mastication and its control by the brain stem · critical reviews in oral biology and medicine,...

Critical Reviews in Oral Biology and Medicine, 2(1):33—64 (1991)

Mastication and its Control by the Brain Stem

J. P. LundDepartment de Stomatologie and Centre de Recherche en Sciences Neurologigues, Ds24, Pav.Prine, Universite de Montreal, CP 6128, Succ A, Montreal, Canada H3C 3J7.

ABSTRACT: This review describes the patterns of mandibular movements that make up the whole sequencefrom ingestion to swallowing food, including the basic types of cycles and their phases. The roles of epithelial,periodontal, articular, and muscular receptors in the control of the movements are discussed. This is followedby a summary of our knowledge of the brain stem neurons that generate the basic pattern of mastication. It issuggested that the production of the rhythm, and of the opener and closer motoneuron bursts, are independentprocesses that are carried out by different groups of cells. After commenting on the relevent properties of thetrigeminal and hypoglossal motoneurons, and of internuerons on the cortico-bulbar and reflex pathways, theway in which the pattern generating neurons modify sensory feedback is discussed.

KEY WORDS: motor control, central pattern generation, mastication, brain stem, motoneurons, reflexes,sensory afferents, interneurons, deafferentation, paralysis.

I. INTRODUCTION

Mastication is the first stage of digestion inmost mammals. It is an intermittant rhythmic actin which the tongue, facial, and jaw muscles actin coordination to position the food between theteeth, cut it up, and then prepare it for swallow-ing. During the course of evolution, the mam-malian jaws and dentitions have evolved in severaldirections from their reptillian prototype in orderto take maximum advantage of the various classesof food that exist.12 Now there are several gen-eral groups of animals with distinct types of mas-ticatory systems. For example, carnivores areadapted to shear meat into pieces and swallowthem with little chewing, while herbivores arespecialized for the almost continuous grinding offibrous food. Although the movements that a cowuses to chew its cud are obviously different fromthose of a dog crunching up bones, there appearto be some features that are the same in all mam-mals that chew, and this suggests that the fun-

damental mechanisms of control are common toall.

II. PATTERNS OF MOVEMENT

The determination of the basic features ofmastication depends on adequate descriptions ofthe patterns of movement and muscle activity,and on comparisons between species. Good de-scriptions of mastication can be found for theopossum,3 cat,45 rat,6 hamster,7 and rabbit,89 butit is unfortunate that there are no comparabledescriptions of human mastication that includethe sequential changes in the form of the mas-ticatory cycle and in the patterns of muscleactivity.

We lack a common terminology, and thismakes the interpretation of data from differentlaboratories and from different species difficult.Since no system of classification is in generaluse, I will use one that was developed from work

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on the rabbit,911 and that in turn is based in largepart on that of Hiiemae.312 This system has threeadvantages: (1) it describes the whole process ofmastication from ingestion to swallowing, (2) itis simple, and (3) it is analogous to the termi-nology used for locomotion, so that comparisonsbetween the two motor systems are easier to make.Descriptions of the various terminologies that havebeen proposed can be found in Hiiemae12 andSchwartz et al.9 Although it has been said thatthe pattern of mastication is stereotyped,1315 thereis, in fact, a great deal of variability betweencycles within the same series of movements (Fig-ure 1), between foods,5 and between individualsubjects.1617 We should not ignore this charac-

teristic, nor try too hard to describe masticationin terms of an average cycle or typical envelopethat contains most movements.1819 Uncoveringthe relationships between the different variableshelps us to understand the system that controlsthe movements. As will be seen, the evidencesuggests that sensory inputs to the brain stemcause most of the variability by modifying a reg-ular centrally generated pattern.

A. Masticatory Sequence

The masticatory sequence (Figure 2) is thewhole set of movements from ingestion to swal-

FIGURE 1. Two-dimensional frontal view of the movement of the mandible of anadult female subject chewing dried beefstick. These data were recorded with amodel 5 kinesiograph. (Stolhler, C. S., unpublished work.)

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PREPARATORYSERIES

CR43A7.722

VERT

PRESWALLOWINGSERIES

26,

FIGURE 2. A masticatory sequence from an awake rabbit. The head was fixed during the recording ofmovements of the mandible with a photodiode system. A piece of rabbit chow was put into the mouth (left),transported to the molar teeth during the preparatory series, chewed during the reduction series, and preparedfor swallowing (preswallowing series). Swallowing occurred during the THY burst. Cycles 4 to 6, 11 to 13,and 25 to 27 appear in Figure 3, while all the cycles of the preparatory and preswallowing series and 5reduction series trials marked with the horizontal bars were used for Figure 4. Abbreviations: VERT, LAT, A-P-vertical, lateral, and anterior-posterior movements of a small light attached to the mandibular symphysis;RDIG-, LDIG-, RDMA-, LDMA-, RPTE-, THY-electromyograms from the right (R) and left (L) digastric, deepmasseter, medial pterygoid, and thyrohyoid muscles, respectively. (From Schwartz, G., Enomoto, S., Vali-quette, C, and Lund, J. P., J. Neurophysioi, 62, 273, 1989. With permission.)

lowing.20 It is made up of masticatory cycles thatchange in form as the food is gathered, movedbackward to the molar teeth, then broken downand prepared for swallowing. The following de-scription of the process is based on the behaviorof the rabbit, with frequent references to otherspecies. Many of the experiments on the neuralcontrol of mastication were also performed onrabbits or on guinea pigs, which chew in a similarway.

Once food has been ingested, rabbits use threebasic types of cycles that differ in shape, dura-tion, and number of phases to prepare it for swal-lowing. We called the cycles types I, II, and III(Figure 3). Type I cycles occur at the beginningof the masticatory sequence and form the prep-aratory series of movements (Figure 1). This isfollowed by the reduction series (mainly type IIcycles) and the preswallowing series (type III).

1. Preparatory Series

There is great inter-species variability in theway in which food is gathered and broken intochewable pieces.12 Most herbivores crop leaves,rodents, and lagomorphs (rabbits and hares) gnaw,while other species cut meat into pieces or breakthe shells of insects.4-5-21'22 Afterward, the foodis moved to the posterior teeth by the tongue,5-20-23

aided in some animals by tossing of the head.4

Movements of the head are not of much impor-tance in rabbits.8 They move the food backwardduring a short series of type I cycles that haveonly two phases, fast closing (FC) and opening(O) (Figure 3). There is usually little lateralmovement during closure (Figure 4A) or electro-myographic activity (EMG) in the jaw-closingmuscles, but the digastrics (jaw-opening mus-cles) are very active (Figure 2). This series comes

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LDMA

RPTE

FC SC O, O2

cycle 26

FIGURE 3. Examples of the three main types of mas-ticatory cycle from the sequence shown in Figure 2,showing the phases and the automatic detection of thestart and end of the EMG bursts. (A) Type I cycle inwhich O and FC are indicated. Note the low level ofcloser muscle EMG activity in FC, the irregularity of thecloser muscle bursts in the first type II cycle, as wellas the intermittent digastric activity in the first half ofSC. (B) Type II cycles later in the series. The closerbursts are less irregular, and there is little activity inthe digastrics during SC. (C) Type III cycles illustratingthe pause between closer and opener activity duringO1 and 02 . (From Schwartz, G., Enomoto, S., Vali-quette, C , and Lund, J. P., J. Neurophysiol., 62, 273,1989. With permission.)

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RIGHT CLOSECR43A7.713

LEFT ANTERIOR CLOSE POSTERIOR

OPEN OPEN

I I l I l I i i i i i i i i

FIGURE 4. Two-dimensional frontal views of man-dibular movements in the rabbit from the sequenceshown in Figure 2. Type I (A), type II (B), and type IIIcycles (C) are shown. The arrows give the direction ofmovement. (From Schwartz, G., Enomoto, S., Vali-quette, C , and Lund, J. P., J. NeurophysioL, 62, 273,1989. With permission.)

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to an abrupt end as the posterior teeth begin toreduce the food (Figures 2 and 3).

2. Reduction Series

Most of the breakdown of the food occurs inthis series of movements, which is the part ofthe masticatory sequence that is the best de-scribed in many papers. The movements of thereduction series are often called chewing cycles:12

we call them type II. Type II cycles have threephases in rabbits and in many other species, in-cluding man.132429 As well as O and FC, thereis a slow closing phase (SC, Figure 3B). Thedigastric burst begins at or soon after the end ofthe closer burst and gradually increases in am-plitude. The opening movement is smooth andfast in rabbits (Figures 3B and 4B), man, andmacaques,133032 but in many other species thereare two or three opening phases in the typicalcycle of the reduction series.5'20'21'23'33-34 In therabbit, this type of three-phase opening move-ment occurs mainly in the preswallowing series.

Since most animals chew unilaterally,23 thejaw usually moves to the working side during FC(Figure 4B). SC begins with the peak of dece-leration that is caused when the teeth engage thefood2935 (Figure 3b). The jaw-closing musclesare not very active during FC, but there is a rapidincrease in EMG activity within a few millise-conds of the start of SC, and the activity contin-ues to rise during the first half of the phase.4'915-29

As the lower jaw moves medially during SC (Fig-ure 4B), the food is ground between the upperand lower molars. For obvious reasons, this phaseis also called the power stroke.12 The verticalamplitude of the movements gradually falls dur-ing the reduction series as the size of the foodparticles gets smaller, and this continues duringthe preswallowing series.

3. Preswallowing Series

A period of preswallowing behavior has beendefined in rabbits, cats, and opossums,89-20 andprobably occurs in other species. As Figure 3Cshows, the type III cycles that compose the serieshave 5 phases: FC, SC, and three opening phases:

a brief but rapid early opening phase (Oj), a pause(O2), and final rapid opening phase (O3). Jaw-closer EMG activity ends prior to Oj, but thedigastric burst does not begin until the start ofO3 in rabbits; this suggests that the movement inO{ occurs passively.9

B. Relationship between Phase andCycle Length

It has been known for several years that thelength of all phases do not necessarily vary equallywhen the duration of the masticatory cyclechanges. For instance, Hiiemae312 and Thextonet al.5 showed that cycle duration of cats is bestcorrelated with the duration of early opening (O,and O2), while Morimoto et al.8 concluded thatthe duration of opening and of SC were bothimportant determinants of cycle length in the rab-bit. The situation was clarified by Schwartz etal.,9 who showed that relationship between theduration of the cycle and its constituent phasesdepends on cycle type.

Type I cycles are the shortest, FC and Odurations are about equal, and variations in thelength of both have an equivalent effect on cycleduration. In turn, the length of the two phases isdetermined by the duration of the digastric burst.The dependence of FC on digastric activity prob-ably occurs because the major jaw-closing mus-cles are almost inactive. Elastic recoil is then themajor force that closes the jaw, and the strengthof this will depend on the length of the stretchedcloser muscles.20-36

Type II cycles are intermediate in duration,longer than type I, but shorter than type III. Al-though O is still an important contributor, vari-ations in FC duration are uncorrelated with cycleduration. Most of the temporal variability in thecycle is due to changes in the SC phase.9 A sim-ilar relationship was found in humans chewinggum.31 In rabbits, the duration of SC is governedby the length of the bursts in the jaw-closingmuscles, particularly those on the working side.

Type III cycles are the longest, but this isnot due to a lengthening of the bursts in eitherjaw-opening or -closing muscles; it is caused bya pause between the end of the closer burst anddigastric burst (Figure 1). Most of the variation



in type III cycle duration is accounted for bychanges in the length of this pause, which in turncontrols O2 duration.9

C. Effect of Food

Differences in the type, number, and size offood pieces appear to influence almost all theparameters of mastication. The length of the mas-ticatory sequence is short for soft foods and longfor those that are hard or tough.5-37 Average du-ration of the cycles in monkeys, cats, and rabbitsincrease with the size and/or toughness offood.513-37 It is probable, though not proven, thatthis is due to the lengthening of SC. Masseteractivity during SC is greater when rabbits eatchow than when they chew carrot, which aresofter,37 and the duration and amplitude of mas-seteric bursts of humans are greater for hardchewing gum than for soft.38 The frontal two-dimensional profiles of human masticatory cyclestend to have a wider and more pronounced SCwhen chewing tough rather than soft foods.17

D. Summary

The evidence from the analysis of the mas-ticatory movements suggests that the control ofmastication is dependent in large part on sensoryfeedback. There is no other way to explain thecoordination of the tongue, lips, and jaws to movethe food around, the effects of different food-stuffs on the pattern of movement, or the abruptchanges from cycle to cycle.

III. ANIMAL MODELS

Animal models are necessary to study theneural mechanisms controlling the movements ofmastication in detail. These were of two basictypes: awake animals chewing on food, and an-esthetized or decerebrate preparations in whichjaw movements are induced by some type ofstimulus.

A. Behaving Animals

Unrestrained, awake preparations have beenused for some studies of masticatory control incats and rabbits.3941 A considerable amount ofinformation has also been derived from chronicexperiments of awake monkeys whose headmovements were restricted during the recordingsessions. These experiments have been particu-larly useful for studies of the behavior of neuronsin the sensorimotor areas of the cerebral cor-tex.4246 This topic will not be discussed here, buta review of these papers can be found in Luscheiand Goldberg14 and Lund and Enomoto.11

B. Other Preparations

Three types of stimulus have been used toinduce mastication in conscious and unconsciousanimals: mechanical, pharmacological, and elec-trical. The latter is most common and has usuallybeen applied to the sensorimotor cortex.

1. Electrical Stimulation of CNS

It has been known for more than 100 yearsthat electrical stimulation of the sensorimotorcortex of many species evokes rhythmic move-ments of the jaws.47 In order to evoke these, thecortex or its output pathway, the cortico-bulbartracts, must be repetitively stimulated at a min-imum of 6 to 10 Hz, but 40 to 60 Hz is theoptimum range.4851 The region from which thesemovements can be produced became known asthe cortical masticatory area. It lies below theprimary motor cortex in the most inferior part ofthe precentral gyrus of humans and monkeys, andin the orbital gyrus in cats.44-52'58 The variousfunctions of the cerebral cortex are not as dif-ferentiated in lower species, and in animals likerabbits and guinea pigs the masticatory area ov-erlies parts of the face area of the primary motorand sensory cortical areas.59-60 New data fromHuang et al.46 show that there may also be anoverlap of functions in the monkey. They report



that rhythmic jaw movements can be evoked byrepetitive intracortical microstimulation frommany sites in the primary motor and sensory faceareas, as well as from the traditional masticatoryarea.

Most studies of the brain stem circuits thatare fundamental to mastication have used cats,rabbits, or guinea pigs. These models were cho-sen because the movements produced by electri-cal stimulation look very natural. Ferrier47 wasthe first to report that stimulation of the cortexof guinea pigs and rabbits evokes movements thatlooked like mastication, and his findings havebeen confirmed many times.48'49-6063 Further-more, the patterns of masticatory movementschange with the site of stimulation within themasticatory area. Bremer62 found that three basicpatterns of masticatory movements that he sawoccurring naturally in the rabbit, gnawing, ver-tical mastication, and ruminatory or millingmovements, were represented in adjacent partsof the cortex. Lund et al.60 confirmed most ofBremer's findings, but they were not able to evokegnawing movements in anesthetized animals.They showed that the masticatory cycles pro-duced by stimulation of the most anterior part ofthe cortical region are similar in form to the typeI cycles of natural chewing. Like type I cycles,they have only two phases and the digastric mus-cles are very active, while the jaw-closer musclesare not. Type II cycles are evoked by stimulationof the posterolateral part of the masticatory area.After several seconds of constant stimulation, thecycle time begins to get longer, opening becomesslower, and eventually these type II cycles changeto type III.10

The pattern of mastication also depends onthe site of stimulation of the cat's masticatoryarea, the orbital gyrus,57-64 and, in addition,rhythmical lapping, licking, and retching can beevoked from adjacent sites.5557-65 Three types ofmasticatory movements can be elicited from dis-tinct sites in the cortex of monkeys.46

Mastication can also be activated by stimu-lation of the basal ganglia, lateral hypothalamus,parts of the amygdala and midbrain reticular for-mation.49-6670

2. Sensory Stimulation

Decerebrate animals can chew. This was firstshown by Bazett and Penfield,71 who fed pre-collicular decerebrate cats by putting food at theback of their mouths. Bremer62 showed that mas-tication in decerebrate rabbits could be causedby touching or rubbing the mucosa or the teeth,and that the type of pattern changed from gnaw-ing to rumination when the site of stimulationwas moved to the back of the mouth. Further-more, lightly anesthetized animals will chew onobjects placed in the mouth,72-73 or in responseto tonic pressure applied to the hard palate.74-75

Thexton et al.76 have found recently that ahigh-frequency digastric rhythm (10 to 18 Hz)can be elicited by electrical stimulation of the lipof decerebrate rabbit pups.

3. Pharmacological Stimulation

Spontaneously occurring periods of rhythmicmovement of the jaws occur when certain an-esthetics are given, and the pattern in guinea pigsunder ketamine has been described.77 Thesemovements are similar to type I masticatory cyclesin that they have only two phases, little lateralmovement and little activity in the jaw-closingmuscles.

A different type of rhythmical jaw movementin guinea pigs is caused by injections of the do-pamine agonist, apomorphine.7778 In these move-ments, the jaw swings widely to the side duringopening and back during closing. This activityis thought to originate in the striatum and to betransmitted to the brain stem via the superiorcolliculus.78 Hashimoto et al.70 suggest that theremay be another relay on this pathway in the mes-encephalic reticular formation.

IV. SENSORY FEEDBACK

In order to understand the contribution ofsensory feedback in the control of mastication,the first requirement is a description of the signals



sent to the brain stem during the movements. Itis important to know which types of primary af-ferents are tonically, phasically, or occasionallyactive, and if possible what causes them to fire.With this knowledge, it is possible to proposefunctions for those that are active. A detailedreview of this topic was published recently byRossignol et al.,79 so only a brief summary ofthe firing patterns of the different classes of re-ceptors during mastication will be given here.The "average'' pattern of firing of some of themare shown schematically in Figure 5.

A. Epithelial Mechanoreceptor Afferents

Primary afferents from skin, hair, and mu-cosal receptors have been recorded in the man-dibular division of the Gasserian (V) ganglion ofanesthetized rabbits.3580 81 About 60% of hair af-ferents were excited during mastication, and theytended to fire throughout the cycle. However,their firing frequency was modulated during thecycle and was found to be proportional to thevelocity of movement in all directions. Some hairafferents that innervated the lower lip were ex-cited if the lips touched together, or if they touched' 'food'' (simulated in these experiments by a rub-ber tube).

Most skin afferents were not active duringmastication. The only ones that fired regularlyand phasically when nothing touched the skin hadreceptive fields close to the corner of the mouth,which is the part of the face where the greateststretching of the skin occurs during jaw move-ments. Some skin afferents that had fields on thelower lip did fire during movement, but onlywhen their receptive fields were touched by thetube or by the upper lip. Mucosal afferents withfields on the lip and elsewhere in the mouth be-haved similarly. When the rubber tube was incontact with the receptive field, bursts of activitywere generated during jaw closure (Figure 5).

B. Periodontal Afferents

Most mechanosensitive periodontal primaryafferents innervate only one root and are sensitiveto the force or rate of change of force applied tothe crown of the tooth.82 86 Two populations have

been identified: the first have their cell bodies inthe V ganglion, while the axons of the secondgroup travel through the ganglion and sensoryroot to join cell bodies that are in the trigeminalmesencephalic nucleus (n V mes.87'89). Most re-ceptors innervated by n. V mes. neurons are inthe apical regions of the periodontal ligament,and these tend to be more slowly adapting thanthe receptors in the coronal portion that are in-nervated by cells in the ganglion (see Byers andDong90 for details).

As one expects, these receptors are activatedby biting and mastication. Larson et al.9192 foundthat the firing frequency of periodontal afferentsrecorded in n. V mes. of awake monkeys is pro-portional to biting force. Appenteng et al.35

showed that most V ganglion periodontal affer-ents from molar teeth are rapidly adapting, andthat they fire a short burst at the start of SC duringmastication on a rubber tube. Slowly adaptingreceptors predominate around the incisor teethand may be active throughout SC. They increasetheir firing frequency as the pressure increaseson the teeth. Most natural foods are not smoothlycompressible like a rubber tube, so rapidly adapt-ing receptors can be expected to fire bursts duringSC each time the tooth vibrates under the impactof the food (Figure 5).

C. Temporomandibular Joint Afferents

Very little is known about the properties oftemporomandibular joint (TMJ) receptors andeven less about their activity during mastication.Injections of horseradish peroxidase (HRP) intothe TMJ space of cats labeled cell bodies in themandibular division of the V ganglion,93 and Lundand Matthews94-95 recorded from neurons in thesame part of the ganglion that appeared to in-nervate the joint capsule of rabbits. The afferentswere not active when the jaw was at rest, butalmost all discharged when the jaw was movedby hand within its normal range of movement.Some coded displacement, others coded velocity,and each seemed to respond best to movementsthat stretched the part of the capsule in whichtheir receptors could be excited by probing. Thefew that could be tested were shown to fire sim-ilarly during mastication.



VERTICALMOVEMENT

Receptors

Periodontal

Lip andMucosa

Spindle

FIGURE 5. Diagrammatic summary of the patterns of activity of the jawmuscles and primary afferent neurons during a typical type II cycle. Thevertical movements of the mandible and the three phases of the cycle areshown on top. The pattern of firing rapidly adapting (RA) and slowly adapting(SA) periodontal and cutaneous afferents, as well as primary and secondaryspindle afferents are displayed below. The cutaneous group includes skinafferents on the lips and mucosal afferents. (Modified from Lund, J. P. andOlsson, K. A., TINS, 6, 458, 1983.)

D. Muscle Afferents

1. Spindle Afferents

The cell bodies of the jaw muscle spindleprimary and secondary afferents are in n. V mes.,which makes it possible to record from them withmicroelectrodes in awake animals. Data have beengathered from monkeys during several behaviors;

voluntarily controlled biting,91-92-96 voluntarytracking,97 and mastication,98-99 and from cats thatwere eating and lapping.34-40100101

Spindle afferents are very active during vol-untary biting. They reach discharge rates of 300Hz during the dynamic phase of the task, fire atlower but constant rates while force is main-tained, and again more rapidly as they arestretched during jaw opening.96 These afferents



are also active during lapping and again fire mostduring opening. Larson et al.91-92 recorded fromn. V mes. afferents during biting and subdividedthem into primaries and secondaries on the basisof their response to stretch. Units with high stretchsensitivity (presumed to be primaries) behavedlike the spindle afferents described by Lund etal.,96 while afferents with low sensitivity (secon-daries) were only active during lapping. How-ever, when Goodwin and Luschei" studied thebehavior of monkey spindle afferents during mas-tication, they were unable to distinguish primaryand secondary afferents on the basis of stretchsensitivity. They found that spindle afferentsshowed a wide variety of patterns of activity dur-ing mastication, ranging from those that wereonly excited during jaw opening to those thatfired strongly during SC and must therefore havebeen responding to fusimotor drive. Some of thelatter had large dynamic responses at the start ofjaw opening, which does suggest that they wereprimary afferents. If brittle food like monkey chowwas eaten, the jaw-closing muscles were oftenrapidly unloaded when the teeth broke through,silencing the spindle afferents and causing a silentperiod in the jaw closer EMG (Figure 5). Taylorand Cody39 and Cody et al.40 divided the n. Vmes. afferents that they recorded in awake catsinto two categories according to their firing fre-quency during jaw opening. They proposed thatthose with high rate of activity were primariesand those with low activity were secondaries.This classification received support from otherexperiments on lightly anesthetized cats in whichsuccinylcholine was injected into the blood-stream. This substance increases the dynamicsensitivity of spindle primary endings tostretch.101102 Neurons in the secondary endinggroup tended to be active at all phases of themovement cycle and their firing frequency wasoften proportional to the degree of jaw opening:they were therefore most active (80 to 200 Hz)at the end of opening. Afferents in the primarygroup showed some length sensitivity, but theirvelocity sensitivity predominated: they fired shortbursts at frequencies of up to 600 Hz at the startof opening. Both groups could be very activeduring SC, particularly when the food was tough.

2. Golgi Tendon Organs and OtherAfferents

Golgi tendon organs have been identified inthe jaw muscles of kittens, in the area of theattachment of the deep masseter muscle to thezygomatic arch and in the temporalis tendon.103

These receptors are in the series with the musclefibers and their firing frequency is an indicatorof muscle tension. Unfortunately, very little isknown of their activity during mastication. Fiveafferents recorded in the V ganglion of the an-esthetized rabbit by Lund and Matthews94 95 weretentatively identified as coming from tendon or-gans because they were excited by probing eitherthe medial pterygoid, masseter muscle, or thetemporalis tendon, and during a local twitch con-traction. They were excited also by manuallystretching the muscle and during contraction ofthe muscle during mastication.

Other neurons that were tentatively identifiedas tendon organs were found in n. V mes. byLarson et al.97 Like the units recorded from theganglion, these increased their firing frequencyduring jaw closure. It was suggested that theywere tendon organ afferents because their in-stantaneous firing frequency was modulated in asawtooth fashion, which Larson et al. believedto be due to the rapid changes in tension broughtabout by the intermittant contraction of a singlemotor unit inserting into the receptor. Appentengand Prochazka104 have shown subsequently thattendon organ afferents from ankle extensor mus-cles do not fire in such a manner. Only IA af-ferents do this, which suggests that the unitsclassified as tendon organs by Larson et al. mayhave been a subpopulation of spindle primaryafferents.

A few "spindle like'' afferents were recordedin the V ganglion by Lund and Matthews.9495

Like the tendon organ afferents, these were ex-cited by probing a muscle, but they were inhib-ited instead of being excited during the twitchcaused by local electrical stimulation. Their fir-ing frequency increased during manual stretchand they showed no dynamic sensitivity. Whenthe cortex was stimulated to cause mastication,they fired only during opening when the mouth



was empty, but they did become active duringclosure when a rubber tube was put between theteeth. Because of their sensory responses and thesmall amplitude of the extracellular action po-tential, it was suggested that the "spindle-like"units could be Group III muscle afferents.

Although pain afferents from muscles andother orofacial tissues must become tonically orphasically active in many pathological condi-tions, no studies of this type appear to have beenpublished. The best that can be done at the mo-ment is an extrapolation based on data from othermuscle groups.105

E. Summary

Most types of low threshold mechanorecep-tors are phasically stimulated at the start of orduring SC. The notable exceptions are musclespindle afferents, which, although very activeduring SC, also fire strongly during jaw opening.These data show that the CNS receives severaltypes of feedback signals that it can use to controlthe jaw-closer muscles during the most criticalphase of mastication.

V. REMOVAL OF AFFERENT INPUTS

Another way to study the role of sensoryinputs in motor programming that has proven tobe very useful is to remove some of all of them.One can then discover which features of the totalmotor program have been changed or lost. Thereare two basic ways of doing this: blockage oftransmission in sensory nerves, or the preventionof movement by paralysis.

A. Selective Deafferentation

Schaerer et al.106 injected local anesthetic toblock intraoral and TMJ receptors of human sub-jects. This did not stop mastication, but, sinceno quantitative analysis was done, we do notknow if the mandibular movements were changed.However, it was noted that the subjects had greatdifficulty manipulating the food bolus and keep-ing it between the teeth. Inoue et al.37 performed

extensive orofacial denervations in rabbits by cut-ting the maxillary and the inferior alveolar nerves.These rabbits would not eat when they recoveredfrom surgery, but they did do so when food wasplaced in the mouth. However, the masticatorysequence was lengthened, the movements weremore irregular, vertical and horizontal ampli-tudes fell, and jaw-closer muscle activity seemedto have been reduced. It appears that these def-icits are mainly due to removal of intraoral af-ferents traveling in the nerves, because Inoue etal.37 found that sectioning only the cutaneousbranches had little effect. Goodwin and Luschei107

found that monkeys preferred to chew on thecontralateral side when one n. V mes. was le-sioned to remove all feedback from muscle spin-dles, as well as some from periodontal afferents.When both nuclei were destroyed, monkeys againchewed on either side and the frequency and tim-ing of the muscle bursts seemed to be unchanged.This shows conclusively that neither muscle spin-dle afferents nor n. V mes. periodontal afferentsare essential to mastication. However, there isother evidence that n. V mes. lesions do reducethe size of the jaw-closer muscle bursts undersome circumstances. This will be discussed inSection VLB.2.

B. Paralysis: the Fictive Pattern

All movement, and thus all somatosensoryfeedback, is topped by a chemical blockade ofthe neuromuscular junction. Meanwhile, the mo-tor output of the central nervous system (CNS)can be analyzed by recording the discharge ofwhole motor nerves or of motoneurons. Exper-iments like these were first done to find out ifthe rhythm of mastication was generated withinsome part of the CNS or by the alternation ofreciprocal reflexes. The conclusion was that manyof the features of mastication could be generatedwithin the brain stem. Dellow and Lund51 showedconclusively that the isolated brain stem had theability to generate the basic features of masti-cation. They cut the spinal cord of paralyzeddecerebrate animals and severed the branchialand cervical nerves to remove all somatic afferentinputs. Furthermore, they were able to show that



the rhythmical masticatory pattern was not dueto signals generated by the vascular or respiratorysystems. Organized rhythmical motor patterns thatremain in the absence of movement are describedas "fictive movements", and the groups of neu-rons that produce them are known as central pat-tern generators (CPG). It is generally acceptedthat circuits of this type control many purposefulrhythmical motor patterns in all classes of ani-mals (e.g., repiration, locomotion, feeding,flying, and swimming). Usually fictive jawmovements have been produced by electricalstimulation of the cortex or other parts of theCNS, although the patterns caused by ketamineand by sensory stimulation of the mouth havealso been studied.36'64'67'70'75108 A comparison ofthe pattern of activity in the motor nerves and inthe muscles before paralysis helps us to determinehow much of the total behavior is centrally gen-erated and what features depend on sensoryfeedback.

The fictive pattern of mastication retains sev-eral features of the EMG pattern evoked beforeparalysis. When the fictive pattern is caused bystimulation of the cortical output, mylohyoidnerve activity gradually builds up into the firstburst of the sequence, just as in mastication, andthis coincides with inhibition of masseter nerveactivity. The masseter burst follows and activitythen alternates in the two nerves throughout therest of the sequence.51109 There are also twogroups of antagonistic hypoglossal motoneurons,one that fires during jaw opening (tongue pro-trusion) and the other during closing (retraction);this alternating activity continues after paraly-sis.64110 Furthermore, the duration of the mas-ticatory cycle and the fictive cycle are similarlyaffected by changes in the stimulus parame-ters.51111 In the rabbit, the frequency of move-ments evoked by a constant level of corticalstimulation with the mouth empty is not changedby paralysis,51 although it does fall by about 10%in the cat.111

Although we lack the detailed comparisonsof the timing of the motoneuron bursts to thevarious muscles and compartments within mus-cles that have been done in other systems,79 somedifferences have been found in the real and fictivepatterns that suggest the general roles that sensoryafferents play in mastication. First, and most im-

portant, when the electrical stimulus is su-prathreshold and constant, the fictive pattern isvery regular,51 in contrast to the natural situation,particularly when tough or brittle foods are beingchewed. Second, the firing frequency of jaw-closer motoneurons is much less in fictive mas-tication; this will be discussed again in SectionsVI and VII.

C. Summary

The rhythmical activation of the various mus-cle groups involved in mastication is generatedby a CPG in the brain stem. Sensory feedback,particularly from intraoral mechanoreceptors,modifies the basic pattern and is particularly im-portant for the proper coordination of tongue,lips, and jaws.

VI. ACTIVATION OF AFFERENTS

Knowing the pattern of activity of the severalclasses of primary afferents, one can suggestwhich groups participate in controlling a partic-ular phase or parameter of the movements. Moreinformation can be acquired by selectively stim-ulating each one.

A. Tonic Stimulation

In Section III.B.2 (animal models) it wasreported that tonic stimulation of periodontal andmucosal afferents can initiate mastication and fic-tive mastication in decerebrate or lightly anes-thetized animals. Sometimes this type of sensorystimulation has to be coupled with subthresholdelectrical stimulation of the CNS of rabbits to beeffective.6772 It has been reported that activationof muscle spindle afferents by tonic stretch ofthe jaw-closing muscles of cats does not normallyinitiate fictive mastication, but that it does makea subthreshold cortical stimulus effective. Thesame sensory stimulus was seen to speed up thefictive mastication evoked by suprathreshold cor-tical stimulation and to increase the amplitude ofthe masseter nerve bursts.111 Chandler et al.112

loaded the mandible of guinea pigs and confirmedthat the amplitude of the masseter burst increased



during spontaneous rhythmical jaw movementsin guinea pigs anesthetized with ketamine; how-ever, there was no change in the cycle frequency,even though the masseter burst was longer.

Tonic pressure on the maxillary incisor ofrabbits causes the lateral jaw reflex, in which themandible swings to the contralateral side by thecoordinated action of several muscles or parts ofmuscles on the two sides.113 The same stimulusgiven during the vertical type of cortically in-duced mastication causes the jaw to swing to thecontralateral side during FC and back to the mid-line in SC,72 i.e., changes type I cycles to typeII. On the other hand, mastication stops if thepressure on the teeth is too strong,72 perhaps be-cause the stimulus has become noxious. Evenwhen tonic noxious stimuli are given far fromthe mouth, they are capable of inhibiting mas-tication. For instance, strong pinching of the fo-repaws or distention of the rectum can stopcortically induced mastication in rabbits.6772

B. Phasic Stimulation

It has become apparent from work on manyrhythmical systems, including mastication, thatthe reflex effects of sensory afferents and theiractions on the CPG can change dramatically fromone phase of the movement to another.79114 Asone might imagine, the details vary betweengroups of receptors.

1. Epithelial Afferents

a. Modulation of the Jaw-Opening Reflex

The jaw-opening reflex (JOR) can be elicitedby phasic mechanical stimulation of low-thresh-old mechanoreceptor afferents in the lips or oralmucosa115116 and by electrical stimulation of Vnerve branches.41117120 In all animals studied ex-cept man, the jaw-closing muscles are inhibitedand the digastric muscles are activated at shortlatency. The responses are bilateral and probablydisynaptic on both sides.117 The jaw-closing mo-toneurons are inhibited in humans, but the di-gastrics are not excited, at least not at a similarshort latency.121 Dessem et al.122 have recentlysuggested that only closer muscle inhibition is

caused by low-threshold mechanoreceptor affer-ents, and that high-threshold afferents, perhapseven nociceptors, must be stimulated before thedigastric motoneurons are excited. However, thereare several reasons to think that digastric moto-neurons receive excitatory inputs from low-threshold afferents, but that these were not strongenough to cause the motoneurons to fire in theanesthetized cat.123

The first study of the interactions betweenreflexes and the central rhythm of masticationwere carried out by Chase and McGinty.124 Theyevoked the digastric jaw-opening reflex by stim-ulation of the inferior alveolar nerve of awakecats and measured its amplitude at rest and duringcortically driven mastication. They reported thatthe reflex was facilitated during jaw opening andinhibited during closure. Other experiments onawake cats41 and anesthetized rabbits120125126 haveshown that the modulation of the digastric re-sponse changes with the strength of stimulation.When the stimulus is weak and probably innoc-uous, the reflex behaves as described by Chaseand McGinty124 (Figure 6). However, there isreally no facilitation of the reflex input to thedigastric motoneurons during jaw opening, be-cause when the effect of the rhythmical excitatorydrive is subtracted, the excitatory effect of thestimulus is seen to be reduced at all phases ofthe cycle.123 This pattern changes if higherthreshold afferents are recruited. When the stim-ulus intensity is raised above 1.5 X reflex thresh-old, phasic facilitation does occur, but during jawclosure, not during the jaw-opening phase (Fig-ure 6). At the same time, the strong stimulusinhibits jaw-closer muscle activity and some-times even abolishes most of the closer muscleburst.120

The modulation of this reflex was shown tobe a property of the CPG when it was found thata similar modulation of digastric nerve activityoccurs during fictive mastication.126 Further-more, it was argued that the cyclical changes inthe digastric responses to the higher intensitystimulation must be due to an action of the CPGon interneurons, and not simply to fluctuationsin motoneuron membrane potential, because thebiggest responses were out of phase with the EMGburst (Figure 6). I will come back to this in Sec-tion VII.



VERTICALMOVEMENT

MembranePotential

Digastric

Masseter

Jaw OpeningReflex

LowT

HighT

Excitabilityof Interneurons

LowT +Resting

HighT

Resting '

FIGURE 6. The input from the CPG to motoneurons during a type IIcycle is shown first. The digastric membrane potential is at about itsresting level during FC and most of SC. A large slow potential occursduring O and the neuron fires repetitively at a high frequency. The mas-seter motoneurons are similarly depolarized during FC and SC, but arestrongly hyperpolarized during O. Below is a diagram of the modulationof the jaw-opening reflex. On the left is shown the control digastric re-sponses with the jaw at rest (control). The amplitude of the test responseto low-intensity stimulation (<1.5 x threshold) is normally less than con-trol during mastication, particularly during FC and SC. In contrast, theresponses to higher intensity stimulation are greatest in SC. Finally, thereis a representation of the change in excitability of neurons that receivelow- and high-threshold sensory that appears to take place during mas-tication. The first are inhibited at all phases, while the excitability of thesecond is low in FC and O and high in SC. (Adapted from Lund, J. P.and Olsson, K. A., TINS, 6, 458, 1983.)

47



b. Modulation of the Masticatory Pattern

Low-intensity intraoral stimulation has littleeffect on the duration of the masticatory cycle inrabbits. However, when a stimulus of higher in-tensity occurs early in closure, the cycle is short-ened because of the reduction of the closer musclebursts, but if the stimulus arrives during jawopening the cycle is lengthened.120126 Similarly,weak electrical stimuli given to the interdentalgingiva of the maxilla of human volunteers hadlittle effect on cycle time, while painful stimuliwere effective.127 The most consistent change wasa lengthening of the cycle when the painful stim-ulus occurred during jaw closure.

2. Periodontal Afferents

a. Modulation of the Jaw-Opening Reflex

The jaw-opening reflex can also be causedby hard taps to the teeth.128129 A pattern of re-sponse like the JOR can occur during SC whenrabbits are eating hard foods:9 the closer musclesare transiently inhibited and the digastrics arebriefly excited. This pattern seems to be causedby sudden increases in the resistance to jaw clo-sure. It is often seen in the first cycle of thereduction series, but is much rarer in later cycles(Figures 2 and 3). Although the JOR could dis-appear because the food gets softer, there is evi-dence that it is actively suppressed after the firsttype II cycle. Lavigne et al.10 studied corticallydriven mastication in anesthetized rabbits withthe mouth empty and also when a steel ball ona rod was thrust between the molar teeth of oneside. They found that a JOR often occurred inthe first cycle in which the ball was introduced,but was absent in subsequent cycles, although,of course, the steel got no softer.

b. Modulation of the Masticatory Pattern

The most interesting finding from the studyof Lavigne et al.10 was that, with the exceptionof the first cycle, the duration and amplitude ofthe jaw-closer muscle burst went up dramaticallyduring SC when the ball was between the teeth.

In addition, SC and the cycle were significantlylonger, and the mandible swung further towardthe contralateral side during SC. There was nosignificant effects on the digastric burst. Most ofthese results have been confirmed by Morimotoet al.,63 who placed plastic strips between theteeth. They showed that the increase in muscleactivity was proportional to the thickness of thestrips. In both experiments, sectioning or anes-thetizing nerves carrying the periodontal affer-ents abolished most, but not all, of the effects ofobstructing jaw closure. These experiments pro-vide strong evidence that action of periodontalinputs on the jaw-closer muscle burst changesfrom inhibition to excitation at the transition fromthe preparatory to the reduction series ofmovements.

3. Muscle Spindle Afferents

When food or an artificial substance stops orslows movement during SC, muscle spindle af-ferents as well as periodontal afferents are stim-ulated (Figure 5). It has long been thought thatthe spindle afferents stimulated in this way shouldincrease jaw-closer motoneuron activity, and thiswas confirmed by Morimoto et al.63 They foundthat lesions of n. V mes. abolished the residualeffect of placing plastic strips between the teethduring cortically evoked mastication in rabbitswithout periodontal afferents.

When brittle food is eaten, periodontal andmuscle spindle primary afferents are alternatelyunloaded and loaded each time the food frac-tures.14 This probably accounts for the fraction-ation of the closer muscle EMG during SC intoalternating silent periods and bursts shown dia-grammatically in Figure 5.

As far as I know, the only study of the effectsof phasically stimulating muscle spindle inputsduring all parts of the masticatory cycle was car-ried out in awake cats by Chase and McGinty.124

They electrically stimulated n. V mes. to excitespindle afferents (and inevitably some periodon-tal afferents) and recorded the resulting H reflexin the masseter muscle. During mastication, theH reflex was facilitated during jaw closure andinhibited during opening.



C. Summary

Certain types of tonic afferent input can in-itiate mastication and probably contribute to thegeneral drive that keeps the movements going.Some phasic inputs are phase promoting, that is,they enhance the activity of the agonist muscles.This is very important during SC, when musclespindle afferents and periodontal pressoreceptorsprovide positive feedback to the jaw-closing mus-cles. Others have the potential to inhibit muscleactivity or to terminate a phase. If these are nor-mally activated by movement, their influence mustbe counteracted by the CPG. If they are highthreshold and are only occasionally activated, theireffects may be enhanced to provide addedprotection.

VII. BRAIN STEM ELEMENTS

The brain stem is the only part of the centralnervous system that is essential for mastication,because decerebrate animals (see above) and an-imals without a cerebellum or spinal cord canchew.7 0 7 2 1 0 9 1 3 0 Our knowledge of differentgroups of brain stem neurons that participate inthe control of mastication will now be summa-rized. The major components and connectionsthat will be discussed are shown diagrammati-cally in Figure 7. An excellent review of trige-minal interneurons can be consulted by those whowant more information.131

A. Central Pattern Generator

The cortex exerts its action on the brain stemCPG via the corticobulbar tracts,51-55'72132 and theprojection is mainly contralateral.133134 The mes-encephalic RF also projects contralaterally to theCPG through a nonpyramidal pathway.70

CPGs vary from simple circuits containing afew neurons, like those that control many inver-tebrate activities,135 to the complex systems thatgenerate mammalian motor rhythms. Feldman etal.136 have shown why it is probable that the twomajor components of pattern of respiration, therhythm or timing (determining the length of thecycle and the frequency of repetition), and themotoneuron bursts (the duration and pattern of

firing of the different motoneuron pools) are gen-erated in separate stages by different groups ofbrain stem neurons. The evidence that suggeststhat this model is also applicable to mastication.

1. Rhythm Generation

The rhythm of mastication seems to be pro-duced by groups of cells in the medial bulbarreticular formation (RF) between n. V. mot andthe inferior olive. There are three pieces of evi-dence in favor of this statement. First, anatomicaland electrophysiological studies have shown thatneurons in the medial nuclei of the medullary RFreceive direct projections, predominantly contra-lateral, from the masticatory area of the cerebralcortex.69137138 Second, lesioning or surgicallyisolating the medial RF abolishes mastica-tion,69139 even when the lateral parvocellular re-ticular nuclei are intact.6970 Finally, neurons inthe medial RF become rhythmically active duringfictive mastication.133

When a cut is made to the base of the brainalong the midline of the caudal medulla, therhythm is abolished on the side ipsilateral to thestimulation site in the cortex, but not on the con-tralateral side. This shows that there are tworhythm generators that can function indepen-dently, that each is mainly controlled by the con-tralateral cortex, and that they are usuallycoordinated by axons that cross to the other side139

(Figure 7).Even when the interstimulus intervals of the

train of cortical shocks are randomly ordered, therhythm generator is capable of producing a reg-ular fictive pattern.51 It seems to do this by thesequential activation of several groups of neurons(Figure 7). Corticobulbar stimulation excitesneurons in and above the dorsal part of n. reti-cularis paragigantocellularis (PGC) and it is pos-sible that the types of sensory stimuli that elicitemastication may excite the same neurons. Er-mirio et al.140 mapped responses to pressure onthe teeth and mucosa throughout the brain stemRF. Mechanical thresholds were quite low, andmost neurons adapted slowly. It is interestingthat, although the predominant response of neu-rons recorded in the mesencephalon and rostralpons was inhibition, several neurons that ap-peared to be in or near PGC were excited.



BURSTGENERATORS

FIGURE 7. A simple model of the brain stem networks controlling mastication.Input from the masticatory cortex (and other higher centers that are now shown)or oral cavity drives the rhythm generator. This controls burst generators closeto n. V mot. The burst generators control the different pools of motoneurons,interneurons, and the primary afferents. (Others are presumed to control VIIand XII motoneurons.) Other burst generators are presumed to control VII andXII motoneurons.

PGC neurons do not fire rhythmically whenthe cortex is stimulated,133 but they do appear toinduce rhythmical firing in neurons in and justabove the rostral part of n. reticularis giganto-cellularis (GCo), and these, in turn, may entraina more caudal group of gigantocellularis neurons(GCc)133 (Figure 7).

In contrast to some other CPGs, we knowvery little about the synaptic processes of mas-ticatory rhythm generation, except that glycineis not an essential transmitter. The frequency ofcortically driven mastication is not altered sig-nificantly by the glycine antagonist, stry-

chnine,141142 or by methysergide, a serotonin(5HT) H2 receptor antagonist.142 However, 5HTshould not be dismissed as a putative transmitterbefore antagonists to the HI receptors have beentried.

Nakamura and co-workers have suggested thatthe neurons of the medial RF control the trige-minal motoneurons directly.58144 This implies thatnot only the rhythm, but also the parameters ofthe motoneuron bursts are encoded by the neu-rons of GCc, and there is some evidence to sup-port this proposition. Stimulation of medial nucleiexcites digastric motonuerons and inhibits mas-



seteric motoneurons at very short latency,145 andmedial RF neurons can be antidromically acti-vated by stimulation of n. V mot.137 On the otherhand, anatomical studies have not provided muchevidence that medial reticular areas have a strongmonosynaptic projection to V motoneurons, sug-gesting that the rhythm generators act mainly viaother groups of premotor neurons close to n. Vmot. This point of view has been expressed inseveral papers from the group at UCLA.59141146

2. Burst Generation

Horseradish peroxidase (HRP) is captured bythe presynaptic terminals and transported back tothe cell body, where it can be revealed by his-tochemical methods. When HRP was injectedinto the trigeminal motor nucleus to label pre-motor neurons, very few of these turned out tobe in or adjacent to GC.147'149 Many labeled so-mata were found in the border zone surroundingn. V mot. that was called regio h by Meesen andOlszewski.150 The dorsal zone of regio h is usu-ally known as the supratrigeminal nucleus (n. Vsup.) and lateral zone as the intertrigeminal nu-cleus (n. V int.). Other groups of labeled neuronslay in the dorsal parts of the Vth main sensorynucleus (n. V princ.) and the most rostral divisionof nucleus oralis (n. V oral.T). Some labeled cellswere found in the lateral parvocellular RF medialto nucleus interpolaris, and there was a smallcompact group of cells just lateral to n XII mot.With the exception of this last group and n. Vprinc, all the regions were labeled bilaterally.

Since cuts made just behind n. V mot. thatisolate the lateral RF do not change mastication,69

it is probable that only the premotor neurons closeto n. V mot. form the burst generators shown inFigure 7. There is now strong evidence that someof the neurons in this area participate in patterngeneration. Donga et al.151 recorded from cellsin n. V sup., n. V int. and n. V oral.T in anes-thetized and paralyzed rabbits, and found thatthere were neurons in each nucleus that firedrhythmical bursts in phase with the fictive rhythminduced by cortical stimulation. They showed thatsome of these were premotor neurons by anti-dromically activating them from the contralateraln. V mot.

For the sake of simplicity, we will only dis-cuss the formation of the opener and closer mus-cle bursts, although the control process must alsoinclude a way of combining the various moto-neuron pools to produce the more complex pat-terns. To explain alternating opening and closure,intracellular recordings from motoneurons (seelater) show that three processes are necessary:

1. Inhibition of closer motoneurons duringopening

2. Generation of the opener burst3. Generation of the closer burst

Opener motoneurons are not inhibited duringclosure.

a. Inhibition of Closer Motoneurons

Inhibition of jaw-closer muscle activity oc-curs before the digastric becomes active in thefirst opening movement of a series and has alower cortical threshold than the opener burst.11152

This means that it cannot be initiated by recip-rocal inhibition. In any case, it is improbable thattrigeminal opener motoneurons reciprocally in-hibit their antagonists even when they are active,because there is little evidence that any form ofrecurrent inhibition occurs in V or XII motoneu-rons.117153154 In the spinal cord, these processesdepend on the activation of la inhibitory inter-neurons and Renshaw cells by recurrent collat-erals, which until recently had never been seenleaving V, VII, and XII motoneuron ax-o n s 154158 However, Moore and Appenteng159

have recently published drawings of 4 HRP-filledrat jaw-closer motoneurons that do appear to showaxon collaterals. It must now be determined ifthis is more than a chance finding.

In the model of the brain stem circuits, theinhibition of closer motoneurons comes from agroup of inhibitory premotor interneurons thatform one of the components of the burst gener-ators (Figure 7). Although these have not beenpositively identified, it is possible that some ofthese are in n. V sup. High-threshold inputs ter-minate the closer muscle bursts and some of theseneurons are excited by strong stimulation of sev-eral trigeminal nerve branches. It was postulated



that neurons in this nucleus mediate disynapticinhibition of jaw-closer motoneurons during thejaw-opening reflex117160161 even before it wasknown that neurons in the nucleus project to n.V mot. on both sides.149162163 Kamogawa et al.164

recently filled commisural (contralaterally proj-ecting) neurons in n. V sup. with HRP and wereable to show that the same neurons also had axoncollaterals to the ipsilateral n. V mot. The ter-minal branches of the axons appeared to arbour-ize among closer motoneurons.

b. Generation of Opener Bursts

The only group of interneurons that is defi-nitely known to project to the digastric moto-neuron pool are in n. V oral.T. Olsson andWestberg165 identified this ipsilateral projectionby antidromic stimulation. These premotor neu-rons received excitatory inputs from low-thresh-old lingual, inferior alveolar nerve afferents, andfrom high-threshold muscle afferents. Most con-tralaterally projecting n. V oral.T. premotor neu-rons recorded by Donga and Lund166 had similarinputs and were not phasically active during fic-tive mastication; however, some did fire burstsduring the opening phase. This supports the sug-gestion that many of the interneurons involvedin the jaw-opening reflex are normally outsidethe burst generator.120139165

The rhythmic excitatory drive to digastricmotoneurons is facilitated by L-glutamate, N-methyl-D-aspartate (NMDA), noradrenaline, and5HT and blocked by the iontophoretic applicationof AVP (D-2-amino-5-phosphovalerate), which isa specific antagonist of the NMDA receptor.167

The latter is an important finding because it hasbeen found that slow rhythmical EPSPs generatedby some other CPGs are caused by the releaseof excitatory amino acides (glutamate or aspar-tate) that activate NMDA receptors in motoneu-rons. This is followed by the opening of voltage-sensitive Na+ channels and it is the resulting Na+

current that completes the depolarization. Re-polarization is very slow during the plateau po-tential that underlies the motoneuron burst.114

c. Generation of Closer Bursts

Although it has usually been assumed that n.V sup. neurons inhibit closer motoneurons, manyof them are excited by sensory inputs that pro-mote the closer muscle burst. Branches leave theaxons of N. V mes. spindle afferents and ter-minate in n. V sup.,154168169 where they excitemany neurons.168170 Although the three reportsdiffer in the percentage of neurons that receivedinput from more than one muscle, all found thata considerable number could be excited by prob-ing both the masseter and the temporalis muscles.Jerge170 reported that pressure on the teeth orgingivae activated units in the caudal parts of thenucleus, and that a few had convergent inputsfor spindles and oral mechanoreceptors.

Appenteng et al.173 used spike-triggered av-eraging in anesthetized rats to show that inter-neurons just caudal to n. V mot. makemonosynaptic excitatory connections within themasseter motoneuron pool. Some of these inter-neurons are also excited by periodontal and mus-cle spindle afferents. Noxious inputs suppress thecloser burst (see earlier) and also inhibit theseneurons.

The boundaries of the burst generators maybe continuously expanding and contracting, de-pending on circumstances and the complexity ofthe movements.79 Imagine an interneuron thatreceives a rhythmic drive from the rhythm gen-erator. As long as this is not strong enough tomake it fire, it is not a part of a burst generator,but if the rhythmic drive increases, if it receivesa convergent excitatory input from higher centersor has a peripheral receptive field, it may beginto fire rhythmically. It is then contributing to thedrive potential that underlies the burst.

B. Control of Motoneurons by the CPG

Although trigeminal (V), facial (VII), andhypoglossal (XII) motoneurons are all importantin the control of mastication, the facial moto-neurons have not been studied during mastica-tion. Unless otherwise stated, the data come fromV motoneurons.

52



There are two basic types of motoneurons.The first, the fusimotor (gamma) motoneurons,have the smaller cell bodies, narrower axons,conduct more slowly, and innervate the contrac-tile portions of the intrafusal fibers within themuscle spindles. The other motoneurons (alpha)innervate extrafusal muscle fibers and thereforedirectly control the contraction of the muscle.The original studies of alpha and gamma moto-neurons showed that they have conduction ve-locities in the approximate range of 50 to 120 m/sand 10 to 50 m/s, respectively, in the cat hind-limb.174 Beta motoneurons that innervate bothintra-and extra-fusal fibers are common in somemuscles,175 and a small number have recentlybeen found to occur in rat masseter.176 Trigeminalmotoneurons are not easily separated by theirphysical properties. The diameters of cat moto-neuron axons are unimodally distributed between1 and 16 |xm177 and motoneuron cell body di-ameters do not form two populations in the rab-bit,178 although they appear to do so in rats.179

However, Sessle180 was able to define two pop-ulations in the cat on the basis of different re-sponses to various stimuli and he estimated thatalpha motoneurons conduct at between 26 to 72m/s and gammas at 16 to 36 m/s.

1. Alpha Motoneurons

Intracellular recordings from motoneuronsduring fictive mastication of guinea pigs and catsshow that the rhythmic bursts of activity of Vand XII motoneurons are caused by large am-plitude slow potentials. Digastric motoneuronsfire in bursts of 150 to 250 ms in duration thatcontain up to 30 spikes, and the instantaneousfrequency can be as high as 250 Hz.

These spikes are superimposed on rhythmicaldepolarizing shifts that drop to about the level ofthe resting membrane potential between the bursts,but they are not hyperpolarized (Figure 6).59'68181

The pattern of activity in XII motoneurons issimilar,64 but closer motoneurons behave verydifferently. The most striking features of the in-tracellular records from masseter motoneuronsare the large, slow hyperpolarizing potentialsduring the phase of digastric activity (opening).These are probably inhibitory postsynaptic po-

tentials (IPSPs) generated at synapses on or closeto the cell soma because they are easily reversedby Cl~ injections through the intracellularelectrodes.68108

The rhythmic IPSPs are one of the mecha-nisms that counteract excitation caused whenmuscle spindles are stretched during the contrac-tion of antagonist muscles.182184 Spindles areplentiful in certain parts of the jaw-closing mus-cles, but neither the digastrics nor the musclesof the tongue of nonprimates contain many.185

This may be the reason that the rhythmic IPSPsare not seen in digastric and XII motoneurons.

The slow depolarizing potentials that alter-nate with the IPSPs are often too small in am-plitude to cause the masseter motoneurons tofire.68181 However, they seem to be much moreactive in the unparalyzed preparation, particu-larly when something is put between the teeth toincrease the activity of periodontal and musclespindle afferents.36

It is well known that many regions of thecerebral cortex, including the masticatory area,project disynaptically to the motoneurons163186

and that synaptic potentials of short duration oftenfollow each cortical shock at short latency. Prom-inent stimulus-linked EPSPs occur in digastricmotoneurons and IPSPs in masseter motoneuronsand the amplitude if these potentials are stronglymodulated during the masticatory cycle.59108146

This has led to the hypothesis that slow drivepotentials are simply an aggregate of these short-latency potentials.59108146 This is an interestingproposition, but other evidence suggests that thetwo processes are independent. First, EMG burstsdo not always contain significant amounts of ac-tivity that are linked to the cortical shocks.60 Sec-ond, there is evidence that the synapticmechanisms of the two types of potential aredifferent. Enomoto et al.142 have shown that theshort-latency IPSPs are probably caused by therelease of glycine by inhibitory interneurons ex-cited by cortical afferents, because strychnine, aglycine antagonist, blocks these potentials. Stry-chnine also increases the amplitude of the short-latency bursts in the digastric muscle.141 How-ever, the slow IPSPs are not blocked by stry-chnine, suggesting that they are transmitted bysynapses from other interneurons that do not useglycine as a neurotransmitter. Furthermore, the



rhythmic drive potentials of digastric motoneu-rons seem to depend on NMD A receptors, whilecortical short-latency EPSPs do not.167

It seems probable, then, that the slow poten-tials represent the fundamental output of the burstgenerators when they are being driven only bythe rhythm generator, and that these potentialsare normally modified by sensory feedback andby inputs from higher centers of the CNS (Figure7).

2. Gamma Motoneurons

Gamma motoneurons have been classifiedinto subtypes according to their action on themuscle spindle. The main division is into staticand dynamic fusimotor neurons: when dynamicgamma motoneurons fire, they increase the sen-sitivity of the spindle primary endings (IA affer-ents) to the rate of change of muscle length(velocity sensitivity), while the main effect ofstatic gammas is to make secondary endings(Group II afferents) more length sensitive.174

There have been no reports of intracellularrecording from trigeminal gamma motoneurons,but Taylor and co-workers have recorded the ac-tivity of axons dissected from the masseter nerveof anesthetized cats and identified fusimotor neu-rons by several tests.100102 They found that fu-simotor neurons were often tonically active whenthe jaw was in its postural position. Just beforerhythmical jaw movements began, one group in-creased their discharge rate, which then remainedrelatively constant throughout the whole seriesof movements. The authors suggested that thesewere dynamic fusimotor neurons. Another groupthat were phasically excited during jaw closurewere thought to be static fusimotor neurons. Theeffect of this activity on the pattern of firing ofspindle afferents was discussed in Section IV.D. 1.

It has also been reported that gamma moto-neurons are very active during voluntary bitingin monkeys.96 Their activity increases at the sametime or even before that of alpha motoneurons,they fire while force is maintained and stop justbefore it is released. Larson et al.9192 suggestthat the gamma motoneurons active during bitingare of the dynamic rather than the static type.However, this is based on their classification of

spindle afferents by their responses to stretch,which may not be a reliable test (see SectionIV.D.I). It is becoming well accepted that therelative balance of static and dynamic sensitivityof the muscle spindle receptors is tailored to aparticular movement pattern,79100 but this is justone of the ways in which the CPG controls af-ferent feedback.

C. Control of Interneurons and PrimaryAfferents by the CPG

It is clear that one of the functions of CPGsis to adjust the gain of reflexes, to suppress thosethat are unnecessary, and to facilitate those thatenhance motor performance.79 They do thisthrough the fusimotor system, and by their directaction on the alpha motoneurons (e.g., slowIPSPs), but there is a lot of evidence that theyalter transmission from the primary afferents tointerneurons, as well as modulate the interneu-rons themselves.

Several experiments have shown that the ex-citability of jaw reflex interneurons and primaryafferent terminals is controlled during mastica-tion. In addition, the sensory detection thresholdrises during movement,187188 and there is someevidence that our perception of oral stimuli ischanged during mastication.189

1. Neurons with Cortical Inputs

The possibility that the CPG modulates cor-tico-bulbar interneurons has already been men-tioned. Neuroanatomical studies have shown thatmost parts of the brain stem that contain thelabeled V premotor neurons also receive inputsfrom the sensorimotor cortex. These include n.V prin., n. V oral T, n. V sup., and n. V int.and lateral reticular areas medial to the spin alnucleus.138146190195 Neurons in all these areascan be excited by cortical stimula-tion 73'131»163'166.196-200

It has already been noted that the amplitudeof EPSPs in digastric motoneurons and the IPSPsin masseter motoneurons that follow corticalstimuli are cyclically modulated.59108146 Much ofthe variation in amplitude probably occurs be-

54



cause of changes in motoneuron membrane prop-erties induced by the slow potentials, but thepremotor neurons are also controlled. Olsson eta j 73,163 j l a v e s h o w n t h ^ t h e responses of manyn. V prin., n. V int., and n. V oral T neurons tocortical shocks are generally reduced during mas-tication (Figure 6). Many of these neurons alsoreceive excitatory low-threshold orofacial inputs.

2. Neurons with Low-ThresholdOrofacial Inputs

The digastric jaw-opening reflex response tolow-threshold inputs is inhibited during all phasesof mastication (Section VLB). The data gatheredduring intracellular recording show that this isunlikely to be due to postsynaptic inhibition ofthe motoneurons by the CPG, because even dur-ing jaw closure digastric motoneurons are nothyperpolarized (Figure 6). This led Lund andOlsson201 to postulate that the interneurons onthis reflex arc must be tonically inhibited by theCPG (Figure 7). Although Olsson et al.73163 didnot identify interneurons, the fact that the re-sponses of low-threshold neurons recorded in n.V prin., n. V int., and n. V oral T to peripheralstimulation was reduced in all phases of masti-cation indicates that the hypothesis is probablycorrect.

Included among the inhibited neurons weresome in n. V prin. and oral, T that projected tothe ventrobasal thalamus,73163 and most neuronsin the nucleus caudalis with low-threshold re-ceptive fields are tonically inhibited during fic-tive mastication.202 A general reduction in theresponsiveness of second-order neurons with low-threshold mechanoreceptive fields may be thereason for a rise in the sensory detection thresholdduring movement.203

3. Neurons with High-ThresholdOrofacial Inputs

Although it is necessary to suppress reflexresponses to low-threshold orofacial mechano-receptors so that the jaw closure can take place,it is still necessary to protect the mouth againstdamage during mastication. This seems to be done

by enhancing the response to high-threshold af-ferents during closure. Although digastric mo-toneurons are more sensitive to high-intensitystimulation of the IA nerve (>1.5 x threshold)during the closing phases of mastication and fic-tive mastication than at rest,120126 this cannot beexplained by the postsynaptic events in the mo-toneurons (Figure 6). To account for this phasemodulation, Lund and Olsson201 postulated thatthe CPG increases the excitability of the high-threshold interneurons during closure. This hy-pothesis was supported by the results of Olssonet al.,73 who recorded from neurons in n. V int.that had thresholds of > 1.5 x the reflex thresh-old. In several cases, the probability firing to IAstimulation rose and the latency of the spikesdecreased during closure (Figure 7).

4. Primary Afferents

The modulation of the amplitude of the low-threshold jaw-opening reflex during masticationseems to be due, at least in part, to changes inthe presynaptic terminals of the primary affer-ents. Kurosawa et al.204 used Wall's techniqueto show that inferior alveolar nerve cutaneousafferent terminals in n. V oral are hyperpolarizedduring the jaw-opening phase and depolarizedduring the closing phase of fictive mastication.This would result in enhanced synaptic trans-mission during opening and decreased transmis-sion during closure. Decreased release of anexcitatory transmitter can explain the reductionin the firing of postsynaptic neurons (and in thedigastric response) during closure, but if there isincreased release during opening the CPG mustbe counteracting this by postsynaptic inhibitionof the relay cells, since their excitability tends tobe lowest during this phase.73

The CPG has at least two ways of controllingmuscle spindle primary afferents during masti-cation. The first is through the fusimotor system(see Section VLB). The second seems to occurby a synaptic action of the CPG on n. V mes.(Figure 7). Kolta et al.205 caused n. V mes. spin-dle afferents to fire tonically by holding the mouthopen and found that approximately 40% of thesewere modulated during fictive mastication. In al-most all cases, this effect was a rhythmical in-

55



hibition: the action potentials coming from theperiphery failed to enter the cell body of thesepseudo-monopolar cells during the jaw-openingphase. It seems plausible that this occurs becausethe neuron is phasically hyperpolarized. Nomuraand Mizuno206 showed that 40% of n. V mes.spindle afferents have dendritic processes, andsynapses on neurons in the nucleus have beenseen in several species.207'210 Some of these syn-apses contain adenosine deaminase and come fromneurons in the hypothalamus and periaquaductalgrey matter.211212 However, it is unlikely thatthese neurons are responsible for the phasic in-hibition during opening because adenosine actsslowly and is usually classified as a modulatorrather than a classic synaptic transmitter.213 Thereare also axonal varicosities in contact with thecell bodies or proximal axon n. V mes. neuronsthat contain encephalin, substance P, serotonin,or immunologically similar substances.214 Whenthese substances are applied microiontophoreti-cally to n. V mes. neurons, neither encephalinnor substance P changes the firing rate,215 butthere is some preliminary evidence that serotoninis inhibitory.216 The somas or axon hillocks ofsome n. V mes. neurons are connected togetherby gap junctions207208 that provide electrotoniccoupling.217 If rhythmical inhibition causes ac-tion potentials to fail in the stem axon, this wouldprevent the generation of an action potential ina coupled cell, thereby reducing the excitatoryinput to jaw-closer motoneurons. In addition, itis likely that the hyperpolarization causes the axonpotentials to fail before they enter the branchesof the stem axon to n. V sup. Inhibition of spindleafferent cell bodies could thereby inhibit the strongdisynaptic stretch reflex218 during jaw opening.

D. Summary

The central pattern of mastication seems tobe generated in two stages: the rhythm by neuronsin the midline reticular formation and the burstsby premotor neurons near the motor nuclei. Theburst generators excite the opener alpha moto-neurons and inhibit the closers during the openingphase, but during the closer burst the opener mo-toneurons are not inhibited. Dynamic gammamotorneurons are tonically active during masti-

cation, while static gammas are excited duringclosure. The CPG also modulates primary affer-ents and interneurons in order to suppress un-wanted reflexes and to favor those that enhancemotor performance.

VIII. CONCLUSIONS

The basic features of mastication can be pro-grammed by the brain stem in the absence ofsensory inputs, but such movements would behighly inefficient and even dangerous to the or-ganism. Sensory feedback from a variety of in-traoral, joint, and muscle receptors interact withthe central control system at several levels toadapt the program to the characteristics of thefood. This is the source of the variability in thepattern of mastication.

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