is based on teaching

patients to control their muscle contractions using an electromyographic recording.

306 J. Park et al.

Table 16.4 Drugs used for treatment of blepharospasm

Antipsychotics

Affective disorder drugs

Anxiolytics (Antianxiety drugs)

Stimulants

Sedatives

Muscle relaxants (Gamma aminobutyric acid, GABA)

Parasympathomimetics

Antimuscarinics

Anticholinergics

Anticonvulsants (Benzodiazepines)

Serotonin antagonists

Antihistamines

Phenothiazine, butyrophenone,

reserpine

Lithium carbonate, tetrabenazine

Meprobamate

Amphetamine

Phenobarbital

Baclofen

Lecithin, choline, physostigmine

Tincture of belladonna, scopolamine,

catecholamine synthesis inhibitors

Orphenadrine, trihexyphenidyl

Diazepam, clonazepam, lorazepam,

oxazepam

Cyproheptadine

Diphenhydramine hydrochloride

16.8.3 Oral Medications

Many drugs have been used for the treatment of blepharospasm and cranial dystonias

(Table 16.4 ) on the basis of three hypothetical pharmacological paradigms:

(1) cholinergic excess, (2) gamma-aminobutyric acid (GABA) hypofunction, and

(3) dopamine excess. Even though some drug studies have reported high percentages

of favorable patient responses, including lorazepam (67% of patients), donazepam

(42%), and trihexyphenidyl HCl (41%), in general, their effects are temporary

and only useful in a small number of patients. The side effects, which include sedation,

may be dangerous in older individuals. Oral medications control symptoms on

a long-term basis in only 25% of patients with cranial dystonia, and their long-term

use is usually limited by side effects. Thus, they are usually reserved as a second

line of treatment or adjuvant therapy for spasms that respond poorly to BoNT and

in patients with middle and lower face spasms, which are dif fi cult to treat with

BoNT injection.

16.8.4 Surgery

Surgery is not usually necessary and should be reserved for patients with severe

symptoms that have failed to respond to other forms of treatment. Options include

orbicularis myectomy, during which the orbicularis oculi and other muscles used in

eyelid closure are excised either surgically (Anderson et al. 1998 b) or chemically

(Wirtschafter and McLoon 1998 ) , and neurectomy, a procedure in which branches

of the facial nerve are cut (Kennedy et al. 1989 ) . However, signi fi cant numbers of

patients who undergo surgeries for blepharospasm need to continue BoNT injection

treatment after the surgery.


307

16.8.4.1 Myectomy

(a) Surgical Myectomy : Surgical myectomy can be divided into limited and

extended myectomy depending on the extent of muscle removal. To determine

which surgical method should be used, the strength of the orbicularis oculi

muscle should be objectively tested 2 weeks after BoNT injection. In patients

with a partial response to BoNT, limited surgical myectomy can be considered,

whereas in patients with no response to BoNT, extended myectomy is more

likely to be bene fi cial. Up to 75% of patients obtain signi fi cant subjective and

objective relief for at least 12 months.

(b) Limited Myectomy : Limited myectomy includes the pretarsal, preseptal, and

orbital portions of orbicularis oculi muscle.

(c) Extended Myectomy : In extended myectomy, there is surgical extirpation of all

the eyelid protractors, including the procerus and corrugators muscles as well

as orbicularis oculi muscle.

Myectomy can be performed through a lid crease incision, suprabrow incision, coronal

incision, or a combination. Mid-forehead or hairline incisions can be considered

in patients with brow ptosis. In most cases, the procedure can be approached

with a lid crease incision, and dermatochalasis and blepharoptosis should be corrected

simultaneously if necessary. Limited myectomy should be performed by

resecting the orbicularis muscle in three en bloc sections. First, the pretarsal orbicularis

between the eyelid crease incision and a position 2.5 mm superior to the lashes

is dissected away. At least 1–2 mm of muscle strip from the eyelid margin should be

left for to allow for normal blinking. Second, the preseptal and orbital orbicularis

muscle from the superior edge of the incision to the inferior edge of the eyebrow is

dissected away. Finally, the orbicularis muscle over the temporal raphe is resected.

For extended myectomy, visualization of the corrugators and lateral procerus can

be enhanced by a suprabrow incision but good exposure of these structures can often

be obtained through the eyelid crease incision without making a suprabrow scar.

Complications of orbicularis myectomy surgery

(a) Button - hole skin defect : During resection of the muscles, the skin over the muscles

can be damaged.

(b) Orbital hemorrhage : This can occur from incomplete hemostasis before wound

closure.

(c) Skin necrosis : Eyelid skin or scalp fl ap necrosis can develop if the subdermal

plexus underneath the dermis is signi fi cantly damaged.

(d) Inclusion cyst formation : In closing the upper lid crease incision, it is important

to evert the thin wound edges, as there is a tendency for the edges of the thin

skin fl aps to roll under and cause inclusion cyst formation.

(e) Alopecia : A thin band of muscle should be left beneath the eyebrow to prevent

alopecia.

(f) Multiple eyelid creases : Adhesion between the dermis and levator palpebrae

superioris muscle or aponeurosis may cause multiple eyelid creases. The orbital

308 J. Park et al.

septum should be preserved to avoid this deformity.

(g) Visible scar : Suprabrow incisions provide better visualization for corrugator

supercilii and procerus muscle removal, but a visible scar above the brow limits

its use.

(h) Hypoesthesia : Removal of the lateral corrugator muscle has a risk of supraorbital

neurovascular bundle damage and consequent hypoesthesia of the forehead.

It can recover within 1 year, but sometimes can be permanent.

(i) Dry eye , lagophthalmos , exposure keratopathy : Dry eye and exposure keratopathy

can be caused or aggravated by orbicularis myectomy as it attenuates eyelid

closure.

(j) Chronic lymphedema : Lymphedema may last for longer than 1 year until new

lymphatic channels begin to function. Upper and lower eyelid myectomy should

be staged to avoid chronic lymphedema that is caused by extensive damage to

lymphatic vessels as a result of simultaneous surgery to both upper and lower

eyelids.

(k) Irregularity of eyelid skin , periorbital contour deformity : Subcutaneous scar

tissue and long standing lymphedema can result in an irregular skin surface.

(l) Recurrence of blepharospasm : Although the resected muscles do not appear to

regenerate, blepharospasm can recur presumably due to incomplete removal of

the orbicularis oculi muscle. In such cases, BoNT injection is necessary after

the surgery. Subcutaneous fi brotic scar tissue from the surgery prevents diffusion

of BoNT and causes the injections to be more painful.

16.8.4.2 Chemomyectomy

Doxorubicin (Adriamycin), a cytotoxic anthracycline used to treat disseminated

neoplasms, is a potent method for the permanent removal of muscle via local injection

and is under investigation as a treatment of patients with BEB and HFS

(Wirtschafter and McLoon 1998 ; Wirtschafter 1991 ; Wirtschafter 1994 ) . It has a

relatively selective effect in damaging muscle fi bers by altering intracellular calcium

hemostasis. Doxorubicin opens calcium channels in internal cisternae and

activates calcium release from the sarcoplasmic reticulum. In animal experiments,

there is loss of muscle mass, which is greatest near injection sites. The drug causes

degeneration of the treated muscles and permanent muscular weakness. One favorable

outcome is a resulting “blepharoplasty” and reduced wrinkling of the eyelids

skin that is normally caused by the underlying muscle fi bers. Skin erythema and

ulceration at injection sites are frequent complications and are dose-dependent

(Wirtschafter 1994 ) .

Doxil (Sequus Pharmaceuticals, Menlo Park, CA) is a liposome-encapsulated

form of doxorubicin (Harrison 2003 ) . In monkeys, the chemomyectomy effect of

Doxil was similar to that of doxorubicin. The bene fi t of the liposome-encapsulated

form of doxorubicin was the reduced incidence of skin injury; however, its myotoxicity

and therefore its ef fi cacy were also reduced compared to doxorubicin alone

(McLoon and Wirtschafter 2001 ) .


309

Another agent that has been investigated for chemodenervation is ricin-mAb35

(Hott et al. 1998 ; Christiansen et al. 2003 ) . Ricin, a potent ribosomal toxin, is conjugated

to a monoclonal antibody to the alpha subunit of the nicotinic acetylcholine

receptor. The agent has been extensively studied in extraocular muscles, with excellent

results. The toxin paralyzes the extraocular muscles for at least 6 months with

no histologic evidence of long-term muscle damage.

16.8.4.3 Selective Facial Nerve Ablation (Neurectomy or Reynolds

Procedure, Differential Section of the Seventh Nerve [CNVII])

Selective facial nerve (CNVII) ablation may be considered in cases refractory to

BoNT and myectomy (Fante and Frueh 2001a ). Among the branches of the facial

nerve, temporal, and zygomatic branches are selectively ablated. This also can be

done by percutaneous thermolysis of the nerve. Recurrence rate is high, and 50% of

patients treated with this technique require more than one operation to control their

spasms. Even in these patients, 50% of the patients have a recurrence of spasms 2

or more years after surgery (Fante and Frueh 2001b ). Its use has declined with the

introduction of BoNT injection as well as the high incidence of complications.

Hemifacial paralysis frequently results from facial nerve dissection. Consequently,

the patients may permanently suffer from dif fi culty in controlling facial expression

and in eating and speaking. Other complications include transient parotid fi stula and

recurrent spasm (Frueh et al. 1992 ; Gillum and Anderson 1981 ; McCord 1984 ) .

16.8.4.4 Superior Cervical Ganglion Block

In some patients in whom BoNT treatment fails, the reason for failure may be the

persistence of severe photophobia (photooculodynia) despite weakening of the

orbicularis muscle. It suggests that the sympathetic nervous system may play a role

in maintaining the afferent loop of the disease.

Photooculodynia can be identi fi ed using a simple clinical test. If patients complain

of signi fi cant spasm and pain with a 25-W light bulb at a distance of 3 ft, a

diagnosis of photooculodynia can be made. These patients are not likely to respond

to myectomy and are referred to a pain clinic for a superior cervical ganglion block

to chemodenervate the orbital sympathetic nerves. It was reported that two-thirds of

patients with photooculodynia had a symptomatic improvement with this treatment

(McCann et al. 1999 ; Fine and Digre 1995 ) .

In summary, although the pathophysiology of blepharospasm is unclear, and there

is no known cure for it, several effective modes of treatment, including botulinum

toxin injection, oral medication, and surgery are currently available. Cumulative success

rates for the treatment of BEB are approximately 85% with BoNT/A injections, 97%

for BoNT/A in conjunction with protractor myectomy, and 98% for a combination of

BoNT/A, myectomy and selective facial nerve ablation (Mauriello et al. 1996 ; Fante

and Frueh 2001 a). Ultimately, most patients (70%) continue to receive BoNT

injections, while 7–11% of the patients spontaneously improve.

310 J. Park et al.

16.9 Hemifacial Spasm

Hemifacial spasm is an involuntary intermittent synchronous contraction of the

facial muscles of the whole face on one side. These facial muscles are innervated by

the facial nerve (CNVII). Hemifacial spasm is not truly a dystonia because it is

generally recognized as resulting from compression of the CNVII by a blood vessel

most commonly, or a tumor, which is rare, as the nerve exits the brainstem. This

nerve compression can result in the common hyperactive (spasm) form or the less

appreciated hypoactive (palsy) form.

Hemifacial spasm may be less debilitating than BEB in that the contralateral side

is not affected; however, it is still dis fi guring and a socially embarrassing disorder.

16.9.1 Epidemiologic Features

The typical form of hemifacial spasm occurs in the third to the seventh decade, with

a peak in middle age. Like BEB, it is more frequent in women with a ratio of 2–3:1.

Incidence rates in the United States are 8 out of 100,000 men and 15 out of 100,000

women. For unknown reasons, hemifacial spasm tends to affect the left side of the

face slight more often than the right. The disorder usually occurs in isolation.

However, occasionally it is associated with trigeminal neuralgia or other concomitant

cranial nerve dysfunction.

16.9.2 Clinical Features

This disorder is characterized by muscle spasms in the ipsilateral hemiface with

eyelid closure and elevation of the corner of the mouth. The onset pattern is variable

but usually is insidious or subacute. In the typical form of the disease, the spasms

usually start in the orbicularis oculi where the twitches are mild and mainly clonic

at its onset. Patients progress over a period of months to years from quick apparent

twitching (clonic contractions) around one eye to repetitive synchronous, sustained

spasms (tonic contractions) of all the facial muscles including the zygomatic, orbicularis

oris, mentalis, and platysma on the affected side (Nerad et al. 2008 ) . The

spasms may become tonic as the disease worsens and cause persistent closure of the

eye and tensing of other affected muscles with deviation of the mouth on the spastic

side (Castelbuono and Miller 1998 ) .

Hemifacial spasm is often associated with ipsilateral facial nerve weakness.

A small proportion of cases of hemifacial spasm represent a post-paralytic form that

develops as a sequelae of facial nerve palsy (Bell’s palsy) or injury. Many patients

show evidence of aberrant innervation by CNVII caused by abnormal reinnervation

as motor function recovers following injury of the nerve.


311

16.9.3 Pathophysiologic Features

The pathogenesis of hemifacial spasm is not yet fully understood. Any compressive

lesions along CNVII may cause axonal damage and stimulate ephaptic impulses,

which cause the involuntary muscle contractions (Ishikawa et al. 1997 ) . The most

frequent location is the exit of CNVII from the brainstem, within the cerebellopontine

(CP) angle, and less commonly at its entry into the internal auditory meatus.

The most common fi nding is vascular pulsatile compression of the nerve by a

dolichoectatic artery; typically the offending vessel is the anterior inferior cerebellar

artery, the posterior inferior cerebellar artery, or the internal auditory artery. A dilated,

tortuous, atherosclerotic basilar artery may cause similar compression as well as

compressing additional cranial nerves simultaneously. Rarer causes include aneurysms

and CP angle tumors (Rahman et al. 2002 ) .

The post-paralytic form of hemifacial spasm may be caused by aberrant reinnervation

of the facial musculature from branches of the functioning facial nerve that

are proximal to the site of nerve injury. Other theories include ephaptic transmission

at the site of injury and spontaneous discharge from the deafferented facial nerve.

16.9.4 Diagnosis and Differential Diagnosis

Patient interview and examination help differentiate hemifacial spasm from blepharospasm

or cranial dystonia, facial myokymia, tic disorders, focal seizures and, rarely,

hysterical conversion reaction. The typical and post-paralytic forms of hemifacial

spasm are differentiated by a history of facial nerve palsy or injury and clinical

examination. In the post-paralytic form, there is residual facial weakness on the

affected side. Spasms in the typical form of hemifacial spasm are brief, stereotyped,

but not synkinetic, unlike post-paralytic facial spasm.

The identi fi cation of associated neurological signs helps differentiate secondary

hemifacial spasm from a primary (idiopathic) hemifacial spasm. Any additional

cranial nerve dysfunction (e.g., in hearing or facial sensation) should prompt a

detailed search for a de fi nable cause. However, even if all fi ndings point towards a

primary hemifacial spasm, imaging studies of the brain must be performed systematically.

Magnetic resonance angiography (MRA) is necessary to demonstrate vascular

compression of facial nerve, which is present in 88% of patients and also

sometimes present on the asymptomatic side. MRI is helpful to rule out any other

intracranial pathology, including a cerebellopontine angle tumor (e.g., pontine

glioma) and tumor or swelling around the temporal bone or stylomastoid foramen,

which may be the cause of 1% of cases (Adler et al. 1992 ; Ho et al. 1999 ) .

312 J. Park et al.

16.9.5 Treatment

BoNT injection into the orbicularis oculi muscle and other affected muscles is now

the most widely used treatment. In cases with obvious compression at the exit zone of

the facial nerve root or refractory hemifacial spasm, a second line of treatment might

be provided by microvascular decompression (MVD) (Kemp and Reich 2004 ) .

16.9.5.1 BoNT Injection

Since Elston fi rst reported the use of BoNT in the successful treatment of patients

with hemifacial spasm, various publications report that BoNT injections reduce

symptoms in 80–90% of patients with hemifacial spasm (Park et al. 1993 ; Soulayrol

et al. 1993 ; Chen et al. 1996 ; Elston 1986, 1992 ; Jedynak et al. 1993 ) . Periodic

BoNT injection is now considered the treatment of choice for hemifacial spasm.

Interestingly, the effect of BoNT injection tends to persist longer in hemifacial

spasm patients, often 4–6 months, than in essential blepharospasm or Meige’s syndrome

patients.

The dose and injection sites of BoNT should be individualized based on the

symptoms and response to BoNT treatment. The treatment regimen is similar to that

of blepharospasm. BoNT can be injected unilaterally or bilaterally into the eyelids

to reduce iatrogenic facial asymmetry. Additional injections may be given to lower

facial muscles using low doses; however, the orbicularis oris muscle should be

avoided because of the risk of causing problems with eating and drinking. Sometimes

the platysma muscle, whose abnormal contractions are often unsightly, is injected

with higher doses. This muscle is easily identi fi able by asking the patients to clench

their teeth keeping the lips open. As long as the anterior fi bers are not injected, the

injections do not cause swallowing problems.

The typical BoNT/A dose injected into each treatment site is 2.5–5 units, and the

total dose for the fi rst session should range between 17.5 and 45 units. In the second

session, if the patient is not satis fi ed with the duration of ef fi cacy or complains of

persisting spasms, doses can be increased to a maximum of 50 units.

Like in BEB, a relatively low dose of BoNT for hemifacial spasm does not appear

to lead to systemic side effects. Local side effects are often caused by the toxin’s

diffusion to other muscles. In addition to the complications described for BoNT in

the treatment of BEB, excessive lower facial weakening especially the orbicularis

oris muscle is a problem. These adverse effects are not common, and more importantly,

they are short-lived.

16.9.5.2 Oral Medication

Antiseizure or antianxiety drugs were used in the past with limited effectiveness and

poorly tolerated side effects, especially drowsiness. Some oral medications including


313

carbamazepine, baclofen, and clonazepam have been found to be useful in small

numbers of patients, but have generally proven much less effective than BoNT

injections or surgical decompression in controlling the spasms in both the typical

and post-paralytic form.

16.9.5.3 Surgery

(a) Neurosurgical decompression ( MVD , Janetta i ): Placing a sponge prosthesis

such as expanded polytetra fl uoroethylene (ePTFE, Gore-Tex ® ), between the

facial nerve and the offending vessel to prevent future compression was fi rst

successfully demonstrated by Janetta ( 1983 ). The reported success rate for this

procedure varies and ranges from 50–90%. Other surgical options, such as

orbicularis myectomy, CNVII neurectomy, crushing the facial nerve at its exit

from the stylomastoid foramen, percutaneous fractional thermolysis, alcohol

injections, and anastomosis of the facial nerve with the CNXI or CNX11 are

rarely indicated because of high complication rates, limited bene fi t, and only

provide temporary relief.

Although MVD of CNVII may be curative in hemifacial spasm and produce better

spasm reduction compared to other surgical treatments, there is always an operative

risk. This was estimated at 2% (Jannetta 1983 ; Jannetta et al. 1977 ) with permanent

sequelae: facial paralysis, deafness, or vestibular disorders, which are

more debilitating than the facial spasm. Reported potential complications include

infection in 1%, hematoma in 0.5%, CSF leak in 3%, facial nerve palsy in 1.4%,

ipsilateral hearing loss in 0.86%, and stroke in less than 0.5% (Kalkanis et al.

2003 ). Therefore, it seems reasonable to treat patients fi rst with BoNT injections

and resort to surgery only if these injections fail or if the patient is not satis fi ed

with the results.

16.9.6 Other Precipitating Factors

Aberrant Regeneration of the Facial Nerve (Facial synkinesia , Facial nerve misdirection

, Post-Bell ’s palsy syndrome ): If the facial nerve is damaged, it might regenerate

aberrantly, with misdirection to other facial muscles on the ipsilateral side or

with cross-innervation to the contralateral side. The abnormal regeneration of CNVII

can result in synkinesis of facial muscles, which in turn can cause unwanted facial

movements during normal facial expressions (Osako and Keltner 1991 ) . The abnormal

synkinetic innervation can develop after facial palsy or facial nerve injury. It

causes unilateral synkinetic facial movements mimicking blepharoptosis, orbicularis

myokymia, or hemifacial spasm. Hemifacial spasm is often accompanied by aberrant

314 J. Park et al.

regeneration because the irritation at the facial nerve root causing hemifacial spasm

can evoke nerve injury and consequently aberrant regeneration (Nerad et al. 2008 ) .

The aberrant regeneration also can result, albeit rarely, as a primary phenomenon

from a slow-growing tumor compressing or in fi ltrating the facial nerve.

The abnormal movements in hemifacial spasm are seen most commonly in the

middle-aged but can occur in childhood. Abnormal reinnervation patterns can begin

several months after an acute facial palsy as motor function recovers. It is most

commonly manifested as ipsilateral narrowing of the palpebral fi ssure with movements

of the mouth such as smiling, chewing, and speaking. In addition, uncontrolled

tearing when eating or in anticipation of food (crocodile tears) occurs when

nerve fi bers destined to supply the salivary glands are misdirected to the lacrimal

gland. Abnormal sweating of face while eating (gustatory sweating or Frey syndrome)

can be seen in the parotid gland area, which is caused by aberrant fi bers

innervating sweat glands.

BoNT injection provides reasonably effective control for synkinetic facial

spasms, and the treatment regimen is similar to that of the typical form of hemifacial

spasm (Putterman 1990 ; Armstrong et al. 1996 ) . BoNT injection into the lacrimal

gland may help reduce or prevent involuntary tearing (Boroojerdi et al. 1998 ) .

16.10 Myokymia and Neuromyotonia

Myokymia is the spontaneous, fi ne fascicular contractions of muscle in the absence

of muscular atrophy or weakness. Facial myokymia is characterized by small, continuous

unilateral contractions of the facial muscles. When associated with ipsilateral

facial contracture and weakness (spastic-paretic facial contracture), a pontine

lesion rostral to the facial nerve nucleus in the brainstem should be considered.

Multiple sclerosis and brain stem tumors are also typical etiologies (Jacobs et al.

1994 ) . Other causes of facial myokymia include stroke, hypoxic injury, meningitis,

hydrocephalus, acoustic neuroma, syringobulbia, and Guillain–Barre syndrome.

Eyelid myokymia (ocular or orbicularis myokymia), which is small, annoying

twitches of an eyelid unilaterally, mainly affect the lower lid, and are very common

in young adults. It tends to be precipitated by fatigue, stress, alcohol, nicotine, or

excessive caffeine consumption.

It is benign and usually idiopathic. Contractions may last for seconds and recur

several times daily over a period of weeks or months. Most patients require only

reassurance and avoidance of precipitating factors because eyelid myokymia usually

resolves spontaneously. Neuroimaging may be necessary only if the twitches

spread to involve other facial muscles. Benzodiazepines or BoNT injection into the

affected parts of twitching muscle can be applied for persistent cases (Pane et al.

2007 ; Banik and Miller 2004 ) .

Facial neuromyotonia, which is similar to myokymia but is de fi ned as a delay in

muscle relaxation after a voluntary contraction, has been reported as a complication

of radiation and responds to carbemazepine (Marti-Fabregas et al. 1997 ) .


315

16.11 Eyelid/Facial Tics

Eyelid tics are brief, stereotyped, repetitive, and involuntary eyelid blinks, winks, or

blepharospasm (Evidente and Adler 1998 ) . Tics may be preceded by a premonitory

urge to perform the movement, which increases until the movement is fi nished. This

premonitory urge may be an unpleasant feeling, such as burning, tension, or a contraction.

A tic may be temporarily suppressed by willpower, but the next time it

occurs, it will often be more violent and explosive.

Tics can be classi fi ed as motor or phonic. Motor tics usually reproduce a normal

movement such as blinking or raising the shoulders. Any muscle can be involved,

but mostly tics occur in the muscles of the face, neck, and shoulders. Phonic tics are

involuntary sounds produced by moving air through the nose, mouth, or throat (e.g.,

grunting) or words, sometimes obscene (coprolalia)

Tics are often idiopathic and considered benign. They also can be associated with

encephalitis, drugs, toxins, stroke, and head trauma. In some instances, eyelid tics

are a fi rst manifestation of Tourette’s syndrome. This is a childhood disorder, affecting

boys more than girls, in which multiple motor tics in eyelid, face, limbs, or body

are combined with one or more phonic tics. Characteristic behavioral manifestations

include obsessive-compulsive disorder, grunting, throat clearing, barking, coprolalia,

and echolalia (Jankovic 1992 ; Jankovic and Stone 1991 ; Jankovic 2001 ) . Facial tics

are treated with reassurance, and BoNT injections are hardly ever recommended.

16.12 Summary

Various movement disorders cause involuntary or rarely voluntary contractions of

the facial muscles and subsequently lead to both esthetic and functional problems.

Although symptomatic therapy including BoNT injection is available, better

approaches are needed and will likely become available as the understanding of the

genetics and pathophysiology improves.

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Part VIII

Summary and Conclusions

Chapter 17

Comparison of the Craniofacial Muscles:

A Unifying Hypothesis

Linda K. McLoon and Francisco H. Andrade

17.1 Introduction

In the fi eld of skeletal muscle research, most research has been performed using limb

skeletal muscle, whether studying myogenesis or the anatomy, cell biology, biochemistry,

and physiology of normal, diseased, or aging muscle. Early studies of limb muscle

led to the description of four basic fi ber types with speci fi c biochemistry and physiological

properties assigned to each. Evidence in the past decade has revealed that this

is an oversimpli fi ed view of the true heterogeneity amongst the myo fi bers within limb

muscles (Caiozzo et al. 2000, 2003 ; Pette and Staron 2000 ; Stephenson 2001 ) .

When one considers the craniofacial muscles, it is apparent that there is an

exponential increase in the complexity of these muscles compared to limb skeletal

muscle. These muscles are responsible for basic life processes: maintaining an open

airway, controlling the intake of food and liquid, fi ne calibration that ensures clearest

vision, and controlling the patency of the apertures of the face. Thus, normal function of

the craniofacial muscles is essential for sustaining the most basic functions of life.

The specialized phenotypes of each group of craniofacial muscles form the basis

of their unusual physiological properties and allow them to (1) produce extremely

rapid yet prolonged contractions, (2) perform highly complex patterns of movement,

(3) respond rapidly to physical injury and changes in innervation, (4) display few

changes normally associated with aging skeletal muscle, and (5) show differential

susceptibility to systemic neuromuscular diseases.

L. K. McLoon , Ph.D. (*)

Department of Ophthalmology , University of Minnesota, 2001 6th Street SE ,

Minneapolis , MN 55455 , USA

e-mail: mcloo001@umn.edu








325

326 L.K. McLoon and F.H. Andrade

17.2 Embryology

One of the most striking differences between limb and craniofacial muscles relates

to the genetic programs that control their early embryologic development. As

described in Chap. 2 , while somite-derived skeletal muscles depend on early expression

of Pax3 to develop (Tajbakhsh et al. 1997 ) , non-somite-derived craniofacial

muscles develop normally in the absence of Pax3. Over the last decade, the genetic

networks that control differentiation of craniofacial muscles have been illuminated,

and are quite divergent from each other as well as from limb skeletal muscles

(Table 17.1 ; for review, see Chap. 2 ; Sambasivan et al. 2011 ; Bothe et al. 2011 ) .

The muscles derived from the pharyngeal arches have some overlapping early

gene control, with Tbx1 being important in the formation of muscles derived from

pharyngeal arches 2 and 3, and partially controlling masticatory muscle formation.

The extraocular muscles represent the most distinct of this group of muscles, and

depend on Pitx2 expression for their formation (Diehl et al. 2006 ) . The importance

of these early genetic differences is underlined by examination of a Pitx2 conditional

knockout, where over time the extraocular muscles from these mice show

decreased expression of slow-tonic and EOM-speci fi c myosin heavy chain (MyHC)

isoforms, as well as decreased numbers of en grappe neuromuscular junctions (Zhou

et al. 2009, 2011 ) , resulting in extraocular muscles that have increased similarity to

limb muscle.

17.3 Fiber Types and Contractile Properties

Limb and body skeletal muscles express four main MyHC isoforms, types IIA, IIB,

IIX, and type I; while these can be co-expressed in a variety of patterns, they still

only express these four isoforms. As we have seen, all the craniofacial muscles

included in this book, as well as muscles within the soft palate and associated with

the ear (Ståhl and Lindman 2000 ; Jung et al. 2004 ) , are predominantly fast twitch

muscles. With the possible exception of the muscles of facial expression, the craniofacial

muscles express “unusual myosins.” These include the alpha-cardiac and

the fetal MyHC isoforms (Stål et al. 1994 ; Korfage et al. 2005 ) . In addition individual

subsets of craniofacial muscles express muscle-speci fi c myosins such as the

Table 17.1 Development

Muscle type Genetic control Mesodermal source

Limb muscles Pax3 Somitic mesoderm

Tongue Pax3 Somitic mesoderm

Laryngeal muscles Tbx1 Pharyngeal arch 3

Facial muscles Tbx1 Pharyngeal arch 2

Masticatory muscles Tcf21 (partial loss,Tbx1), Pitx2 Pharyngeal arch 1

Extraocular muscles Pitx2 Non-segmented cranial mesoderm

17 Comparison of the Craniofacial Muscles: A Unifying Hypothesis

327

Table 17.2 Myosins and muscle contractile properties

Muscle type Myosins

Unloaded shortening

velocities (Vo) (ML/s)

Twitch contraction

times (ms)

Limb 4

a

2.2–3.7 14–22

Tongue 8, but majority are same ?

b

8–33

as limb

Laryngeal 6

a

4–5 3–7 c

Facial 4

d

8.5–33

Masticatory 8 including masticatory

e

2.2 13–32

speci fi c

Extraocular ³ 9 including EOM speci fi c 19 f 5.27

ML/s muscle lengths per second

? indicates no one has published this measurement in tongue muscle

a

Larsson and Moss ( 1993 ) and Sciote et al. ( 2003 )

b

(Sokoloff ( 2000 )

c

Hinrichsen and Dulhunty ( 1982 )

d

Lindquist ( 1973 )

e

Toniolo et al. ( 2004 )

f

Asmussen et al. ( 1994 ) and McLoon et al. ( 2011 )

superfast MyHC in the jaw-closing muscles (Hoh 2002 ) and the EOM-speci fi c

MyHC in the EOM and variably in the laryngeal muscles (Wieczorek et al. 1985 ;

Shiotani and Flint 1998 ; Toniolo et al. 2005 ) . These diverse MyHCs are combined

in single fi bers, and this complexity of MyHC isoform co-expression results in

myo fi bers with a greater range of shortening velocities (Morris et al. 2001 ; Sciote

et al. 2002 ; McLoon et al. 2011 ) . There is also a mismatching of myosin light chains

(MLC) with the various MyHC isoforms (Stål et al. 1994 ; Bergrin et al. 2006 ; Bicer

and Reiser 2009 ) . Thus, the craniofacial muscles demonstrate that one motor neuron

does not connect to myo fi bers of only one MyHC or MyLC isoform, but rather

controls the contraction characteristics of groups of myo fi bers with different MyHC

compositions (Kwa et al. 1995 ) . This is hypothesized to result from their distinct

embryological origins.

The masticatory, laryngeal, and extraocular muscles in particular display

extremely fast shortening velocities, the fastest of any mammalian skeletal muscles

(Table 17.2 ; Close and Luff 1974 ; Asmussen et al. 1994 ) , although it should be

pointed out that the masticatory muscles also have myo fi bers that are slower than

those seen in limb muscle (Morris et al. 2001 ) . EOM and laryngeal muscles also

contain slow tonic MyHC along a portion of their length (Jacoby et al. 1989 ; Hoh

2005 ) . As a group, the craniofacial muscles are fatigue resistant (Asmussen and

Gaunitz 1981 ; Fuchs and Binder 1983 ; Prsa et al. 2010 ) . Fatigue resistance in these

muscles is associated with the unusual co-expression of succinic dehydrogenase

(SDH) and glycerophosphate dehydrogenase (GPDH) in single myo fi bers, enzymes

involved in oxidative and glycolytic energy pathways, respectively (Asmussen et al.

2008 ) . These complex fi ber types and specialized contractile characteristics increase

the functional repertoire of these muscles, presumably critical for their ability to

adapt quickly to changing physiological needs.


17.4 Adaptability

Another explanation for the diversity of myo fi ber types is that it is a sequella of their

rapid adaptability in response to local changes in muscle activation and stretch,

hormones, and the like (Korfage et al. 2005 ) . The craniofacial muscles respond

rapidly to perturbations such as functional denervation (Ugalde et al. 2005 ; Spencer

and McNeer 1987 ) , yet still maintain relative overall normalcy relative to fi ber types

and function (Wu et al. 2004 ) . This ability may be due, in part, to their myogenic

precursor cell populations which retain the ability to express craniofacial musclespeci

fi c properties when placed in vitro (Kang et al. 2010 ) . In addition, at least

extraocular, laryngeal, and pharyngeal muscles contain a population of myogenic

precursor cells which continue to divide and fuse into normal myo fi bers continuously

throughout life (McLoon and Wirtschafter 2002, 2003 ; McLoon et al. 2004 ;

Goding et al. 2005 ) . We have postulated that this ability may play a role in their

differential sparing in aging and skeletal muscle disease (Kallestad et al. 2011 ) .

How these myogenic precursor cell populations affect muscle function is illustrated

by the demonstration that even 2 years after denervation, human laryngeal muscles

contain activated myogenic precursor cells (Donghui et al. 2009 ) , in contrast to the

atrophy that is seen after similar lengths of denervation in limb skeletal muscle

(Borisov et al. 2005 ) , and allows successful reinnervation of denervated laryngeal

muscles even 2 years later (Tucker 1978 ) . We and others have shown that there is

minimal atrophy in the denervated laryngeal muscles, except for the vocalis muscle,

even at 24 weeks (Wu et al. 2004 ; Shinners et al. 2006 ) . The ability of extraocular

and facial muscles to maintain relative normalcy after injections of local anesthetics,

known to be myotoxic in limb skeletal muscles (Porter et al. 1988 ; McLoon and

Wirtschafter 1993 ) , also suggests a rapid capacity to respond to injury such that

relatively normal muscle morphology is maintained. As these muscles are required

for basic functions of life, maintaining an open airway for example, this ability

would allow these functions to be minimally affected.

17.5 Disease Sparing

One area that is particularly striking, but not well understood, is the differential

ability of various craniofacial muscles to be spared from select skeletal muscle

diseases. While some small degree of change from normalcy often can be seen in

these muscles, they are generally comparatively spared relative to the degeneration

seen in limb skeletal muscle in animal models and patients suffering from these

degenerative diseases. Several speci fi c examples will be used as illustration, but this

chapter is not meant to be a complete review of this topic (Table 17.3 ).

In the continuum of skeletal muscle allotypes, extraocular muscles appear to

represent the far end of the continuum. They are spared in a myriad of skeletal


329

Table 17.3 Susceptibility of muscle types to disease and aging

Muscle type Disease sparing Aging

Limb muscles No Yes

Tongue ? No

Laryngeal muscles DMD, congenital muscular dystrophy Some evidence of weakness

type 1A

Facial muscles Myotonic dystrophy Delayed compared to limb

muscle

Masticatory muscles “Critical illness” myopathy,

spinocerebellar ataxia type 3

Delayed compared to limb

muscle

Extraocular muscles DMD, Becker, congenital muscular

dystrophy, a -sarcoglycan de fi ciency,

merosin-de fi cient muscular dystrophy,

actin myopathies, dermatomyositis

? sparing propensity unknown

Few to none; some evidence

of mitochondria de fi cits

with aging

muscle diseases, including Duchenne and Becker muscular dystrophy (Khurana

et al. 1995 ; Kaminski et al. 1992 ) , laminin alpha2-chain-de fi cient congenital muscular

dystrophy (Kjellgren et al. 2004 ) , sarcoglycan-and merosin-de fi cient dystrophies

(Porter and Karathanasis 1998 ; Porter et al. 2001 ) , alpha-actin diseases

(Ravenscroft et al. 2008 ) , and even dermatomyositis (Scopetta et al. 1985 ) . The

laryngeal muscles are also morphologically and functionally spared in Duchenne

muscular dystrophy (DMD) (Marques et al. 2007 ; Thomas et al. 2008 ) , as well as

congenital muscular dystrophy type 1A (Häger and Durbeej 2009 ) . Reports differ as

to the morphologic sparing or involvement of the masticatory muscles in DMD

(Muller et al. 2001 ; Spassov et al. 2010 ) . Functionally, the masseter in particular

becomes weaker as the disease duration increases (Botteron et al. 2009 ) , although

the extent of loss in force production is not as dramatic as seen in the limb muscles.

The tongue becomes hypotonic and shows morphologic signs of muscle degeneration

(Kiliaridis and Katsaros 1998 ; Spassov et al. 2010 ) ; however, the orbicularis

oris is less affected than either the tongue or the masticatory muscles (Kiliaridis and

Katsaros 1998 ) . These complex patterns of sparing and/or involvement of the craniofacial

muscles in DMD vary according to the age of the mdx mouse or patient, but

generally their overall pathology is less than seen in limb skeletal muscles (Muller

et al. 2001 ) .

Myotonic dystrophy 1 results in some saccadic slowing, but other aspects of eye

movements are normal (Di Constanzo et al. 1997 ) . While laryngeal muscles are

spared in congenital muscular dystrophy type 1A (Häger and Durbeej 2009 ) , the

tongue, masticatory, and facial muscles show reduced strength as the disease progresses

(Odman and Kiliaridis 1996 ; Eckardt and Harzer 1996 ; Sjögreen et al.

2007 ) . Thus, there appears to be a continuum within the different groups of craniofacial

muscles relative to disease sparing. It is hypothesized that this may be due to

the different genes that control their early development and the maintenance of the

adult phenotype in each of these muscles.


17.6 Aging

Aging also affects the craniofacial muscles differently than limb skeletal muscles.

Again, while some alterations from normal have been described, relative to the

signi fi cant atrophy that can be seen in aging skeletal muscle, the craniofacial muscles

remain relatively normal. We will give some examples (Table 17.3 ), but this is

not meant to be a complete summary of the work in this fi eld.

As might be expected from the differential susceptibility to disease, aging affects

each craniofacial muscle group differentially. Extraocular muscles again show the

fewest age-related changes both morphologically and functionally (Yang and

Kapoula 2008 ; Valez et al. 2012 ) , although some changes in connective tissue density

and an increase in mitochondrial defects occur (McMullen et al. 2009 ) . Masseter

also shows constancy in muscle structure and function during aging (Norton et al.

2001 ) . Laryngeal muscles display fewer age-related changes compared to limb

muscle, but still show elevation in connective tissue, some increased variation in

myo fi ber cross-sectional area, changes in neuromuscular junction structure (Connor

et al. 2002 ), plus less force and slower shortening velocity (Kersing and Jennekens

2004 ; McMullen and Andrade 2006, 2009 ) . In facial muscles, while the skin undergoes

signi fi cant loss of elastin, the facial muscles themselves are normal (Lee et al.

2011 ) . Aging changes in tongue muscles are quite interesting; aging retrusive tongue

muscles do not show a decrement in overall contractile speed or force production,

but signi fi cant changes in forces is seen in aging protrusive tongue muscles (Nagai

et al. 2008 ; Connor et al. 2009 ) . The basis for this difference in unclear. However,

all of the changes in craniofacial muscles are relatively minor compared to those

seen in aging limb skeletal muscle where signi fi cant atrophy, fat conversion, fi brosis,

and denervation changes can occur.

17.7 Conclusions and Future Studies

It is clear from the collective chapters in this book that one cannot draw conclusions

about structure and function of craniofacial muscles from the study of limb skeletal

muscles. Their behavior cannot be predicted by studies of limb skeletal muscle;

often they change in diametrically opposed ways in the presence of myogenic signaling

factors (Tzahor et al. 2003 ) or during aging (Monemi et al. 1999 ) . The craniofacial

muscles appear to represent one end of the continuum of skeletal muscle

types in the body, with the relatively more homogeneous soleus at one end and

extraocular and laryngeal muscles at the other. Except for tongue muscles, from

their onset craniofacial muscles are derived from non-segmented, non-somitic

cranial mesoderm, with different genes controlling their formation compared to

those that direct the formation of somitic muscle. The mature muscles each display

a relatively unique set of contractile and metabolic proteins, which are mirrored in

the collective physiological and contractile differences seen in the craniofacial


331

muscles compared to those in limb skeletal muscle. From a clinical viewpoint, they

represent both challenges and opportunities in their differential propensity for or

sparing from limb skeletal muscle diseases and pathology.

There is a great deal more work that needs to be done before we understand the

basis for the molecular, cellular, and physiological differences between the craniofacial

and limb skeletal muscles. They are complex muscles, dif fi cult to study, and

few laboratories are studying them. This, however, provides for opportunity, as the

clinical potential for understanding how these muscles function and the mechanism(s)

for their preferential sparing from or involvement in skeletal muscle diseases should

yield important new approaches for the treatment of limb skeletal muscle pathology

as well as ways to treat craniofacial muscle pathology.

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Index

A

Abducens nucleus

vs. lateral rectus motoneurons , 64

neuroanatomy , 58–59

neurophysiology

eye movements, neural response , 61–62

eye position sensitivity , 62

motoneuron discharge , 62

saccadic eye movement and eye

velocity , 62–64

and oculomotor nuclei, anatomical

connection , 59–61

Adenosine triphosphate (ATP) , 147–148

Adnexal disease , 288

Alopecia , 307

a -glycerophosphate dehydrogenase , 43

Amyotrophic lateral sclerosis (ALS) , 6

extraocular muscles , 82–84

laryngeal muscle response , 190–192

Anterior cingulate cortex (ACC) , 232, 233

Apraxia , 293–294

B

Benign essential blepharospasm (BEB) , 289

b -catenin , 18

Bilateral facial palsy , 270, 282

Blepharoptosis , 303–304

Blepharospasm

adnexal disease , 288

clinical features

anatomic changes , 291

dry eye , 291

excessive blinking, eye , 290

JRS score , 290

parkinsonian symptoms , 291

retro-orbital discomfort , 290

spasmodic dysphonia , 291

CNVII facial nerve , 288

cranial dystonia , 288

differential diagnosis

eyelid myokymia , 294–295

eyelid opening apraxia , 293–294

Meige syndrome , 294

re fl ex blepharospasm , 293

epidemiologic features , 289

oromandibular dystonia , 289

pathophysiologic features , 291

Bony orbit , 33

Botulinum neurotoxin (BoNT) injection

anaerobic bacteria strains , 297

antitoxin antibody , 302

Botox

®

, 300

botulinum neurotoxin preparation ,

298, 299

cholinergic hyperactivity , 297

complications

after injection , 303–305

during injection , 303

contraindications , 303

Dysport ® , 301

erythema, eyelid , 302

neurotoxin acts , 300

SNAP-25 , 300

type A , 298

type B , 298

Xeomin

®

, 301

Brain-derived neurotrophic factor

(BDNF) , 197

Brueghel syndrome , 289

Bruxism , 134

Button-hole skin defect , 307



DOI 10.1007/978-1-4614-4466-4, © Springer Science+Business Media New York 2013

337

338 Index

C

Central pattern generator

(CPG) , 115, 233, 235

Cerebral cortex, masticatory muscle

intracortical microstimulation , 122–124

movements types , 121–122

neuronal recording and ablation

fi nding , 124–125

Cervical dystonia , 288

Chronic lymphedema , 304, 308

Chronic progressive external ophthalmoplegia

(CPEO) , 79–81

Ciona intestinalis , 22

Conjugate horizontal eye movements

abducens nucleus

anatomical connection , 59–61


neurophysiology , 61–64

horizontal recti , 58

oculomotor nucleus


neurophysiology , 66

Corneal ulcers , 266

Cortical masticatory area (CMA) , 115

Cranial dystonia , 288

Cranial nerves

EOM innervation , 34, 51

facial nerve ( see Facial nerve)

hypoglossal nerve, motor

activation , 230–232

motor nuclei , 116, 117

sucking rhythm generators , 237

tongue sensation , 232–233

Cranial neural crest cells

head muscle development , 19–20

masticatory muscles , 132

Craniofacial muscles

adaptability , 328

aging , 330

disease sparing , 328–329

embryology , 326

extraocular muscle ( see Extraocular

muscle (EOM))

facial muscles ( see Spastic facial muscle

disorders)

fi ber types , 326–327

future aspects , 330–331

head ( see Head muscle development)

head and neck evolution , 4

larynx ( see Laryngeal muscle)

masticatory muscle (see Masticatory muscle)

mesodermal origin , 12

muscle function , 5

neuromuscular disease , 5–6

pharynx ( see Pharyngeal muscle)

physiological properties , 325

tongue ( see Tongue)

Cyclovertical eye movements

agonist–antagonist pair , 67

superior rectus and oblique

muscles , 66–67

trochlear motoneurons , 68

trochlear nuclei , 67–68

D

Diplopia , 79

BoNT injections , 304

EOM, thyroid disease , 82

Dizziness , 272

Dorsal medullary reticular column

(DMRC) , 233

Doxorubicin , 308

Dry eye , 304

Duchenne muscular dystrophy

(DMD) , 6, 16, 329

extraocular muscles , 84–85

laryngeal muscle response to

clinical characteristics , 187

cricothyroid (CT) muscle , 188–190

extracellular and intracellular

calcium , 187–188

lateral cricoarytenoid muscle , 188

medial and lateral thyroarytenoid

muscle , 188

muscle weakness , 188

Dyskinesias , 287–288

Dysport ® , 301

E

Ear pain , 271

Electromyography (EMG)

brainstem re fl exes , 119

cricopharyngeus (CP) muscle , 160

facial palsy , 272

jaw movement , 248

laryngeal muscle

amyotrophic lateral sclerosis , 190

cricothyroid muscle , 145

myasthenia gravis , 193

sternothyroid muscle , 155

swallowing , 146–147, 157

masticatory muscles

aged masticatory muscles , 135–136

DMD and ALS , 133

jaw-opening and jaw-closing

muscles , 119

Index

339

Embryonic myosin heavy chain , 95

Endomysial collagen , 102

Entactin , 97

Erythema , 302, 303

Essential blepharospasm. See also

Blepharospasm

clinical features , 289–290

de fi nition , 288–289

diagnosis and differential

diagnosis , 292–293

pathophysiology , 292

Evoked electromyography (EEMG),

facial palsy , 272

Exposure keratopathy , 304, 308

Extraocular muscle (EOM) , 12

amyotrophic lateral sclerosis , 82–84

anatomy

agonist/antagonist pairs , 33

bony orbit , 33

cranial nerves , 34

eye movements , 32

levator palpebrae superioris

muscle , 31–32

yoked muscles , 33

embryological origins , 34–35

mitochondrial disorders

chronic progressive external

ophthalmoplegia , 79–80

cytochrome-c-oxidase loss , 80–81

MELAS , 80

mtDNA mutations , 79–80

molecular expression

Krebs cycle , 43, 44

myosin-binding protein , 41

SERCA content , 42–43

motor control

conjugate horizontal eye movements

( see Conjugate horizontal eye

movements)

cyclovertical movements , 66–68

vergence movements , 68–69

motor innervation , 36–38

muscle fi bers , 36, 37

myonuclear turnover and

regeneration , 44–45

myosin heavy chain isoforms

hybrid fi bers , 41–42

limb and body skeletal muscle , 39

mismatched fi ber , 41, 42

orbital and global layers , 39

single fi ber segments , 42

neuromuscular diseases

Miller Fisher syndrome , 76–78

myasthenia gravis , 77–79

oculopharyngeal muscular

dystrophy , 81

thyroid disease , 81–82

Eye. See also Extraocular muscle (EOM)

biomechanical characteristics

“eye-pull” study , 52–53

Maxwell element , 53

ocular biomechanics , 53–56

plant modeling , 52, 55–57

Voigt elements , 52–53

conjugate horizontal movements


movements)



Eyelid creases , 307

Eyelid tics , 315

F

Face primary motor cortex (face MI) , 121

Face primary somatosensory area

(face SI) , 121

Facial nerve

aberrant regeneration of , 295

ablation , 309

anatomy

facial nerve (CNVII) function , 268

lacrimal secretions , 267

marginal mandibular and cervical

branches , 268

pontine lesions , 266

temporal branch , 267

voluntary facial expression , 266

zygomatic and buccal

branches , 267

palsy ( see Facial palsy)

Facial palsy

acute surgical management , 276

Bell’s palsy

age , 273–374

Copenhagen Facial Nerve

Study , 273

FPRI , 275

herpes simplex virus , 273

House–Brackmann system , 275

HZV diagnosis , 274

natural history , 273

pediatrics , 274

rheumatism , 273

bilateral facial palsy , 282

chronic surgical management

eyelids , 277–278

forehead , 278

340 Index

Facial palsy (cont.)

lower lip , 282

midface and mouth , 279–281

clinical examination and investigation

auditory system and otoscopy , 272

denervation , 271–272

dizziness , 272

ear pain , 271

electrophysiological testing , 272

salivation and stapedial re fl ex , 272

corneal ulcers , 266

etiology , 268–271

idiopathic paralysis , 265

life-threatening causes , 275

nonsurgical management , 276

subcutaneous muscular tension , 265

Facial paralysis recovery index (FPRI) , 275

Facial tics , 315

G

Global (GLOB) layer , 36, 37

Glottic closure re fl ex , 177

Goldenhar-Gorlin syndrome , 132

Graves’ disease , 81

Growth hormone (GH)–IGF axis , 100

Guillain–Barre syndrome (GBS) , 270

H

Head muscle development

cellular and molecular parallels , 12

EOM , 12

extrinsic regulation , 18–19

genetic programs , 16–17

hypobranchial muscles , 12

mesodermal origins , 13–14

patterning and differentiation , 19–20

pharyngeal arch-derived muscles

clonal analysis , 21

LIM-homeodomain protein Islet1 , 21

pharyngeal mesoderm evolution , 22

PM-derived cardiogenesis , 20–21

satellite cells , 14–16

somites , 12

tongue muscles , 12

Hemifacial microsomia , 132

Hemifacial spasm

clinical features , 310

CNVII facial nerve , 310

differential diagnosis , 312

pathophysiologic features , 311

treatment

BoNT Injection , 312

neurosurgical decompression , 313

oral medication , 312–313

precipitating factors , 313–314

Heparan sulphate proteoglycans (HSPG) , 97

High-resolution manometry (HRM) , 160

House–Brackmann system , 275

Hyoid positions, tongue , 230

Hyo-laryngeal complex elevation , 175

Hypobranchial muscles , 12

Hypoesthesia , 308

Hypoglossal (cranial nerve XII)

motor neurons , 230

Hypoxia , 235

I

IGF binding proteins (IGFBPs) , 100

Insulin-like growth factor (IGF) , 100

Intracortical microstimulation (ICMS) , 122

Intrinsic laryngeal muscles

(ILMs) , 147, 151

breathing , 145–146

canine larynx , 143, 144

classi fi cation , 141–143

denervation and reinnervation effects

morphology , 196

MyHC isoforms , 197

PCA samples , 198

RLN nerve section , 197–198

TA muscle biology , 197

fi ber’s energy supply , 147

LCA muscle , 145

mitochondrial density , 148–149

MyHC , 149–151

nerve–muscle connections , 151–153

permanent rhythmic activity , 145

phonation movements , 143

slow tonic fi bers , 150–151

slow vs. fast muscle fi ber types , 147–148

swallowing , 146–147

TA muscle

activition , 146

components , 144–145

vocal fry , 145

J

Jaw–tongue coordination , 233

K

Krebs cycle , 43, 44

Index

L

Lagophthalmos , 304, 308

Laminin , 97

Laryngeal adductor response (LAR) , 177

Laryngeal mechanoreceptor stimulation , 235

Laryngeal muscle

amyotrophic lateral sclerosis , 190–192

anatomical and physiological differences ,

185

biological and functional diversity , 186

extrinsic muscles

swallowing , 156–157

voice production and modulation ,

154–156

ILMs ( see Intrinsic laryngeal muscles

(ILMs))

limb vs. craniofacial muscles

neuromuscular disease and injury , 187

unique phenotypes , 186–187

motor control and biomechanics

automatic motor control , 168–169

central nervous system control ,

170–171

central neural control , 178

innervation , 170–171

neurological diseases , 178–179

sensory-motor interactions control ,

177–178

neuromuscular disease

limb and craniofacial muscle

response , 187

muscular dystrophy , 187–190


peripheral paralysis , 194

recurrent laryngeal nerve paralysis

bilateral , 194–195

unilateral , 194

superior laryngeal nerve paralysis ,

195–196

Lateral cricoarytenoid (LCA) , 143

Lateral pterygoid muscle , 93

Levator palpebrae superioris muscle , 31–32

LIM-homeodomain protein Islet1 (Isl1) , 21

Listing’s law , 54–55

Lyme disease , 270

M

Masseter muscle , 99

anatomy , 93

craniofacial skeletal parameters , 94

Frankfort horizontal plane , 94

MRI scans , 93–94

vs. non-cranial muscles , 102

341

satellite cell nuclei , 99

TIMP-1 expression , 98

type II fi bres in , 96

Masticatory muscle

aging

animal studies , 135

EMG activity , 135–136

fi ber type and MyHC isoform , 135

myosin composition and synapse

remodeling , 134–135

anatomy

lateral pterygoid muscle , 93

masseter muscle ( see Masseter muscle)

medial pterygoid muscle , 92–93

temporalis muscle , 92

biochemistry , 97–98

biomechanics

jaw movement , 113

motor function , 113, 115

multi-axis force transducer and axes

orientation , 113, 114

bruxism , 134

characteristics , 131

cortical neuroplasticity and control

ICMS-evoked tongue motor

response , 126–127

jaw-opening and tongue-protrusive

muscles , 123, 126

pain adaptation model , 127

structure and function , 125–126

developmental anomalies , 132

motor function

chewing , 116

cyclic jaw movements , 116

voluntary movements , 115

myosin heavy chains

embryonic and neonatal , 95

extraocular MyHC , 96

gene expression , 96–97

isoforms , 94

jaw-closing mechanism , 96

jaw-opening mechanism , 96

masticatory , 95

neural process

brainstem re fl exes , 118–119

cerebral cortex process , 121–125

CNVII and CNXII motor nuclei ,

117–118

descending modulatory in fl uences , 115,

119–120

peripheral mechanisms , 117

subcortical processes , 115, 120–121

oromandibular dystonia , 134

pain , 134

342 Index

Masticatory muscle (cont.)

primary pathology

DMD , 133


Parkinson’s disease , 134

regeneration and adaptation

animal models , 99

fi broblasts , 102

growth factor , 100

macrophages , 101–102

satellite cells ( see Satellite cells)

stem cell niche , 101

sparing in

critical illness myopathy , 133

DMD and ALS , 133

SCA forms , 132

trismus , 134

Matrix metalloproteinases (MMPs) , 97, 98

Maximal stimulation test (MST) , 272

Maxwell element , 53

Medial pterygoid muscle , 92–93

Meige syndrome , 289, 294

Miller Fisher syndrome (MFS) , 76–78

Mitochondrial disorders, EOM

chronic progressive external

ophthalmoplegia , 79–80

cytochrome-c-oxidase loss , 80–81

MELAS , 80

mtDNA mutations , 79–80

Motor activation, hypoglossal nerve , 230–232

Motor control

extraocular muscle

conjugate horizontal eye movements


movements)



laryngeal muscle


central nervous system control ,

170–171





177–178

masticatory muscle ( see Masticatory

muscle)

pharyngeal muscle



genioglossus , 172


inspiration dilator muscles , 173, 175



177–178

swallowing constrictor muscles , 174,

175

tongue ( see Tongue)

Motor unit potential (MUP) reinnervation , 133

Muscle-speci fi c kinase (MuSK) , 78

Muscular dystrophy , 187–190. See also

Duchenne muscular dystrophy

(DMD)

Myasthenia gravis (MG)

extraocular muscle , 77–79

laryngeal muscle , 193

masticatory muscle , 133–134

Myectomy , 307–308

Myoblasts , 13, 19

Myogenic regulatory factor (MRF) , 11

Myokymia , 294–295, 314

Myosin heavy chain (MyHC) , 37, 38, 147,

196, 234

extraocular muscle

hybrid fi bers , 41–42

limb and body skeletal muscle , 39

mismatched fi ber , 41, 42

orbital and global layers , 39

single fi ber segments , 42

isoforms , 96, 236, 327

masticatory muscle

embryonic and neonatal , 95

extraocular MyHC , 96

gene expression , 96–97

isoforms , 94

jaw-closing mechanism , 96

jaw-opening mechanism , 96

masticatory , 95

Myotonic dystrophy , 329

N

Neonatal myosin heavy chain , 95

Nerve growth factor (NGF) , 197

Neurodegenerative disorders , 295–296

Neuromuscular disease , 5–6

extraocular muscle

Duchenne muscular dystrophy , 84–85

Miller fi sher syndrome , 76–78


OPMD , 81

laryngeal muscle

limb and craniofacial muscle

response , 187

Index

muscular dystrophy , 187–190


muscular hydrostat , 242

sensational disorders , 241

tongue kinematics ( see Tongue kinematics)

tongue musculature , 241, 259

volumetric reduction and motor function

( see Volumetric reduction, tongue)

Neuromyotonia , 314

Nico-tinic acetylcholine receptor , 38

Nucleus tractus solitarius (NTS) , 233

O

Ocular biomechanics , 53–56

Oculomotor nucleus , 64–66

Oculopharyngeal muscular dystrophy

(OPMD) , 6, 81

Orbital hemorrhage , 307

Orbital (ORB) layer , 36–38

Oromandibular dystonia , 134, 289

P

Paralysis , 267

Paralysis musculorum faciei rheumatica , 273

Parkinson’s disease , 292

Periorbital contour deformity , 304, 308

Pharyngeal arch , 132

Pharyngeal mesoderm (PM)

domains , 13

evolution , 22

progenitors , 20

Pharyngeal muscle

motor control and biomechanics



genioglossus , 172


inspiration dilator muscles , 173, 175



177–178

swallowing constrictor muscles ,

174, 175

muscle fi ber types , 142–143, 158

pharyngeal movement , 142–143, 157

structure and function , 142–143, 158

UES

CP innervation , 159–160

CP muscle dysfunction , 160–161

cricopharyngeus muscle , 159

HRM , 160, 161

manometry measurements , 158

muscle fi ber properties , 159

Pharyngoesophageal segment (PES) , 158

Photooculodynia , 309

Pontine lesions , 266

Posterior cricoarytenoid muscle (PCA) , 143

R

Rapsyn , 78

Respiration, tongue , 218, 234–235

Rhythmic activity bursts, tongue , 247

Ryanodine , 78

343

S

Sarcolemma , 98

Satellite cells

animal models , 99

classic quail-chick chimera

experiments , 99

FGF and IGF-I , 100

fi bre type distribution , 98

head vs. trunk-derived muscles , 16

lineage tracing techniques , 15

masseter muscle , 99

myonuclear turnover and regeneration ,

44–45

Pax3 expression , 16

sarcolemma , 98

self-renewal mechanism , 15

Skin necrosis , 307

Somatic sensation, tongue , 232–233

Somites , 12

Sonic hedgehog (Shh) , 18

Spasmodic dysphonia , 291

Spasmodic torticollis , 291

Spastic facial muscle disorders

blepharospasm ( see Blepharospasm)

drug-induced facial dyskinesias , 296–297

dyskinesias , 287, 288

eyelid/facial tics , 315

facial nerve synkinesia , 295

hemifacial spasm ( see Hemifacial spasm)

myokymia , 314

neurologic disorders , 295–296

neuromyotonia , 314

psychological problems , 296

superior cervical ganglion block , 309

treatment

BoNT injection ( see Botulinum

neurotoxin (BoNT) injection)

chemomyectomy , 308–309

344 Index

Spastic facial muscle disorders (cont.)

myectomy , 307–308

neurectomy , 309

oral medications , 306

psychotherapy , 305–306

selective facial nerve (CNVII)

ablation , 309

superior cervical ganglion block , 309

Suc-cinic dehydrogenase , 43

Superior cricoarytenoid (SCA) , 188

Swallow expansion device (SED) , 161

T

Tardive dyskinesia , 296–297

Temporalis muscle , 92

Temporomandibular disorders (TMD) , 112

Thyroarytenoid muscle (TA) , 143

Thyroid-associated ophthalmopathy

(TAO) , 81–82

Thyroid disease , 81–82

Tissue inhibitors of the metalloproteinases

(TIMPs) , 97, 98

Titin , 78

Tongue , 207–208

biomechanics , 230, 242

functions

food manipulation , 235–237

protrusion , 233–234

respiration , 234–235

retrusion , 233–234

speech , 237–238

suckling and swallowing , 235–237

hypoglossal nerve, motor activation

dorsal compartment , 232

hypoglossal nucleus , 230, 231

innervation , 230

motoneuron projections , 230, 231

kinematics

chewing , 245

crystal pairs locations , 244, 245

drinking cycle , 245–246

expansion–contraction , 246

hypoglossal motor system , 243–244

ingestion cycles , 245

jaw movement and muscle

activity , 248–250

mastication , 245

pharyngeal constrictor , 245

post-injury adaptations , 251

respiration , 246–247

rhythmic activity bursts , 247

spatio-temporal coupling , 247–248

swallowing , 245

ultrasonic crystal array , 242, 243

volumetric mass reduction

( see Volumetric reduction, tongue)

mastication , 218

movement, neuromuscular basis

anatomy and localization , 217–218

MEP morphology and muscle fi ber

innervation , 216

physiology , 215–216

theoretical considerations , 215–216

muscle fi ber biochemistry

aging , 222–223

capillarization and oxidative

metabolism , 221–222

MyHC composition , 220–221

MyHC isoform , 219–220

speech production , 218

muscular anatomy

deformable solid , 209–211

muscle anatomy and


primarily longitudinal

orientation , 214–215

primarily transverse

orientation , 213–214

respiration , 218

somatic sensation , 232–233

type II tongue, animals , 229

Tonic-positive myo fi bers , 43

Tourette’s syndrome , 315

Transcranial magnetic stimulation

(TMS) , 121, 172

Trismus , 134

Trunk muscle-associated satellite

cells , 16

U

Upper esophageal sphincter (UES) , 158

V

Vagal nerve injury , 171

Vergence eye movements , 68–69

Vestibulo-ocular re fl ex , 55

Visible scar , 308

Voigt elements , 52–53

Volumetric reduction, tongue

craniofacial growth and dentition

formation , 257–259

mass reduction and tongue kinematics

food leaking , 252

functional modi fi cation , 252

genioglossus , 251

Index

345

hydrostat mass reduction , 251

maladaptation , 253

muscular mass reduction , 252

morphological and histologic

consequences

immunohistochemical study , 256

mandibular dentition , 253, 254

partial fi brosis , 257

sham tongues comparison , 255

surgical incisions , 254

surgical injury , 257

W

Wallenberg syndrome , 171

X

Xeomin

®

, 301

Xeropthalmia , 267

Y

Yoked muscles , 33

Craniofacial Muscles

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