Brain Stem Control of Swallowing: Neuronal Network and Cellular Mechanisms

PHYSIOLOGICAL REVIEWS
Vol. 81, No. 2, April 2001

Printed in U.S.A.
Brain Stem Control of Swallowing:

Neuronal Network and Cellular Mechanisms
ANDRÉ JEAN
Laboratoire de Neurobiologie des Fonctions Végétatives, Département de Physiologie et Neurophysiologie,

Faculté des Sciences et Techniques Saint Jérôme, Marseille, France
I. Introduction 929
II. Motor Activity 931
A. The sequential swallowing pattern: oropharyngeal deglutition and primary peristalsis
of the esophagus 931
B. Rhythmic swallowing movements 933
C. Motility of the esophagus: secondary and autonomic peristalsis 934
D. Other types of movements 934
III. The Neuronal Network Generating Swallowing 935
A. Localization and functional significance of the swallowing center neurons 935
B. Organization of the neuronal network 941
IV. Activation of the Neuronal Network and Modulation of Network Activity 945
A. Role of sensory inputs 945
B. Supramedullary influences on swallowing 947
C. Action of brain stem neurotransmitter systems 948
V. Neural Mechanisms 952
A. Central pattern generation 952
B. Mechanisms of deglutition and secondary peristalsis 957
C. Nature of the swallowing CPG 958
VI. Conclusion and Prospects 960
Jean, André. Brain Stem Control of Swallowing: Neuronal Network and Cellular Mechanisms. Physiol Rev 81:
929 –969, 2001.—Swallowing movements are produced by a central pattern generator located in the medulla
oblongata. It has been established on the basis of microelectrode recordings that the swallowing network includes
two main groups of neurons. One group is located within the dorsal medulla and contains the generator neurons
involved in triggering, shaping, and timing the sequential or rhythmic swallowing pattern. Interestingly, these
generator neurons are situated within a primary sensory relay, that is, the nucleus tractus solitarii. The second group
is located in the ventrolateral medulla and contains switching neurons, which distribute the swallowing drive to the
various pools of motoneurons involved in swallowing. This review focuses on the brain stem mechanisms underlying
the generation of sequential and rhythmic swallowing movements. It analyzes the neuronal circuitry, the cellular
properties of neurons, and the neurotransmitters possibly involved, as well as the peripheral and central inputs
which shape the output of the network appropriately so that the swallowing movements correspond to the bolus to
be swallowed. The mechanisms possibly involved in pattern generation and the possible flexibility of the swallowing
central pattern generator are discussed.
I. INTRODUCTION also protects the upper respiratory tract by cleaning the

naso- and oropharynx and closing the nasopharynx and
The act of swallowing is a fundamental motor activity the larynx, to prevent the pulmonary aspiration of food
in mammals, since it serves two vital functions. By pro- particles (34, 87, 90, 110, 226, 248).
pulsing food from the oral cavity into the stomach via the Swallowing is known to be a complex but stereo-
pharynx and the esophagus, swallowing subserves an typed motor sequence, with the implication that it in-
alimentary function and thus constitutes the first, irre- volves a fixed behavioral pattern. It constitutes, however,
versible step in feeding behavior. The swallowing reflex one of the most elaborate motor functions, even in hu-
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Copyright © 2001 American Physiological Society. All rights reserved.
930 ANDRÉ JEAN Volume 81
mans, since it requires coordinating an extraordinary bi- lowing is a suitable model not only for the neurophysio-
lateral sequence of activation and inhibition among more logical analysis of sequential motor events, but also for
than 25 pairs of muscles in the mouth, pharynx, larynx, that of rhythmic motor behaviors. However, it should be
and esophagus (70, 87, 226). One of the most striking stressed that the rhythmic motor pattern is mainly asso-
characteristics of swallowing is that the motor sequence ciated with the oropharyngeal phase of swallowing, and
can be readily initiated by stimulating a nerve, namely, the the uppermost part of the cervical esophagus when the
internal branch of the superior laryngeal nerve (SLN) (61, rhythmic frequency is low. No esophageal peristalsis oc-
87, 149, 225, 279). Swallowing therefore probably consti- curs during the successive oropharyngeal sequences, and
tutes, as Doty (87) has said, one of “the most complex only the last oropharyngeal event in the series is followed
stereotyped pattern of behavior that can be consistently by the complete esophageal stage (79, 111, 279, 350, 353).
evoked by electrical stimulation of a peripheral nerve.” In mammals, all the muscles involved in the oropha-
Because the motor event elicited by stimulating the SLN ryngeal stage are striated and are therefore driven by
includes all the components of the physiological motor several pools of motoneurons located in various cranial
pattern, swallowing provides a suitable model for study- motor nuclei in the brain stem and the uppermost levels
ing the neurophysiological mechanisms underlying motor of the cervical spinal cord (51, 87, 156, 226). The esoph-
pattern generation. ageal muscle is entirely composed of striated fibers in
Since Magendie (208), the act of swallowing has gen- species such as rat, guinea pig, rabbit, dog, sheep, and
erally been described as having three phases or stages cow and is therefore controlled by cranial motoneurons.
(34, 51, 70, 87, 89, 226). As regards the motor pattern In some species however, e.g., cats, opossums, and pri-
occurring during feeding behavior, swallowing has been mates, a variable portion of the lower esophagus is com-
subdivided into an oral, preparatory phase, followed by a posed of smooth muscle fibers, controlled by the auto-
pharyngeal phase, and then by an esophageal phase, cor- nomic nervous system (60, 79, 110, 111, 280).
responding to the primary peristalsis of the esophagus It has by now been clearly established, as originally
(78, 110, 142, 164, 280). In fact, the oral, preparatory phase postulated in the pioneering work by Meltzer (218 –220),
during which the alimentary bolus is formed is almost that the sequential and rhythmic patterns of swallowing
entirely voluntary and can be interrupted at any time, are formed and organized by a central pattern generator
whereas the pharyngeal and esophageal phases are invol- (CPG). The CPG was previously described as a swallow-
untary. Moreover, once it has been initiated, the pharyn- ing center that can be subdivided into three systems: an
geal phase of swallowing constitutes an irreversible mo- afferent system corresponding to the central and periph-
tor event. The same irreversible motor sequence is eral inputs to the center; an efferent system correspond-
observed both during the swallowing, which is not asso- ing to the outputs from the center, consisting of the
ciated with food consumption, but serves to clear the various motoneuron pools involved in swallowing; and an
oropharynx of small amounts of saliva, and during the organizing system corresponding to the interneuronal net-
reflex swallowing elicited by stimulation of the SLN (87). work that programs the motor pattern (51, 87, 156, 280).
Under these swallowing conditions, the pharyngeal phase In fact, the concept of a swallowing center implies the
of deglutition involves not only pharyngeal and laryngeal idea of an anatomical localization, whereas that of a CPG
muscles, but also muscles in the oral cavity such as the is based on a more functional principle focusing on the
tongue and suprahyoid muscles. Therefore, the actual activity of the various pools of neurons, i.e., motoneurons
motor event of swallowing can be best described as being and interneurons, involved in the motor activity. The
composed of an oropharyngeal stage and a subsequent swallowing CPG is located within the medulla oblongata
esophageal stage. It is this overall motor pattern, corre- (156, 161). Swallowing is indeed a primitive reflex, which
sponding to the basic or fundamental swallow, which has means that it is present in all animals with organs serving
been mainly studied in neurophysiological investigations differentiated functions and that it emerges early during
(154 –156). development. The normal human fetus can swallow by
Classically, swallowing has been taken to be a se- the 12th gestational week, before the cortical and subcor-
quential motor event and not a rhythmic motor behavior tical structures have developed (139). It has also been
like mastication, respiration, or locomotion. Deglutition reported that swallowing is still possible in human anen-
can occur repeatedly during feeding, but this is generally cephalic fetuses (266, 269). Experimental studies have
regarded as simply involving the repetition at a low fre- shown, moreover, that the destruction of several nervous
quency of a single sequential motor performance (87, 164, structures such as the forebrain, cerebellum, and pons
194). However, under the appropriate stimulus, some does not alter swallowing (34). In fact, the basic sequen-
components of the swallowing act can take on the prop- tial motor pattern seems to remain nearly normal as long
erties of a rhythmic motor behavior (51, 87, 149, 161, 279). as the nervous structures located between the C1 level
A typical rhythmic pattern of swallowing is elicited during and the trigeminal motor nuclei are intact (86, 89, 150,
long-lasting repetitive stimulation of the SLN. Thus swal- 152, 231).

April 2001 BRAIN STEM CONTROL OF SWALLOWING 931
Swallowing, which can be triggered by stimulating a tongue muscles, facial muscles, lip muscles, and levator
peripheral nerve and involves limited regions of the cen- mandible muscles, may or may not participate in swal-
tral nervous system, is an attractive model for the neuro- lowing, depending on either the species or the swallowing
physiological analysis of sequential and rhythmic motor conditions, and therefore constitute facultative degluti-
behaviors. However, it has received less attention than tion muscles (90).
other fundamental motor activities such as locomotion, The onset of the oropharyngeal stage of swallowing
mastication, or respiration (65). This is probably due to starts in most species with the contraction of the mylo-
the complexity of the motor pattern along with the great hoid muscle, which can be taken to be the first muscle to
number of muscles and cranial nerves involved, which become active in swallowing (87, 88). At the same time or
renders neurophysiological studies difficult. In addition, after a very short delay of 30 – 40 ms, a contraction also
the whole swallowing sequence is difficult to initiate in begins in the anterior digastric and internal pterygoid
anesthetized animals (149, 152). muscles, concurrently with that occurring in the geniohy-
Since the extensive review by Doty (87), several re- oid, stylohyoid, styloglossus, posterior tongue, superior
views on swallowing and its various aspects, such as constrictor, palatoglossus, and palatopharyngeus. All
those relating to esophageal motility, have been published these muscles constitute, along with the mylohyoid, the
(51, 70, 72, 78, 79, 84, 90, 110, 111, 129, 132, 154 –156, 161, “leading complex” that invariably initiates the act of swal-
164, 226 –228, 278, 280, 353). However, the brain stem lowing (Fig. 1A) (88). The sequence continues with a
mechanisms contributing to the sequential and rhythmic pattern of excitation and inhibition in pharyngeal and
motor events involved in swallowing have not been ana- laryngeal muscles. The middle and inferior pharyngeal
lyzed so far in detail. This review therefore focuses on the constrictors fire in an overlapping sequence, and the in-
brain stem CPG responsible for swallowing. It deals with hibitory phenomena are particularly striking in laryngeal
the results obtained over the last 25 years, first using muscles such as the posterior crycoarytenoid, which be-
classical electrophysiological techniques and then phar- comes silent for several hundred of milliseconds (87). The
macological approaches, as well as neuroanatomical oropharyngeal phase ends when the wave of contraction
methods, such as tract-tracing techniques. These results reaches the upper esophageal sphincter. At rest, the
have been mainly obtained on anesthetized or decere- sphincter is closed by the tonic contraction of the crico-
brate animals, and in some cases on in vitro brain stem pharyngeal muscle, which plays the main role in the
slices. The brain stem CPG will be analyzed here in terms sphincteric function (8, 9, 13, 49, 129, 301). Inhibition of
of its location, the firing behavior of the neurons, the the tonic contraction, resulting in the relaxation and
patterns of connectivity and the neurotransmitters in- opening of the sphincter, starts at the onset of swallowing
volved. The regulation of the central program by central and lasts until the cricopharyngeal muscle becomes ac-
or peripheral inputs and some tentative mechanisms pos- tive and propels the bolus into the esophageal body (Fig.
sibly underlying CPG activity will also be examined. Al- 1, A and B) (110, 111, 164, 226).
though a detailed analysis of the swallowing motor pat- The duration of the whole oropharyngeal sequence is
tern is beyond the scope of this review, the various motor in the range of 0.6 –1 s and remarkably constant in all the
patterns correlated with swallowing, which are relevant mammals studied, including humans (87, 110). The elec-
to the interpretation of central nervous mechanisms, will tromyographic activity in each individual muscle consists
be briefly described before the neurophysiological analy- of a phasic discharge, in the form of a burst of spikes,
ses are discussed. which ranges in general between 200 and 600 ms, depend-
ing on the muscle (88, 140, 171). The wave of contraction
travels down the oro- and hypopharynx at a speed of
II. MOTOR ACTIVITY
⬃10 –20 cm/s before reaching the upper esophageal
sphincter. This wave of contraction develops a force with
A. The Sequential Swallowing Pattern: a peak amplitude in the range of 100 mmHg in the oro-
Oropharyngeal Deglutition and Primary pharynx, reaching up to 200 mmHg in the human hypo-
Peristalsis of the Esophagus pharynx (Fig. 1B) (110, 353). When initiated by stimula-
tion of the SLN, swallowing does not start immediately
The motor activity of the two stages of swallowing but occurs after a variable delay. Depending on the spe-
shows different features. The oropharyngeal stage of the cies, this delay ranges from 100 ms in sheep to 40 – 60 ms
basic or fundamental swallowing is a complex, stereo- in rats (Fig. 4) (149, 152, 174). The presence of this delay
typed sequence of excitatory and inhibitory events (87). It suggests that the central nervous system comes into play
involves a set of muscles that always participate in this during this period and participates in organizing the swal-
fundamental motor pattern, and therefore, these muscles lowing motor pattern.
have been termed obligate muscles (87, 90). In addition to In addition to the firing activity, when background
the obligate muscles, other muscles, such as extrinsic activity is present in the muscles, it is abruptly inhibited

FIG. 1. The swallowing motor pattern. A: diagram of the electromyographic activity (EMG) of muscles active during
the swallowing sequence. Note that during the oropharyngeal phase several muscles are active synchronously, i.e.,
muscles of the leading complex, and that the sequentially activated muscles overlap considerably. Note the difference
in the timing of the propagation of the peristaltic wave between the oropharyngeal and the esophageal phases. A
downward deflection indicates inhibition of the tonic activity. The broken line indicates a possible inhibition that could
not be definitely confirmed under the experimental conditions used (see text for comments). Whatever the case may be,
note that when the inhibition is present, it begins at nearly the same time at each level of the swallowing tract. [Adapted
from Doty and Bosma (88).] B: pressure profiles of the contraction wave in pharynx, superior esophageal sphincter,
esophagus, and lower esophageal sphincter. Note that the contraction is stronger and faster during the oropharyngeal
than during the esophageal phase.
with the onset of firing in the leading complex, and this is no tonic or rhythmic activity. The peristaltic contrac-
inhibition is maintained until the actual swallowing con- tion moves from the proximal to the distal part of the
traction begins (Fig. 1A) (87, 88, 140, 171). Inhibition can esophagus at a speed that may show a fairly high degree
also be detected in muscles of the leading complex just of variability, depending on the species and the nature of
before they contract during swallowing (88). A strong the muscles, i.e., on whether an esophagus is composed of
inhibition of the background activity is also observed striated muscle alone or of both striated and smooth
after the cessation of the firing activity. Therefore, the muscle. For example, the whole esophageal phase can
oropharyngeal stage comprises an extraordinary se- last less than 2 s in anesthetized sheep and exceed 10 s in
quence of inhibition and activation in pairs of muscles, conscious humans (79, 87, 110, 149, 152, 353). Among all
which have to be synchronized during the motor se- the species combined, the mean velocity of the peristaltic
quence (70, 87). It is particularly striking that this com- wave can be evaluated at between 2 and 4 cm/s, a value
plex motor sequence constitutes an “all or none” motor conspicuously lower than that obtained in the case of the
activity, just like simpler reflexes. In other words, once it oropharyngeal sequence. The amplitude of the peristaltic
has been initiated, the sequence invariably reaches the wave is more variable than in the oropharynx. It may be
pharyngo-esophageal junction (87, 231). lower, ranging between 35 and 70 mmHg, but may reach
In comparison with the extraordinary complexity of upper values of 180 –200 mmHg (Fig. 1B) (110, 111, 275,
the oropharyngeal phase, the esophageal phase of swal- 353). The duration of the contraction at the segmental
lowing is quite simple. It consists of a peristaltic wave of level is longer than that observed in the oropharyngeal
contraction, which propagates down the esophagus, en- muscles. It generally exceeds 1 s and can reach values of
abling the alimentary bolus to be transported from the up to 4 s, depending on the level of the esophagus and the
pharynx to the stomach (111, 128, 129, 142, 164). At rest, nature of the muscle (129, 336). The esophageal phase
the esophagus is electromyographically silent, i.e., there ends when the contraction wave reaches the lower esoph-

ageal sphincter and propels the bolus down into the stom- B. Rhythmic Swallowing Movements
ach. At rest, the lower sphincter is the site of a high
pressure zone that prevents the reflux of food from the Rhythmic swallowing behavior can occur during
stomach. The factors contributing to the basal sphincter physiological activities such as drinking, which involves a
tone are multiple (78, 79, 110, 111, 164). In most species, train of closely spaced swallows. It has been reported that
the tonic contraction is mediated by a tonic depolariza- depending on the amount of liquid being drunk, several
tion of the smooth muscle fibers, without any action successive swallows occur, numbering up to 100 in horses
potentials (111, 280). During swallowing, the sphincteric (87). Under experimental conditions, the best way of
tone is inhibited at the beginning of a swallow or after a inducing rhythmic swallowing is to apply long-lasting re-
short delay. That is to say that this tone is inhibited during petitive stimulation to the SLN (Fig. 3) (86, 149, 225, 279).
the whole swallowing sequence until a phasic contraction Under repetitive stimulation of the SLN, at 20 –30 Hz,
of the sphincter occurs, as at the upper sphincteric level swallowing rates of 1–2/s can be readily induced in spe-
(Fig. 1, A and B) (79, 110, 164). cies such as rats and sheep during short periods of time
Because there is no basal tone in the esophagus at (4 –10 s) (149, 152, 174). Even during very long-lasting
rest, esophageal peristalsis has been thought of as just a stimulation, the rhythmic pattern can continue, although
sequence of excitatory events corresponding to the prop- obviously with a lower frequency. Under urethane anes-
agation of the contraction wave. However, several lines of thesia for example, a dog can swallow repetitively for 1 h
evidence suggest that the esophageal peristaltic contrac- at a rate of 0.4 Hz (87). In fact, as long as there is a bolus
tion, like the oropharyngeal sequence, not only consists of to swallow, or at least saliva, it is possible to observe
a single sequential contraction but that this contraction is sustained swallowing at a rapid rate with only slight signs
preceded by an inhibitory input, which has been called of fatigue.
deglutitive inhibition. The lower sphincter relaxation is a When swallows occur at a fast rate, the motor pattern
component of the deglutitive inhibition. At the other lev- consists of a series of complete oropharyngeal phases,
els of the esophagus, the inhibition is not usually detect- whereas the esophagus remains quiescent and the lower
able in the absence of basal tone, but becomes clearly esophageal sphincter is relaxed. A normal peristaltic con-
visible during repetitive swallowing (79, 110, 353). By traction wave does not occur until after the last swallow
artifically setting up a high pressure zone in the human in the series (Fig. 3A) (12, 221, 350). That is to say that
during repetitive swallowing, the so-called deglutitive in-
esophagus by inserting an intraluminal balloon and inflat-
hibition continuously blocks the esophageal activity.
ing it to a critical level, Sifrim et al. (303, 304) have also
When the rate of the oropharyngeal swallowing is slow,
observed the occurrence of a deglutitive-induced inhibi-
the esophageal peristalsis is initiated but then interrupted
tory influence before the esophageal contraction. This
or modified depending on when the subsequent swallow
inhibition begins simultaneously at various levels of the
occurs during the peristalsis and on the nature of the
esophagus but lasts progressively longer as it reaches the
muscle (striated or smooth) (350). When striated muscle
more distal segments. In addition, in vivo recordings on
only is involved, a second swallow initiated during the
the opossum smooth muscle have shown that even with-
primary peristalsis results in the immediate and complete
out any pressure changes in the esophageal body, a mem- inhibition of the contractile activity induced by the first
brane hyperpolarization of variable amplitude and dura- swallow, and the first wave progresses no further (Fig.
tion precedes the muscular contraction (273, 311). 3A) (129, 152, 277, 279). In the species with smooth mus-
Therefore, it seems very likely that, as in the oropharynx, cle distal esophagus, the pattern may be different, prob-
the sequential pattern occurring in the esophagus is a ably due to intricate interactions between central and
sequence of inhibitory and excitatory events. peripheral effects. When the first swallowing wave has
Upon comparing the duration of the contractions, the reached the smooth muscle segment of the esophagus,
velocity of the contraction waves and the pressures de- the peristaltic wave is not interrupted at this segment by
veloped, it becomes quite obvious that the esophageal the next swallow, but can proceed distally, although it
phase has quite different characteristics from the oropha- decreases gradually in amplitude until it disappears (350).
ryngeal phase. In addition, unlike the oropharyngeal In these species, a previous swallow or the presence of a
phase, esophageal peristalsis shows some degree of vari- swallowing wave within the esophagus can dramatically
ability. The contraction wave can stop before reaching the alter the nature of the subsequent esophageal wave by
sphincter, even in awake animals (9, 86, 149, 152, 218, 302, decreasing its amplitude, modifying its velocity, and
353). Esophageal peristalsis is therefore not an all or none sometimes rendering it nonperistaltic (350). Whatever the
sequence, which suggests that some differences may exist case may be, depending on the duration of the whole
between the central mechanisms involved in the esopha- swallowing sequence and the frequency of the rhythmic
geal versus the oropharyngeal sequence. activities, the rhythmic swallowing motor pattern mainly

involves the oropharyngeal phase, which suggests that an mastication, respiration, speech, and several protective
oscillatory activity may take place at the central level. reflexes.
1. Elementary reflexes
C. Motility of the Esophagus: Secondary and
Autonomic Peristalsis Electrical or natural stimulation of either the oro-
pharyngo-laryngeal area or the esophagus can evoke in
Part of the swallowing sequence, namely, an esoph- the same musculature a variety of simple reflexes. These
ageal peristalsis, can also be induced in the absence of the responses can also be elicited by stimulating central end
oropharyngeal phase of swallowing and is called second- of nerves which innervate these regions such as the tri-
ary peristalsis (219). Secondary peristalsis occurs in re- geminal, lingual, glossopharyngeal, vagal, superior laryn-
sponse to stimulation of sensory receptors in the esoph- geal, and recurrent laryngeal nerves (Fig. 4A) (87, 88, 90,
agus. For example, the transient esophageal distension 212, 279). The reflex response evoked by nerve stimula-
induced by rapidly inflating an intraluminal balloon can tion is generally ipsilateral, or at least it is much stronger
induce peristaltic contractions in the esophagus. This may ipsilaterally. The motor responses evoked consist of short
correspond to the distensions produced when the esoph- electromyographic activities, lasting for ⬃10 ms. The la-
ageal content is not completely cleared by the first swal- tency of the responses is also short, since the minimal
low, or when reflux of the gastric contents occurs into latency is in the range of 6 –10 ms, depending on the
the esophagus. Secondary peristalsis may be initiated muscle and the afferent fibers involved (87, 90). The reflex
at the level of either the striated or the smooth muscle. pathway may be monosynaptic, as in the case of the jaw
The wave of contraction usually begins at the level of closing muscles, but most of these elementary reflexes
the distension or just above it (79, 110, 111, 280, 353). are mediated via oligosynaptic circuits (90).
Once initiated, the secondary peristaltic wave With regard to the swallowing muscles, the elemen-
progresses distally through the esophagus, like the pri- tary reflexes evoked by stimulating the SLN can also
mary peristalsis (101, 129, 280). The amplitude and veloc- involve many nonlaryngeal muscles such as the geniohy-
ity of the peristaltic contractions induced by esophageal oid, palatopharyngeus, and thyrohyoid muscles, the pha-
distension are similar to those observed during primary ryngeal constrictors, and muscles of the tongue and upper
peristalsis. Secondary peristalsis can also be either com- cervical esophagus (87, 90, 279). All these muscles are
plete or interrupted at a variable distance from the level at obligate swallowing muscles, which means that the SLN
which it has been initiated. It should be noted, however, strongly influences the motoneurons that innervate these
that whether or not a transient distension suffices to muscles. The elementary reflex responses interact with
induce secondary peristalsis in the smooth muscle esoph- the more complex swallowing behavior. The latter exerts
agus, the presence of a bolus may be required for the the most powerful control on the motoneuronal pool and
peristaltic wave to be propagated down the whole esoph- to a large degree overrides the effects of the elementary
agus in species with a striated muscle esophagus (147, reflexes (Fig. 4A) (88). These findings indicate that the
149, 152, 276, 277). Secondary peristalsis also involves a circuitry involved in the elementary reflexes, or at least
sequence of inhibitory and excitatory events, as shown by part of this circuitry, also participates in swallowing.
the relaxation of the lower esophageal sphincter, which
begins when the wave of contraction is initiated and 2. Involvement of swallowing muscles in other
lasts until the contraction reaches the sphincteric level motor behaviors
(111, 263).
Swallowing muscles in the oropharynx and larynx
Finally, a peristaltic contraction can still be obtained
are also involved in several other integrated behaviors,
in the smooth muscle segment of the esophagus in the
such as the activities involved in the preparatory oral
absence of any extrinsic innervation. This peristaltic con-
phases of ingestive behavior, i.e., lapping, licking, suck-
traction is called tertiary or autonomic peristalsis because
ing, and mastication (90, 296, 326, 368). Muscles inner-
of the peripheral nature of the underlying mechanisms
vated by the trigeminal motor nucleus, such as the mylo-
(60, 78, 79, 111, 280).
hyoid, anterior digastric, and lateral pterygoid, are
involved in jaw opening and chewing, during which they
D. Other Types of Movements have a typical rhythmic activity (90, 215, 322, 326, 368).
Muscles innervated by the facial motor nucleus, such as
Some of the muscles that are involved in the motor the stylohyoid and posterior digastric muscles, intervene
performance of swallowing also participate in several in jaw movements (90). Tongue muscles controlled by the
other types of motor behavior. These motor activities can hypoglossal nucleus, such as the genioglossus and stylo-
be subdivided into simple motor events, called elemen- glossus, which are involved in protrusion and retrusion of
tary reflexes, and more complex motor patterns such as the tongue, respectively, are also among those mainly

involved in all oral activities such as chewing, licking, and tagonistic pairs of activities as respiration and swallow-
sucking (83, 200, 296, 326, 342). ing, speaking and swallowing, or jaw opening and swal-
Several swallowing muscles in the mouth, pharynx, lowing. They constitute an example subscribing to the
and larynx exhibit either an inspiratory or an expiratory general rule whereby motoneurons serve as a common
activity. This respiratory activity in oro-pharyngo-laryn- final pathway.
geal muscles ensures the patency of the upper airway and
regulates the airflow during the respiratory cycle (19, 81,
III. THE NEURONAL NETWORK GENERATING
143, 352). Adductor muscles of the larynx are active dur-
SWALLOWING
ing the expiratory phase of the respiratory cycle and
regulate the rate of airflow during expiration, whereas
abductor muscles become active during inspiration, thus A. Localization and Functional Significance of the
ensuring airway patency (19, 87). In addition to partici- Swallowing Center Neurons
pating in swallowing and respiration, laryngeal muscles
obviously participate strongly in the various types of pho- Primary lesion experiments as well as electrophysi-
nation (105, 239, 241, 369). Intrinsic and extrinsic tongue ological and more recent pharmacological and neuroana-
muscles, such as the genioglossus, also contribute to the tomical experiments have generally yielded fairly concor-
respiratory activity and may be active during either inspi- dant results as regards the swallowing CPG (24, 51, 87,
ration or expiration (200, 201, 372). The tongue tonus, in 156, 226, 280). It was on the basis of microelectrode
particular, is important in the maintenance of the appro- recordings, however, that the swallowing-related neurons
priate airway aperture. Pharyngeal muscles can also be were identified and the structures where they are located
active during one or the other phase of the respiratory were mainly established, and a general picture of the
cycle (112, 299, 352). With regard to the relationships organization and functional principles of the swallowing
between swallowing and respiration, in early asphyxia, CPG was built up (154, 156, 161). Most of the data ob-
most or all of the muscles active in deglutition are re- tained in this connection were obtained in experiments
cruited and participate in the respiratory effort. In these performed on anesthetized or decerebrate animals. In
cases, the muscles are active only in respiration (88). addition, under these experimental conditions, swallow-
Under these conditions, the respiratory drive therefore ing was frequently reflexively elicited by applying electri-
overrides the swallowing drive. cal stimulation to the SLN, in many cases in paralyzed
Emesis is a complex sequential and coordinated mo- animals, thus resulting in a fictive swallowing pattern.
tor activity, which involves some of the muscles which Therefore, these results relate more to the stereotyped
participate in swallowing (187, 188). During emesis, an basic swallowing movement than to the physiological
opening of both the lower and upper esophageal sphinc- motor activity involved in alimentary and drinking behav-
ters occurs and antiperistaltic contractions of the esoph- ior, which shows greater variability and a higher degree of
agus are generated, particularly in its cervical portion complexity (87, 90, 164).
(187–189). Several oropharyngeal muscles also contract, As regards the swallowing CPG, microelectrode data
especially the laryngeal muscles acting as glottis closers, have been obtained on several species, such as the cat,
pharyngeal dilator muscles, geniohyoid, genioglossus, and dog, monkey, rat, and sheep (59, 149, 174, 246, 255, 314,
digastric muscles (113, 347). Most of these muscles are 345), but the most extensive studies have been carried out
also active during retching, which may precede the expul- on anesthetized sheep (5, 46, 47, 61, 62, 149, 151, 152, 159,
sion phase of the emetic reflex. Rumination is a reflex 160). In addition, most of these results have been obtained
motor sequence whereby animals such as cow and sheep by performing extracellular recordings. Only recently
regurgitate food from the stomach back to the mouth, have intracellular recordings been successfully obtained
where it is chewed again and then reswallowed (52, 91, on swallowing neurons, focusing mainly on the activity of
110, 276, 277, 308). During rumination, the esophageal motoneurons (337, 376, 377), whereas few intracellular
sphincters relax and an antiperistaltic wave occurs con- recordings have been carried out so far on swallowing
comitantly, in this case involving the whole esophagus. interneurons (106). When recorded extracellularly, the
Swallowing muscles are also activated during activities vast majority of the swallowing-related neurons, which
such as coughing, belching, eructation, regurgitation, will be referred to hereafter as swallowing neurons, are
and several other rather particular types of behavior phasic neurons that are usually silent but produce a burst
(110). of spikes, which has been called “swallowing activity”
This brief survey shows the extraordinary diversity (Fig. 2) (149), the timing of which is correlated with the
of the behavior in which the muscles participating in swallowing motor activity. Spontaneously active neurons
swallowing are also involved. These muscles can partici- have also been found to participate in swallowing. De-
pate in reverse motor activities, such as rumination or pending on the neuron, they can exhibit either a tempo-
vomiting compared with deglutition, or even in such an- rary increase in their discharge frequency or a phasic

inhibition of their spontaneous discharge during swallow-

ing (Fig. 2A) (149, 152, 174, 345). Depending on the tem-
poral relationship between their activity and the onset of
swallowing, these swallowing neurons have been classi-
fied into three categories: “early” or oropharyngeal neu-
rons, firing before or during the oropharyngeal phase of
swallowing, and “late” and “very late” esophageal neu-
rons, discharging during the esophageal peristalsis, that is
to say during the cervical or thoracic esophageal contrac-
tions, respectively (Fig. 2) (149, 152). In addition to firing
during the motor swallowing sequence, the swallowing
neurons can also be activated by a local distension of the
region of the alimentary canal which contracts in phase
with the neuronal firing (Fig. 6A1). The swallowing neu-
rons can furthermore be subdivided into motoneurons
and interneurons.
1. Motoneurons
Motoneurons active in swallowing have been identi-

fied using criteria such as whether they are antidromically
activated in response to stimulation of motor nerves, their
discharge frequency, and the location of the recording
electrode site. However, no very extensive electrophysi-
ological studies have been carried out so far on swal-
lowing motoneurons. These motoneurons are localized
within the trigeminal (V), facial (VII), and hypoglossal
(XII) motor nuclei, the nucleus ambiguus (IX, X), the
dorsal motor nucleus of the vagus (X), and at the cervical
spinal level between C1 and C3 (51, 87, 90, 156, 226).
However, depending on which muscles are innervated by
these motor nuclei and on the size of the population of
motoneurons actually involved in swallowing, these mo-
tor nuclei do not all participate to an equal extent in
swallowing, at least during the basic pattern.
V and VII motor nuclei do not deal mainly with
swallowing (87, 90). They are most strongly involved in
several other orofacial activities such as jaw reflexes,
mastication, licking, and sucking (90, 326, 368). Lesion
FIG. 2. Sequential firing of dorsal medullary neurons during swal-
experiments have shown for example that abolishing the
lowing. A: firing patterns of oropharyngeal (early) neurons. MHm V motor nuclei does not affect the swallowing sequence
gives the EMG of the mylohyoid, indicative of the onset of swallow- (87, 89, 152). Trigeminal motoneurons mainly involved in
ing, and SwN is the activity of various neurons recorded at the
nucleus tractus solitarii (NTS) level during swallowing triggered by swallowing innervate the mylohyoid, anterior digastric,
stimulating the superior laryngeal nerve. Recordings have been lateral pterygoid, and tensor veli palatini (87). Within the
aligned on the onset of the mylohyoid EMG (t0, broken line). Only the VII motor nucleus, motoneurons greatly involved in swal-
burst firing (“swallowing activity”) or the cessation of neuronal ac-
tivity is shown; the initial activity induced by each laryngeal stimu- lowing control the posterior digastric and stylohyoid (87).
lation is not represented (see Fig. 4). Note the large overlap between Other muscles innervated by these two motor nuclei, such
the sequential burst firing. The neuronal activity shown in the first as the medial pterygoid, temporal, and masseter are more
trace is that of a neuron with a preswallowing discharge; in this case,
continuous firing occurred from the superior laryngeal nerve (SLN) facultative swallowing muscles (70, 90). In fact, the main
stimulation up to the swallowing burst. [Adapted from Jean (149, motor nuclei involved in swallowing are the XII motor
152).] B: activity of esophageal (late and very late) neurons. Note the
differences between the discharge duration and burst firing frequency
nucleus and the nucleus ambiguus. Most, if not all, of the
in esophageal versus oropharyngeal neurons. [Adapted from Jean motoneurons within these nuclei, which innervate the
(149).] intrinsic and extrinsic muscles of the tongue, such as the
genioglossus, geniohyoid, styloglossus and hyoglossus,

and the pharynx, larynx, and esophagus, participate in neurons have also been identified in the nucleus am-
swallowing (87, 226). biguus (66, 247). Unlike the striated motoneurons, which
Data have shown the existence of a myotopic pattern are located compactly in a single region, the preganglionic
of organization within the motor nuclei. This pattern of esophageal neurons consist of two separate groups: the
organization is based on a series of dorsoventral and one located in the rostral part of the X motor nucleus and
mediolateral subdivisions in V, VII, and XII motor nuclei the other in its caudal portion (66, 284).
(341), i.e., the mylohyoid and anterior digastric motoneu- Extracellular recordings have shown that within V
rons are situated in the ventromedial region of V motor and XII motor nuclei and the nucleus ambiguus (46, 47,
nucleus, and tongue protrudor motoneurons are located 149, 151, 152, 174), the oropharyngeal motoneurons,
in XII ventrolateral nucleus, whereas the tongue retrac- which are generally silent at rest, exhibit during swallow-
tors are to be found more dorsolaterally (102, 181, 182, ing a short burst of low-frequency (40 –50 Hz) spikes with
196, 207, 234, 256, 344). The myotopic organization of the a duration in the 50- to 200-ms range and considerable
nucleus ambiguus corresponds to the well-known rostro- overlapping between the discharge of the various neu-
caudal pattern of organization of the motoneurons inner- rons. The bursting discharge can either precede the be-
vating the esophagus, pharynx, and larynx (28, 191–193), ginning of swallowing by a few milliseconds or lag be-
where the esophageal motoneurons are localized in the tween 0 and 200 ms behind the onset of the sequence. The
rostral compact formation of the nucleus, the pharyngeal firing behavior of esophageal motoneurons is somewhat
and soft palate motoneurons in the intermediate semi- different (152, 183, 377). However, the results published
compact formation, and most of the laryngeal motoneu- to date on these motoneurons are mainly restricted to
rons in the caudal loose formation of the nucleus. This sheep. The bursting discharge has a longer duration (up to
scheme of organization results in the sequential firing of 800 ms) and a very low frequency (10 –20 Hz) and lags
nucleus ambiguus motoneurons during swallowing. How- from 200 –300 ms to 2 s behind the onset of swallowing.
ever, the various pools of motor nuclei are not involved in Therefore, the swallowing activity has a longer duration
any ordered sequence during swallowing, since the con- and a lower frequency in the esophageal than in the
traction of muscles in the leading complex involves mo- oropharyngeal motoneurons; the later the neuron be-
toneurons in V, VII, and XII motor nuclei and the nucleus comes active during swallowing, the longer it will fire and
ambiguus (88). the lower its discharge frequency will be (see Table 1).
With regard to the innervation of the smooth muscle In addition to the burst firing that occurs in motoneu-
esophagus, the majority of the preganglionic neurons are rons during swallowing, they can exhibit a short-latency
located within the X motor nucleus. It has been reported (7–12 ms) synaptic activation, which is also called initial
that experimental lesion of this nucleus in the cat impairs activity. This initial activity consists of one spike elicited
the motility of the smooth muscle esophagus (131). More- in oropharyngeal or esophageal neurons by stimulating
over, after injecting tracer into the cat esophagus and the afferent fibers present in the SLN or the vagus nerve,
lower esophageal sphincter, most of the labeled cells have respectively (46, 47, 149, 151, 152, 174, 317). This initial
been observed in the X motor nucleus, although some activity has been observed only in response to ipsilateral
1. Comparison of discharge characteristics and localization between oropharyngeal and esophageal

TABLE
medullary neurons
Oropharyngeal Neurons Esophageal Neurons
Interneurons Interneurons
DSG VSG Motoneurons DSG VSG Motoneurons
Burst duration, ms 90–400 80–300 50–200 150–1200 150–800

Firing mean frequency, Hz 50–250 40–250 40–50 10–40 10–40
(3–8 for preganglionic
fibers)
Latency of synaptic activity, ms
Peripheral afferent fibers 1–4 6–12 7–12 3–4 (SLN) 7–12 (SLN)
(SLN/IX) (SLN/IX) (SLN/IX) 6–10 (cervical X) ?
Cortex 5–8 10–16 10–16 10–12
Localization NTS subnuclei Ventrolateral V, VII, XII NTS subnuclei nA (X) (X dorsal
(interstitial, reticular nerve nuclei (centralis, motor nucleus for
intermediate, ventral, formation nA (IX/X) intermediate) preganglionic
and ventrolateral) neurons)
For further explanations and references, see text (sects. III and IV, A and B). nA, nucleus ambiguus; NTS, nucleus tractus solitarii.

stimulation applied to afferent fibers. Several pulses are the pons, at the level of the sensory nucleus of the tri-
generally required to initiate the spike, the latency of geminal nerve (46, 47, 152, 160, 174, 254).
which is variable and suggests the existence of a polysyn- The results of microelectrode recording studies have
aptic pathway. not corroborated the lesion and anatomical data, suggest-
No central recordings have been performed so far on ing that the swallowing CPG might be located rostrally in
the activity of the preganglionic vagal neurons that inner- the medial reticular formation. Doty et al. (89) postulated
vate the smooth muscle esophagus. The data available on that the interneuronal network that organizes swallowing
this subject were obtained in cross-innervation experi- might be located within the medial reticular formation,
ments and by directly recording the activity of vagal fibers between the posterior pole of the facial nucleus and the
(109, 281). They show that these neurons operate an rostral pole of the inferior olive. This assumption was
ordered sequence during swallowing, which suggests that based on lesion experiments performed on various spe-
a central control may be at work even in the case of the cies (e.g., on cats, dogs, and monkeys), which severely
smooth muscle esophagus. The burst firing of the pregan- affected the motor pattern. The anatomical results ob-
glionic vagal neurons driving the smooth muscle esopha- tained on the cat by Holstege et al. (137) have suggested
gus has a long duration, in the range of 1 s, and a very low that part of the “swallowing center” might be present in
frequency, i.e., 3– 8 Hz (109, 281). Recordings of the vagal the pontine tegmental area just dorsomedial to the supe-
efferent fibers innervating the opossum esophagus and rior olivary complex. In fact, the latter data were obtained
the dog lower esophageal sphincter, both of which are with tracing techniques, which can be used to demon-
composed of smooth muscle, indicate that both the vagal strate connections between neurons but not to identify
excitatory and inhibitory pathways are involved in swal- the function of any such connections. Moreover, there is
lowing (109, 233). These results therefore show that the no direct evidence that any swallowing-related neurons
CPG exerts both an excitatory and an inhibitory drive on exist within these regions: their possible role in swallow-
the smooth musculature. ing still remains to be determined.
Recent intracellular recordings on hypoglossal and A) DORSAL SWALLOWING GROUP: THE INTERNEURONAL POPULA-
nucleus ambiguus motoneurons (337, 376, 377) have TION IN THE NTS. Within the NTS, there exist neurons that
shown that, during swallowing, the firing of motoneurons fire during either the oropharyngeal or the esophageal
was superimposed on a bell-shaped membrane depolar- phase of swallowing (149, 152). These neurons exhibit a
ization. This simple bell-shaped depolarization of the typical sequential firing pattern that parallels the sequen-
membrane potential is not the only event that has been tial motor pattern typical of deglutition (Fig. 2). When
found to accompany the firing of these motoneurons. In rhythmic oropharyngeal phases of swallowing are elic-
some cases, complex depolarizing-hyperpolarizing or hy- ited, NTS neurons involved in the oropharyngeal se-
perpolarizing-depolarizing waves of membrane potential quence produce rhythmic bursting discharges that are
are evoked in motoneurons during swallowing (Fig. 6D). closely linked to the motor pattern (Fig. 3). Because these
This indicates that in addition to an excitatory drive, these neurons are still active during fictive swallowing elicited
motoneurons may also receive inhibitory inputs or have in paralyzed animals, their bursting discharge cannot be
complex intrinsic properties that are activated by the due to peripheral afferent inputs generated by the mus-
swallowing drive. cular contraction and actually correspond to a central
swallowing activity (149, 152, 174). These results have
2. Interneurons amply confirmed that swallowing is a centrally patterned
motor activity, as suggested in the pioneer study by Melt-
Extensive microelectrode recordings, first performed zer (218), and demonstrate that NTS medullary neurons
on sheep (5, 61, 62, 149, 151, 152, 159) and subsequently form part of the neuronal network that generates swal-
on the rat, dog, cat, and monkey (59, 94, 174, 190, 202, 246, lowing. In previous studies on the cat, Sumi (314) failed to
345), have shown that the swallowing neurons are located detect any bursting activity in the NTS during fictive
in two main brain stem areas: 1) in the dorsal medulla swallowing. However, recent studies have provided evi-
within the nucleus tractus solitarii (NTS) and in the adja- dence that in the cat also, there exist NTS neurons in-
cent reticular formation, where they form the dorsal swal- volved in swallowing that have a centrally patterned ac-
lowing group (DSG), and 2) in the ventrolateral medulla, tivity (106, 345).
just above the nucleus ambiguus, where they form the Most of the oropharyngeal neurons are active either
ventral swallowing group (VSG). Swallowing neurons are just a few milliseconds before or during the oropharyn-
therefore located in the same medullary sites where are geal phase of swallowing. The firing pattern of these
situated neurons that belong to CPGs involved in respira- neurons is characterized by a short burst of spikes, with a
tion and cardiovascular regulation (21, 73, 99, 163). In duration in the range of 100 –300 ms, a steady or an
addition, other swallowing-related neurons have been increasing-decreasing frequency with a mean value in the
identified within or very close to the motor nuclei and in range of 100 Hz, and an instantaneous frequency that can

FIG. 3. Rhythmic patterns of swallowing. A: rhythmic swallowing elicited in sheep by repetitively stimulating the SLN
at 30 Hz. Note that the rhythmic pattern consisted of a series of oropharyngeal stages (MHm: mylohyoid EMG), and in
this case, rhythmic contractions of the uppermost part of the esophagus (cEs1: upper cervical esophagus EMG). Only
the last swallow in the series is complete with primary peristalsis after the oropharyngeal stage, as shown by the EMG
of the lower cervical esophagus (cEs2) and the pressure wave recorded at thoracic level (thEs). [From Jean (152).]
B: rhythmic burst firing of an oropharyngeal NTS neuron with preswallowing discharge (SwN), during repetitive fictive
swallowing elicited in paralyzed sheep by applying long-lasting stimulation to the SLN. XII shows the neuronal activity
recorded in the hypoglossal nerve. (From Jean, unpublished data.) C: intracellular recording of a swallowing neuron
within the cat NTS, during rhythmic swallowing elicited by applying repetitive stimulation to the SLN. Note that the burst
firing was superimposed on a high-amplitude bell-shaped depolarization of the neuron. [Adapted from Gestreau et al.
(106).]
be as high as 400 Hz (Figs. 2A and 4B) (149, 152, 174). duration of the discharge and a decrease in the firing
Recent intracellular studies on cats have shown that the frequency when the neuron is active later during swallow-
bursting activity of oropharyngeal NTS neurons is super- ing (Table 1). No central recordings have been performed
imposed on a high-amplitude depolarizing wave, between so far on esophageal neurons in species with a smooth
15 and 20 mV, which indicates that a strong central drive muscle esophagus.
is exerted during swallowing (Fig. 3C) (106). As in the When stimulation is applied to afferent fibers, both
case of the muscular pattern, considerable overlaps occur types (oropharyngeal and esophageal) of interneurons
between the sequential burst firing of the various neurons. produce a synaptic response (initial activity) in the form
The esophageal neurons obviously fire later on during of a single spike. This initial activity can be elicited by
swallowing, with a phase lag of 200 –300 ms to 2 s after the stimulating the ipsilateral SLN in all the oropharyngeal
onset of the motor activity, at least in sheep (149, 151, NTS neurons and in the late esophageal neurons, the
152). As we saw above with the motoneurons, the firing firing behavior of which is linked to the activity of the
behavior of the esophageal neurons differs from that of upper cervical esophagus (Figs. 4B and 6A). In the very
the oropharyngeal neurons. The duration of the bursts of late esophageal neurons, an initial activity can be elicited
spikes is longer (between 200 ms and 1 s), and the firing by stimulating the cervical vagus (149, 152). The synaptic
frequency is much lower, since it does not exceed 40 Hz response may occur with a very short, stable latency of
in the case of the late neurons and is as low as 10 –20 Hz 1–2 ms, indicating that, at least some, of these neurons are
in that of the very late neurons (Fig. 2B). At the level of monosynaptically connected to afferent fibers (149, 152,
the interneurons, one can also observe an increase in the 255, 294). In these types of neurons, the synaptic response

FIG. 4. Characteristics of motor and neuronal swallowing patterns. A: elementary reflexes and swallowing motor
event. EMG activity recorded in rat suprahyoid muscles (SHm) or sheep cervical esophagus (cEs) during swallowing
evoked by repetitive (1) or single-pulse (2) stimulation of the SLN. Note that in addition to the swallowing bursting
activity, the stimulating pulses elicited short-duration EMG responses with a brief latency, i.e., the so-called elementary
reflexes. Note also in A1 the inhibition of the elementary reflexes during swallowing and several milliseconds later. [1)
Adapted from Kessler and Jean, unpublished data; 2) adapted from Roman and Car (279).] B: activity of two oropha-
ryngeal neurons (SwN) recorded within the sheep NTS during swallowing (indicated by the EMG of the mylohyoid:
MHm) evoked by applying repetitive (1) or single-pulse (2) stimulation to the ipsilateral SLN. As in the muscles, the
laryngeal stimulation elicited an initial synaptic response in the form of one short latency spike in addition to the
swallowing burst firing. Note that when no swallowing occurs (first stimulation in 2), only the initial response is evoked.
[Adapted from Jean (149, 152).] C: patterns of an oropharyngeal neuron with preswallowing activity. When the
stimulation is ineffective in inducing swallowing, the ipsilateral SLN stimulation triggers only preswallowing activity with
a variable duration; the preswallowing discharge pattern becomes a swallowing burst firing pattern when swallowing
occurs (MHm: mylohyoid EMG; middle traces). Note that when swallowing is triggered by applying stimulation to the
contralateral SLN (bottom traces), the preswallowing discharge is lacking, and only the swallowing burst is initiated.
[Adapted from Jean (152).] D: neuronal firing (SwN) elicited in an oropharyngeal neuron with preswallowing discharge,
recorded from the sheep NTS, in response to stimulation applied to either the ipsilateral SLN or the glossopharyngeal
nerve (IX). Note that the IX stimulation, which does not trigger swallowing in sheep, evokes only preswallowing activity,
which lasts longer when the stimulation is repeated. [Adapted from Ciampini and Jean (61).]
and the burst firing activity are clearly separated by an (Figs. 2 and 4, C and D). This pattern of discharge sug-
interval of variable length, depending on the order at gests that these neurons are involved in the initiation of
which the neuron is recruited in the sequence (Figs. 4B swallowing, and it has been postulated that they may
and 6A). constitute the trigger neurons in deglutition (149, 152).
Among NTS oropharyngeal neurons, some exhibit a As regards the location of NTS swallowing neurons,
particular pattern of bursting activity starting before the most of the relevant data were obtained before the cyto-
onset of the swallowing motor sequence. Unlike those architectonic subdivisions of the nucleus were estab-
neurons, where the swallowing burst occurs with a phase lished on the basis of anatomical studies (1, 17, 157, 167).
lag after stimulation and only when a swallow is initiated, Therefore, their location has not been specified in relation
these neurons exhibit a continuous discharge in response to these subdivisions. However, in all the species studied,
to the stimulus. This discharge, called “preswallowing it has emerged that the oropharyngeal neurons are situ-
activity,” starts long before the beginning of the muscular ated rostrocaudally at the level of the intermediate-sub-
contraction. It decreases and stops quite rapidly when no postremal portion of the NTS (17), within the medial part
swallowing occurs, but continues and increases, turning of the lateral NTS which overlaps the interstitial, interme-
into a swallowing activity, when swallowing is initiated diate, ventral, and, to some extent, the ventrolateral sub-

divisions of the nucleus (149, 152, 161, 174). The esopha- C) INTERNEURONS IN THE MOTONEURONAL POOLS. Apart from
geal neurons, which to date have been clearly identified the VSG in the ventrolateral medulla, which probably
only in sheep, are also situated at the level of the inter- plays an important role within the swallowing CPG (see
mediate-subpostremal part of the nucleus, between the sect. IIIB), swallowing interneurons have been identified
tractus solitarius and the X motor nucleus (149, 152), a within V and XII motor nuclei or in their close vicinity.
region which may correspond to the centralis subdivision These neurons produce a high-frequency discharge, and
of the NTS in the rat (1, 202). Interestingly, anatomical when tested by stimulating the motor nerves, they failed
results have shown that both laryngeal and pharyngeal to respond antidromically (46, 47, 149, 174). These neu-
afferent fibers project mainly to the interstitial subdivi- rons may play the role of premotor neurons or be involved
sion of the NTS in all the species studied and that the in the organization of the swallowing drive to the various
esophageal afferent fibers end within the NTS subnucleus motoneurons involved in swallowing within a single mo-
centralis, at least in the rat (1, 238). Therefore, within the tor nucleus (254). Electrophysiological and neuroana-
NTS, there are these two subnuclei that are mainly con- tomical data also suggest that they might be involved in
cerned with swallowing (see Table 1). the bilateral coordination of the motoneuronal pools (5,
B) VSG. In the ventrolateral medulla above the nucleus 46, 47, 158, 235). The exact function of these neurons has
ambiguus, there also exists a large population of oropha- not yet been elucidated, however, and further experi-
ryngeal swallowing neurons (59, 94, 149, 151, 152, 174, ments will be required before this is possible.
252, 345). These neurons have been identified as interneu- D) PONTINE INTERNEURONS. In sheep, a population of
rons on the basis of criteria, such as the lack of anti- neurons exhibiting burst firing in phase with the oropha-
dromic activation by vagus nerve stimulation and a high ryngeal stage of swallowing has been found to exist more
discharge frequency. In addition, several neurons in this rostrally in the pons, in a region extending rostrally to the
region fire during the leading phase of swallowing, before exit of the facial nerve, above the V motor nucleus, at the
most of the motoneurons in the nucleus ambiguus be- level of the principal sensory trigeminal nucleus (160).
come active. The burst firing behavior of the VSG neurons These neurons, which are spontaneously active, present a
is very similar to that of the DSG neurons in terms of the swallowing activity in the form of a burst of spikes lasting
sequential firing pattern, in which there is considerable some 40 –380 ms, with a similar discharge frequency to
overlap, discharge duration, and frequency. This popula- that of the medullary interneurons, ranging between 60
tion has, however, a lower instantaneous discharge fre- and 340 Hz. In addition, they can be synaptically activated
quency, which never reaches the higher instantaneous by applying stimulation to the ipsilateral SLN with a la-
values (400 Hz) observed in the DSG neurons (149, 152, tency of 1.5– 4 ms resembling that of the NTS neurons.
174). The main difference lies in the synaptic response to However, there are two striking differences between
stimulation of the SLN. The initial activity is not readily these and the NTS neurons. In the pons, the swallowing
triggered in these VSG neurons with a single pulse, and burst always occurs after the beginning of swallowing and
several pulses are generally required to initiate the reis abolished after motor paralysis of the animal. In addi-
sponse. Moreover, the fact that the latency is visibly tion, unlike NTS neurons, the pontine neurons are anti-
longer (between 7 and 12 ms) and shows some degree of dromically activated when stimulation is applied to the
variability suggests the existence of a polysynaptic con- ventro-postero-medial nucleus of the thalamus (160). On
nection between the afferent fibers and the neurons (149, the basis of these results, these pontine neurons have
174, 255; see Table 1). been classified as sensory relay neurons and are thought
The existence of a large population of esophageal to be involved in providing information from the oropha-
interneurons in the ventrolateral medulla is less clear. ryngeal receptors to the higher nervous centers. They
Bursting discharges in phase with esophageal peristalsis therefore do not belong to the swallowing CPG.
have been recorded in the medullary region above the
nucleus ambiguus (152). However, in the case of esopha- B. Organization of the Neuronal Network
geal neurons, applying stimulation to the vagus nerve
systematically induces an antidromic field potential. With- The detailed connections between the various groups
out any intracellular evidence, it is therefore not possible of neurons within the swallowing CPG still remain to be
in the case of esophageal neurons to clearly distinguish mapped. However, the results of electrophysiological and
between motoneurons and actual interneurons (151, 152). anatomical experiments have provided some information
Whatever the case may be, swallowing neurons about the organization of the DSG, VSG, and motoneurons
within the ventrolateral medulla are still active during (2, 152, 154, 156).
fictive swallowing. Their bursting activity is therefore ac-
tually a central discharge, and these neurons, like those in 1. Connections between the various neuronal groups
the NTS, belong to the neuronal network that generates The latency of the synaptic response (initial activity)
swallowing. is shorter among the neurons of the DSG than those of the

VSG. In the case of SLN stimulation, the latency is 1– 4 ms is also connected to the homologous contralateral med-
in the DSG and 7–12 ms in the VSG (149, 151, 152, 159, ullary region and to VII, X, and XII motor nuclei, all of
174, 255). A synaptic response can also be initiated in which are also involved in swallowing (158). The ventro-
swallowing neurons by stimulating a specific cortical lateral medulla, which contains swallowing neurons, is
area, which induces swallowing (see sect. IV). Here again, therefore connected to all the various groups of moto-
the latency of the response is shorter in the NTS swallow- neurons involved in swallowing: this conclusion is in
ing neurons (5– 8 ms) than in the neurons in the ventro- complete agreement with other anatomical data (138,
lateral medulla (10 –16 ms) (152, 159). These results sug- 195, 343).
gest that the neurons of the VSG are probably activated These results suggest that within the swallowing net-
via neurons of the DSG. Indeed, regardless of which af- work, VSG neurons are activated via DSG neurons and
ferent pathway is stimulated, the initial response of the that motoneurons are driven by neurons of the VSG (Fig. 5
VSG neurons is abolished after lesion of the DSG (152, and Table 2). If we therefore consider the swallowing
159). Although no direct evidence is available at the single CPG, there exist simple circuits linking together the af-
cell level that a connection of this kind exists between the ferent fibers, the DSG neurons, the VSG neurons, and the
DSG and VSG, connections between the NTS region and motoneurons. At each level obviously, i.e., within the
the ventrolateral reticular formation surrounding the nu- NTS, the ventrolateral medulla and the motoneuronal
cleus ambiguus, where swallowing neurons are located, pools, circuits more complex than a simple monosynaptic
have been found to exist in several anatomical experi- connection may exist. However, the trisynaptic circuits
ments (57, 69, 236, 249, 257, 258, 283, 288). Other anatom- are probably basic elements in the functioning of the
ical results have shown that the ventrolateral medulla also CPG. Such reflex loops are also probably basic in the
projects to the NTS region (20, 126, 198, 282, 349). How- elementary reflexes.
ever, whether or not these possible reciprocal connec- Recent results obtained with retrograde tract tracing
tions are involved in swallowing still remains to be estab- techniques or by performing transneuronal labeling with
lished. pseudorabies virus indicate that a direct connection may
Electrophysiological experiments on sheep have exist between swallowing regions in the NTS and mo-
shown that only the swallowing neurons within the VSG toneurons in the nucleus ambiguus, at least in the rat (16,
could be antidromically activated by stimulating the swal- 18, 39, 125, 126). These studies show that NTS neurons,
lowing region of V motor nucleus, i.e., that region where which are supposed to be esophageal neurons, since they
swallowing motoneurons are located, while none of the are located in the subnucleus centralis where esophageal
neurons within the DSG exhibited any antidromic activa- afferent fibers project, send axon terminals in the rostral
tion under the same conditions (5). These results indicate compact formation of the nucleus ambiguus where esoph-
that the V motor nucleus is connected to only one of the ageal motoneurons are situated. A direct connection be-
medullary regions involved in swallowing, namely, the tween NTS esophageal neurons and esophageal motoneu-
VSG. Similar results have also been obtained on the XII rons may exist, since the existence of an interneuronal
motor nucleus, the stimulation of which evoked an anti- pool of esophageal neurons has not been clearly demon-
dromic potential in swallowing neurons of the VSG (4). In strated in the ventrolateral medulla. However, it seems
addition, more recent electrophysiological studies on unlikely that a direct connection of this kind exists in the
sheep and cats have established that within the VSG, the case of oropharyngeal neurons (see sect. IIIA2). All the
same identified swallowing neuron can project to more results available to date on functionally identified swal-
than one motor nucleus. It has been shown, for example, lowing neurons have shown that motoneurons are driven
that the same neuron can project either to V and XII by oropharyngeal neurons within the VSG. Therefore, it is
motor nuclei, or to the XII motor nucleus and the nucleus puzzling that the oropharyngeal population of interneu-
ambiguus (6, 94). Some data also suggest that the same rons within the ventrolateral medulla, i.e., the VSG, was
neuron might project to V and XII motor nuclei and the not determined in the anatomical studies. Recordings will
nucleus ambiguus (94), which are all motor nuclei in- have to be made on functionally identified neurons to be
volved in swallowing. These electrophysiological data fit able to ascertain whether there exists a monosynaptic
in well with those coming from anatomical studies. It has link between neurons in the DSG and motoneurons.
been shown that retrograde transport of peroxidase, in-
jected under electrophysiological control into the region 2. Role of the various interneuronal groups in the CPG
of the V motor nucleus where swallowing motoneurons
are situated, resulted in labeling of neurons in the ventro- It has been established in several networks involved
lateral medulla. Control experiments with tritiated in basic motor behavior, such as locomotion, that within
leucine, injected in the VSG region, show labeling in the a given CPG all the neurons are not equal since some of
ventromedial region of the V motor nucleus. In addition, them play a preeminent role (10, 117). As regards swal-
these experiments showed that the ventrolateral medulla lowing, data already obtained suggest that neurons in the

FIG. 5. Diagram of the swallowing

central pattern generator (CPG). The
CPG includes two main groups of neu-
rons located within the medulla oblon-
gata: a dorsal swallowing group (DSG)
located within the nucleus tractus solita-
rii (NTS) and the adjacent reticular for-
mation and a ventral swallowing group
(VSG) located in the ventrolateral me-
dulla (VLM) adjacent to the nucleus am-
biguus (nA). The DSG contains the gen-
erator neurons involved in triggering,
shaping, and timing the sequential or
rhythmic swallowing pattern. The VSG
contains the switching neurons, which
distribute the swallowing drive to the
various pools of motoneurons involved
in swallowing. It should be noted that the
pathway including the peripheral affer-
ent fibers, neurons in the DSG and VSG,
and motoneurons forms an oligosynaptic
loop involved in swallowing and the ele-
mentary reflexes (see text for additional
information). [Adapted from Jean (153).]
DSG are likely candidates to act as generator neurons in afferent fibers belonging to the solitary tract. The wide
the initiation and organization of the sequential or rhyth- dispersion of the active points suggests, however, that not
mic motor pattern (149, 152). The swallowing network in only afferent fibers were stimulated but also neurons in or
mammals therefore provides a unique example of neu- very close to the NTS. The assumption that NTS neurons
rons located within a primary sensory relay, i.e., the NTS, may trigger swallowing was fully confirmed by more re-
which nevertheless play the role of generator neurons. cent pharmacological experiments using fine microinjec-
Several lines of evidence support the idea that NTS neu- tions of excitatory amino acids (EAA), which are thought
rons play a leading role in swallowing. NTS neurons ex- to stimulate neuronal cell bodies and not passing fibers. It
hibit a sequential or rhythmic firing pattern that parallels was established in these experiments that activating spe-
the motor pattern (149, 152, 174). As this firing remains cific EAA receptors within the NTS elicit both the sequen-
unaltered after complete motor paralysis, it is clear that it tial and rhythmic motor swallowing patterns, whereas
is actually a centrally generated premotor activity. More- microinjections of the same drugs into the ventrolateral
over, most of the neurons, if not all those which have a medulla failed to induce the swallowing motor pattern
preswallowing activity, are located within the NTS (149, (124, 173, 178). Furthermore, electrolytic lesion of the
152). In addition, systematic exploration of the brain stem NTS results in the abolition of not only the swallowing
with concentric bipolar electrodes to determine which elicited by stimulating the SLN but also that elicited by
central structures responded to stimulation by triggering stimulating the swallowing cortical area (152, 159). Fi-
deglutition have shown that the active points are situated nally, fine lesions performed on sheep in the NTS region,
only in the region of the solitary complex (50, 174, 225). It which contains neurons that control esophageal motility,
may be that deglutition results from the stimulation of abolished the esophageal phase of swallowing without
TABLE 2. Connections between medullary swallowing neurons

Inputs From
Oropharyngeal VSG Oropharyngeal Esophageal DSG Esophageal

Inputs to neurons motoneurons neurons motoneurons
Oropharyngeal DSG neurons E (EAA) ? I (GABA)/E (ACh) I (?)

Oropharyngeal VSG neurons E (EAA)
Esophageal DSG neurons E (EAA)
Connections have been established on the basis of electrophysiological and anatomical tract tracing techniques (see text and sects. IIIB and
IVC for references). DSG, dorsal swallowing group; VSG, ventral swallowing group; E, excitatory connection; I, inhibitory connection; EAA,
excitatory amino acids; ACh, acetylcholine.

affecting the oropharyngeal phase, which indicates that midline through the solitary tract, does not affect swal-
some of the neurons actually involved in the generation of lowing, i.e., a bilateral deglutition still occurs in response
esophageal motility had been destroyed within the NTS to unilateral stimulation of the SLN (87). Moreover, mi-
(150, 152). croelectrode recordings have shown that the synaptic
As regards the swallowing neurons in the ventrolat- activity of swallowing neurons induced by stimulating the
eral medulla, the results available are consistent with the ipsilateral SLN is absent when it is the contralateral nerve
view that during swallowing these neurons are driven by that is stimulated (Fig. 4C). This finding indicates that the
NTS neurons. As neurons of the VSG are connected to swallowing neurons receive a direct input only via the
motoneurons, one of their functions probably consists of ipsilateral afferent fibers. There probably therefore exist
activating the motoneuronal pools during swallowing. connections between central neurons that play the key
The existence of neurons with collaterals to several pools role in the coordination between the two hemi-CPGs.
of motoneurons also suggests that they may also partici- Anatomical connections mediated by fibers crossing the
pate in the coordination of the motoneuronal pools during midline have been found to exist between the two med-
swallowing (6, 94, 158). Within the swallowing CPG, the ullary regions where swallowing neurons are located, i.e.,
ventral swallowing neurons can therefore be said to act as the DSG and VSG (41, 158, 268).
switching neurons that distribute and coordinate the se- The mechanisms involved in synchronization seem to
quential or rhythmic drive generated in the dorsal group include all the swallowing neurons, i.e., motoneurons as
to the various pools of motoneurons involved in swallow- well as dorsal and ventral interneurons. Microelectrode
ing. It may well be that these neurons are also concerned recordings have shown that in each case, a particular
in the coordination of the activity of motor nuclei (V, VII, swallowing neuron produces a swallowing bursting dis-
IX, X, and XII) that are involved in several other types of charge in response to stimulation of the ipsilateral as well
motor behavior (see sect. II). as to that of the contralateral afferent fibers, regardless of
This scheme of organization of the diverse groups of the type of swallowing neuron tested. This indicates that
swallowing neurons does not mean that the connections at each step in the network operation, the entire popula-
between the dorsal group and the ventral group and those tion of neurons within the NTS, the ventrolateral medulla,
between the ventral group and the motoneurons include or the motoneuronal pools is active. Here again, however,
only excitatory connections. Indeed, recent results ob- the neuronal population within the NTS seems to play a
tained in intracellular studies on swallowing motoneu- particularly important role in the synchronization pro-
rons in XII motor nucleus and the nucleus ambiguus (337, cesses. The results of lesion experiments performed on
376, 377) have suggested that during the functioning of the NTS esophageal neuronal population have shown that
the network, both excitatory and inhibitory drives can be upon stimulating the ipsilateral SLN, only an oropharyn-
exerted along the anatomical pathways. geal stage of swallowing is elicited, whereas upon stimu-
lating the contralateral nerve, a complete process of de-
3. Synchronization of the two swallowing CPGs glutition including the esophageal stage is initiated (150,
152). These results also suggest that, at each step, the
In fact, the CPG for swallowing consists of two hemi- appropriate coordination must take place between each
CPGs, each located on one side of the medulla (87). The NTS interneuronal populations for the drive to be distrib-
existence of two hemi-CPGs was established by making uted to the motoneurons.
longitudinal midline sections of the medulla. After this These results suggest in addition that under ipsilat-
splitting, stimulation applied to the SLN on one side trig- eral stimulation conditions, the swallowing motor se-
gered a “unilateral swallowing,” i.e., a swallowing sequence is mainly generated in the ipsilateral hemi-CPG
quence involving only the ipsilateral oropharyngeal mus- and that this CPG transfers the swallowing premotor
cles, except for the middle and inferior pharyngeal signal to the contralateral CPG. This assumption is also
constrictors in some species (87, 89, 150, 152). These supported by recordings showing the activity of neurons
results indicate that under physiological conditions, the with preswallowing activity. These neurons displayed a
two hemi-CPGs are tightly synchronized and organize clear-cut preswallowing discharge before the swallowing
the coordinated contraction of the bilateral muscles of burst only when the ipsilateral SLN was stimulated. Upon
the oropharyngeal region. stimulating the contralateral nerve, only the swallowing
The mechanisms underlying the synchronization of burst was recorded, which suggests that the preswallow-
the two hemi-CPGs are not known, and this matter has ing discharge occurs only in the corresponding neurons
not yet been well documented. It is likely that the periph- on the ipsilateral side and that only the swallowing drive
eral afferent fibers do not play an important role in the is transmitted to the contralateral side (Fig. 4C) (152).
coordination of the CPGs, since lesion experiments have Further experiments are required to elucidate the mech-
shown that splitting the medulla caudal to the obex, anisms underlying the synchronization of the two hemi-
which interrupts the vagal afferent fibers crossing the CPGs. The lesion and electrophysiological data available

indicate, however, that swallowing NTS neurons play a of swallowing. Within the SLN, there exist some fibers
crucial role in these synchronization processes. belonging to the groups A␣ and A␦ which are mainly
involved in swallowing (8, 230). In addition, it should be
noted that esophageal afferent fibers running in the vagus
IV. ACTIVATION OF THE NEURONAL
can initiate part of the swallowing sequence, that is,
NETWORK AND MODULATION OF
NETWORK ACTIVITY esophageal peristalsis . These fibers are of the types A and
C (63, 64, 96, 217, 293).
At the central level, all the afferent fibers involved in
A. Role of Sensory Inputs initiating or facilitating swallowing converge in the soli-
tary tract and end in the NTS (67, 68, 167, 270, 338). The
Sensory inputs from peripheral areas play an essen- solitary tract and the NTS therefore constitute the main
tial part in inducing the whole swallowing motor se- afferent central structures involved in swallowing, partic-
quence or parts of this motor sequence such as esopha- ularly the intermediate-subpostremal part of the solitary
geal peristalsis (51, 87, 90, 156, 226). They play the prime system, which receives vagal afferent fibers including
role in reflex swallowing or secondary peristalsis, and those from the SLN (17, 87, 156). Indeed, stimulation
they are also involved in voluntary swallowing. It is obvi- applied to the solitary tract and its nucleus (NTS) can
ously very difficult to perform deglutition without having induce a very similar swallowing pattern to that obtained
anything to swallow, and this is also the case when the in response to SLN stimulation (50, 174, 225, 231, 244,
oropharyngeal mucosa is anesthetized (87, 211, 267). 367). Furthermore, lesion of the solitary tract abolishes
Moreover, sensory inputs modulate the central network the swallowing induced by SLN stimulation (89, 152, 367).
activity to adapt the forthcoming motor sequence to the Results obtained at the cellular level on swallowing-
information arising from peripheral receptors (155, 156). related neurons have supported the idea that SLN afferent
It is generally assumed that the afferent fibers in- fibers play a major role in the initiation of swallowing. In
volved in the initiation of swallowing are those running
all the species studied, the results have shown that almost
within the maxillary branch of the trigeminal nerve, the
all the NTS swallowing neurons are synaptically activated
glossopharyngeal nerve, and the vagus nerve, especially
by the SLN (149, 152, 174, 255, 345). In addition, it is very
its SLN (87, 90, 224, 226). These nerves innervate periph-
likely that in most cases, the swallowing neurons may
eral areas such as the dorsum of the tongue, the epiglottis,
receive a direct, i.e., monosynaptic, input from SLN affer-
pillars of the fauces, and walls of the posterior pharynx,
ent fibers (149, 174, 255). The arrangement of the SLN
the tactile or chemical stimulation of which induces swal-
terminals in the interstitial NTS subnucleus, in the form of
lowing (87, 90, 226, 231). Electrical stimulation of these
rosettes or glomeruli, also suggests that laryngeal afferent
nerves can also trigger swallowing. In fact, all the results
obtained so far show that only stimulation applied to the fibers may exert strong synaptic effects on postsynaptic
SLN induces the highly specific swallowing pattern with- elements (238). Electrophysiological results have indi-
out any additional orofacial activity, i.e., “pure” swallow- cated that most of the NTS oropharyngeal neurons can be
ing, with a minimal latency. Interestingly, among the var- activated also via IX afferent fibers (61, 255). It has been
ious patterns of stimulation used for this purpose and observed, in sheep and cats, that IX afferent fibers acti-
whatever the species under investigation, repetitive stim- vated ⬃90% of the oropharyngeal neurons studied. How-
ulation applied to the SLN at a frequency of around 30 Hz ever, the IX fibers seem to have less impact than SLN
(in the 20- to 40-Hz range) acts like “magic” by producing fibers on the swallowing neurons. Although the latency of
pure swallowing at the lowest stimulus threshold (86, 87, the synaptic response to IX stimulation is in the same
149, 174, 225, 279). Applying stimulation to the other range as that recorded following SLN stimulation, it
afferent fibers is less effective, and the results obtained seems most likely that it is not monosynaptic, judging
have been variable and often conflicting, depending on from the conduction distance and the variable latency (30,
the species studied (61, 62, 86, 87, 255, 305, 306, 309, 310). 61, 255, 294). These findings probably explain why the IX
Frequently, the motor pattern was very different from that afferent fibers are relatively inefficient at initiating swal-
of pure swallowing and induced only at high stimulation lowing. It is still puzzling, however, that, at least in sheep,
intensities and after a long latency (87). It has been ob- all the NTS neurons that display preswallowing activity
served in a comparative study on sheep that IX nerve have been found to be synaptically activated by both the
stimulation can facilitate swallowing but does not suffice SLN and the IX nerve (61). SLN afferent fibers can never-
to trigger the motor pattern, and stimulation applied to theless induce a swallowing burst in these neurons upon
the maxillary branch of the V nerve cannot induce swal- receiving either a single stimulating pulse or repeated
lowing (61, 62). Therefore, although SLN afferent fibers stimulation, whereas the IX can induce only preswallow-
are involved in triggering several other reflexes, they con- ing activity even when undergoing repetitive stimulation,
stitute the main afferent pathway involved in the initiation which indicates that the activation of IX afferent fibers

alone does not suffice for the swallowing threshold to be 217). Studies on the activity of vagal sensory fibers in
reached (Fig. 4D) (61). anesthetized cats and rats or conscious sheep have indi-
Although the swallowing motor sequence is centrally cated that these fibers are strongly excited by the pres-
organized, it can change as the result of peripheral affer- ence of a bolus or the passage of the peristaltic wave. All
ent information (155). Studies on the swallowing motor these results suggest that continuous sensory feedback
sequence have strongly suggested that it is controlled by may influence the neurons of the CPG and thus modulate
a peripheral feedback mechanism. It has been established the central program (95, 155). In fact, results obtained at
that the amplitude and duration of the electromyographic the cellular level have shown that applying continuous
activity of oropharyngeal muscles partly depends on the stimulation to peripheral receptors by means of an in-
consistency of the bolus (140). The importance of sensory flated balloon can either induce a permanent activity in
feedback for esophageal peristalsis was shown by exper- the neurons that are active during swallowing or modify
iments in which “wet” swallows (with various volumes of the bursting activity occurring during swallowing (Fig.
water) were found to be associated with a contraction 6A). The early neurons can be activated by locally dis-
wave with a slower speed and a greater amplitude and tending the pharyngeal cavity, whereas the late and very
duration than “dry” swallows (85, 136). Direct evidence late neurons respond to local distension of the proximal
that sensory feedback intervenes during swallowing has and distal esophagus, respectively (149, 152). To be effi-
been provided by afferent nerve recordings (9, 64, 98, cient, the distension must be performed more and more
FIG. 6. Inhibitory phenomena involved in swallowing. A: inhibition of the activity of esophageal neurons during
swallowing. In 1, the top traces show the burst firing (SwN) of a late neuron in the dorsal group during swallowing
(mylohyoid activity: MHm) elicited by stimulating the SLN. A local distension of the cervical esophagus produced by
inflating an intraluminal balloon (indicated by the arrows, EsP: pressure in the esophageal balloon) induces a continuous
discharge from the neuron (bottom traces). It is worth noting that when a swallow is triggered by stimulating the SLN,
the inhibition of the neuronal firing does not occur only during the oropharyngeal stage but starts before the beginning
of the swallow. In 2, the top traces show the swallowing burst of an esophageal neuron (SwN) during swallowing (MHm),
elicited by applying several pulses to the SLN, with a slightly inflated balloon within the hypopharynx (PhP: pressure in
the pharyngeal balloon). Note that the swallowing discharge of the neuron is inhibited when the intrapharyngeal balloon
is more strongly inflated. [Adapted from Jean (149) (1) and (155) (2).] B and C: field potentials (N) recorded at
esophageal sites within the sheep NTS. In B1 and C, stimulation of the SLN induces a single swallow (MHm); note that
the potential may be composed of either a single wave (B1) or a biphasic wave in C. The first wave reflects the inhibition
of the neuronal population, whereas the second wave indicates that the neuronal excitability has increased. When absent
during a single swallow (B1), the second wave can be initiated during rhythmic swallowing (B2), which is known to
increase the excitability of the esophageal neurons in anesthetized animals. These recordings suggest that the inhibition
of the esophageal neurons during the oropharyngeal stage may be followed by a long-lasting state of increased
excitability, which is also triggered by the oropharyngeal stage. (From Jean, unpublished data.) D: intracellular recording
of an esophageal motoneuron within the nucleus ambiguus. During swallowing elicited by stimulating the SLN (GHm,
PHm, and cEs: EMG of genohyoid, middle constrictor, and cervical esophagus, respectively), note that the burst firing
of the neuron, superimposed on a depolarization of the membrane potential, occurs after a hyperpolarization of the
membrane potential, indicating that the neuron has undergone inhibition during the oropharyngeal stage. [Adapted from
Zoungrana et al. (377).]

distally as the neuronal discharge occurs later and later structures also influence swallowing (51, 87, 119, 156, 214,
during swallowing. Furthermore, the swallowing activity 226). The fact that an individual can swallow voluntarily
of medullary neurons increases either when a bolus is without the existence of any need to ingest food or to
swallowed or during a subliminal distension of the corre- protect the upper airways shows that the medullary swal-
sponding region of the tract (149, 152). The burst firing lowing network can be activated at least by inputs from
activity of the neuron increases in terms of both its dura- the cerebral cortex. In addition, several clinical reports
tion and frequency. The changes resulting from peripheral have indicated that cortical dysfunction of the kind result-
stimulation are more striking in the case of the esopha- ing from cerebrovascular accidents, cerebral palsy, or
geal than the oropharyngeal neurons: depending on the neurological diseases such as Parkinsonism, may result in
volume of the balloon inserted, a twofold increase in the dysphagia or swallowing impairments or may affect
duration and a fivefold increase in the frequency can be esophageal peristalsis (127, 153, 180, 214, 260, 365). These
observed (152). The activation of peripheral receptors observations point to the involvement of supramedullary
during swallowing therefore results in a decrease in the influences, although the peripheral afferent pathway and
velocity of the peristalsis, which makes the duration of the CPG, which is localized in the caudal brain stem, seem
the whole sequence longer and the muscular contraction to remain unaltered in these patients.
more powerful. Sensory feedback can therefore be said to Supramedullary structures may be responsible for
modify the central program, by adjusting the motor out- various effects on swallowing such as initiating the motor
puts depending on the contents of the tract (155). activity, or modulating reflex swallowing. However, most
In addition to these excitatory phenomena, the sen- of the data available were obtained in stimulation exper-
sory inputs can also trigger inhibitory effects via central iments and were difficult to interpret, since it is generally
connections, as suggested by electromyographic data and not a pure swallowing motor activity that is initiated in
vagal motor fiber recordings (129, 276, 281). The occur- this way, but more complex feeding behavior, i.e., masti-
rence of these inhibitory phenomena has been fully con- cation and swallowing, or lapping, mastication and swal-
firmed by microelectrode recordings showing that all the lowing, or licking and swallowing, etc. (42, 316). In addi-
esophageal neurons are strongly inhibited during the oro- tion, it is difficult to identify among these effects those
pharyngeal stage of swallowing; they were also inhibited which are due to the afferent feedback and to distinguish
during a pharyngeal distension that stimulated the periph- between centrally organized movements and motor activ-
eral receptors (Fig. 6A) (149, 152, 155). Oropharyngeal ities involving feedback phenomena. Moreover, the pre-
distension excites the early interneurons, which results in sumed centrally induced effects may actually arise from
an inhibition of the late and very late neurons via central the stimulated site or from passing fibers.
inhibitory connections. The inhibitory effect depends on There exist a number of subcortical sites, including
the size of the inflated balloon; when it is greatly inflated, the corticofugal swallowing pathway, which can trigger
swallowing activity is completely abolished, whereas dur- or modify swallowing, in particular the internal capsule,
ing a slight inflation, this activity is only weakened and subthalamus, amygdala, hypothalamus, substantia nigra,
delayed (149, 152). The discharge of the very late neurons mesencephalic reticular formation, and monoaminergic
is also inhibited during the activation of the cervical brain stem nuclei (27, 43, 44, 90, 177, 319 –321). These
esophageal receptors. The strength of this inhibition is influences can be either excitatory or inhibitory. It has
variable depending on the size of the inflated balloon. been reported that several forebrain regions, including
These data indicate that the swallowing neurons con- the amygdala and the lateral hypothalamus, may facilitate
trolling the distal regions of the swallowing tract are swallowing by means of dopaminergic mechanisms (26,
inhibited when neurons controlling the more proximal 27, 132, 366). Inhibitory effects can be evoked by stimu-
regions are excited. They support the idea that there lating brain stem structures such as the periaqueductal
may exist a rostrocaudal inhibition within the swallow- gray, the ventrolateral pontine reticular formation, and
ing network, as suggested by the blockade of the esoph- some monoaminergic cell groups (177, 295, 320, 321).
ageal peristalsis that occurs during rhythmic swallow- Results suggest that these inhibitory effects probably in-
ing (149, 152, 155, 277). volve opiate and monoaminergic mechanisms at the level
of the NTS (177, 289, 295, 297). Whether these influences
act directly on the medullary CPG or may involve a more
B. Supramedullary Influences on Swallowing complex central pathway is not known. Few studies have
in fact dealt with these central effects on the neurons of
Experimental data have shown that the basic swal- the CPG. As far as the supramedullary influences on
lowing pattern can be induced without any supramedul- swallowing and their action at the cellular brain stem
lary structures being involved. Under physiological con- level are concerned, all the results available so far have
ditions, however, the swallowing network receives inputs been obtained in studies on the cortical influences on
from higher centers, and several cortical and subcortical swallowing.

In several species, swallowing can be initiated by pathway from the cortex to motoneuronal pools involved
stimulating a limited area of the cortical surface. In rab- in swallowing has been mapped using tracing techniques
bits, an efficient region of this kind has been detected (184 –186), these results indicate that the cortical input to
within the anterolateral frontal cortex (316). A specific identified swallowing neurons mainly focuses on swal-
swallowing zone, i.e., one inducing pure swallowing, is lowing neurons in the DSG and involves the same circuit
situated anterior to the orbital gyrus in sheep (42). It is as the afferent fibers do, at least in sheep (Fig. 5). The
worth noting that as in the case of peripheral afferent DSG neurons therefore receive convergent information
stimulation, swallowing is best initiated by applying re- from both cortical and peripheral inputs that trigger swal-
petitive stimulation to the cortex at a frequency in the 20- lowing.
to 40-Hz range. Recent results have shown, however, in On the basis of the finding that during swallowing
the conscious dog, that a single stimulus applied by trans- sensory feedback is conveyed to the cortical area via a
cutaneous magnetic stimulation can induce swallowing first relay in the pons, the swallowing cortical area may
(348). Moreover, with the use of this technique, it has have a further function (48, 160, 320, 321). Neurons in this
been shown in humans that cortical stimulation can pro- area may belong to a ponto-cortico-medullary loop so that
duce, as does stimulation of the afferent fibers (see sect. upon receiving sensory information, they might control
IID1), short-latency electromyographic responses in sev- the activity of the CPG swallowing neurons as they fire
eral oropharyngeal muscles and in the cervical esophagus successively, just as peripheral afferent fibers do (159). It
(119). The corticofugal swallowing pathway, which in- has been shown that cortical neurons in the swallowing
cludes structures such as the internal capsule, the pyram- cortical area of sheep are activated or inhibited during
idal pathway, and the mesencephalic reticular formation, swallowing (45). More recent findings on monkeys indi-
ends within the solitary system (43, 44, 159). Lesion of the cate that cortical areas associated with feeding behavior
NTS area involved abolishes the swallowing evoked by are involved in swallowing (213, 214, 242, 243, 245). How-
cortical stimulation, which further indicates that the sol- ever, changes in the firing activity of cortical neurons
itary system is the main central system responsible for during swallowing have been shown to depend on sen-
swallowing (152, 159). sory feedback, since it is abolished in paralyzed animals.
Results obtained on anesthetized sheep (152, 159) Because only early and a few late neurons respond to
indicate that most of the early neurons in the DSG can be cortical stimulation, the control of swallowing may be
activated by applying cortical stimulation. This is in agree- restricted to the oropharyngeal phase and the beginning
ment with the idea that one of the functions of the cortical of the esophageal phase. Therefore, the cortical swallow-
area may be to trigger the “voluntary” swallowing motor ing area may serve mainly to trigger deglutition and con-
sequence. Cortically induced swallowing, however, re- trol the beginning of the motor sequence, after which the
quires repetitive stimulation, whereas a single pulse ap- sequence might be carried out without any further corti-
plied to SLN is generally effective under identical exper- cal control (159).
imental conditions (42, 159). Although direct cortical
projections to the NTS have been shown to exist (35, 157,
371), this difference can probably be accounted for by the C. Action of Brain Stem Neurotransmitter Systems
fact that the pathway from the cortical area to the CPG is
polysynaptic (42, 43). Moreover, although all the swallow- Some pharmacological results relating to swallowing
ing neurons with preswallowing activity tested so far have have been reviewed previously (24, 25). The present re-
been found to be activated by the cortex, this was so in view focuses mainly on local effects that can be clearly
the case of only 79% of the remaining oropharyngeal linked to the initiation and programming of the swallow-
neurons studied (152, 159). In line with what occurs with ing motor sequence. In this connection, data have been
SLN stimulation, cortical stimulation induces an initial obtained using in situ ejection of drugs by ionophoresis or
activity followed by the swallowing burst that accompa- application of pressure, and most of these results have
nies the onset of swallowing. Both the latency and the been obtained at the level of the DSG in rats (24, 25, 161).
number of neurons activated depend on the neuronal To date there has been only one study dealing with the
group involved. Early neurons in the DSG were cortically action of drugs on functionally identified neurons, i.e.,
activated with a shorter latency than those in the VSG swallowing-related neurons (172). However, other exper-
(5– 8 ms vs. 10 –16 ms), and only 32% of all the neurons in iments on “reflex” interneurons in the NTS, i.e., neurons
the ventrolateral medulla were cortically activated. Late which can be synaptically activated via SLN or IX nerves,
neurons in the DSG also responded to cortical stimula- or on neurons studied in vitro in swallowing medullary
tion, but in small numbers (38%) and with a longer latency regions, have provided some complementary information
of 10 –12 ms. None of the late neurons in the VSG nor the at the cellular level (161, 298).
very late neurons either in the DSG or the VSG was At the level of the NTS, i.e., the DSG, experiments
activated by cortical stimulation (159). Although a direct based on intracerebral microinjections have yielded deci-

sive information about the involvement of EAA receptors induce either a single motor event or series of rhythmic
in swallowing mechanisms. In both anesthetized and de- swallowing events similar to those elicited by long repet-
cerebrate rats, glutamate microinjections performed itive stimulation of the SLN. Microinjections of glutamate
within the swallowing area of the NTS elicited swallows are likely to have resulted in generalized neuronal exci-
that were very similar to those triggered by either electri- tation within the area covered by the agent. The fact that
cal stimulation of the SLN or mechanical stimulation of these injections into the NTS can produce a patterned
the pharyngeal mucosa (Fig. 7A) (124, 173, 178). Both the response instead of a disorganized muscular activity is
oropharyngeal stages of swallowing and complete swal- quite remarkable and indicates that this region contains
lowing, i.e., the oropharyngeal stage followed by esopha- neurons that play a prime role in initiating and patterning
geal persistalsis, can be obtained by performing microin- deglutition and esophageal peristalsis (161). Results ob-
jections into the interstitial NTS subnucleus (173). tained using EAA receptor agonists and antagonists have
Specific esophageal peristaltic contractions can be initi- clearly demonstrated that deglutition and esophageal con-
ated by injecting glutamate and EAA agonists into the tractions can be triggered by activating either N-methyl-
region of the subnucleus centralis (23, 124). Furthermore, D-aspartate (NMDA) or non-NMDA receptors (124, 173,
depending on the dose, glutamate microinjections can 178). The effects of NMDA are particularly striking, since
FIG. 7. Effects of neurotransmitter systems on swallowing. A: effects of excitatory amino acids. 1: Comparison
between the swallowing elicited by stimulating the SLN (top traces: SHm, electromyographic recording of suprahyoid
muscles; EsP, intraesophageal pressure recording) and by microinjecting glutamate (25 pmol, 5 nl) into the NTS. 2:
Rhythmic swallowing elicited by NTS microinjections of glutamate (500 pmol) and N-methyl-D-aspartate (NMDA; 50
pmol) applied to the same site. Note the inhibition of the respiratory cycle (R, tracheal airflow recording). Only the
beginning of the effect of NMDA (total duration, 130 s) is shown. [Adapted from Kessler et al. (173).] B: repetitive
oropharyngeal swallows evoked by kainic acid applied to the dorsal surface of NTS. It of interest to note that when
bicuculline is ejected at an esophageal site within the subnucleus centralis, an esophageal persistalsis occurs after each
oropharyngeal stage (Ph, cEs, thEs: intrapharyngeal and intraesophageal pressure recordings, respectively). [Adapted
from Wang and Bieger (360).] C: inhibitory effects of systemic injection of methscopolamine on esophageal peristalsis.
1: Control swallowing pattern produced by applying electrical stimulation to the solitary complex (Ph, Es: intrapharyn-
geal and intraesophageal pressure recordings, respectively). 2: Note the inhibition of the esophageal peristalsis after
intravenous injection of methscopolamine. [Adapted from Bieger (23).] D: diagram of the possible sites of action of
transmitters within the swallowing CPG. Excitatory amino acids (EAA) are involved at the NTS level in triggering
swallowing. They may be released either by laryngeal afferents or by local glutamatergic neurons. EAA are also involved
in the transfer of the swallowing drive from the NTS neurons to interneurons in the ventrolateral medulla (VLM) and
motoneurons (Mn) in the nucleus ambiguus. The pathway may involve only EAA or synapses with unknown transmitters.
The connections between oropharyngeal (OP) and esophageal (Es) NTS neurons may involve both GABA and acetyl-
choline, in the case of inhibitory and excitatory connections respectively (see text for comments).

this agent can elicit long series of rhythmic swallows, the ventral level have been less fully documented. Micro-
including more than 100 motor events (178). At esopha- injections performed in vivo failed to elicit the oscillatory
geal sites, activation of NMDA receptors seems to be behavior characteristic of rhythmic swallowing (24). Re-
more potent than that of non-NMDA receptors (24). This sults obtained by Kessler (172) have indicated that the
is in keeping with the existence of large numbers of swallowing activity of neurons in the VSG depends on the
NMDA receptors within the subnucleus centralis (40). At activation of EAA receptors, that is to say that the swal-
the cellular level, it has been reported that glutamate lowing drive set up in the DSG and transferred to the
activated almost all the reflex neurons tested (130, 298). swallowing neurons in the VSG involves at least the EAA
With the use of brain stem slices, it has been found (Fig. 7D). This result is in keeping with anatomical data
that neurons located in NTS regions known to contain showing the existence of glutamatergic connections be-
swallowing neurons possess both types of EEA recep- tween NTS and ventrolateral medulla (307). Here again,
tors (330). both types of EAA receptors, i.e., NMDA and non-NMDA
Within the DSG, EAA mechanisms may contribute to receptors, are involved. In studies on brain stem slices, it
initiating the motor sequence and to building up the swal- has been established that the NMDA receptors play a
lowing pattern. EAA may be released either by afferent critical but paradoxical role, since they are involved in the
fibers involved in swallowing or by intrinsic NTS neurons, rising phase of the excitatory postsynaptic potentials elic-
or both (Fig. 7D). Although there is no direct evidence ited in these neurons in response to stimulation applied to
that swallowing afferent fibers actually use EAA as a the solitario-ambigual pathway (361).
transmitter, microinjections of either DL-2-amino-5- Inhibitory phenomena are thought to play an impor-
phosphonovalerate (APV), a NMDA receptor antagonist, tant role in the swallowing mechanisms (see sect. V).
or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non- However, little is known so far about the function of
NMDA receptor antagonist, performed within the NTS of neurotransmitters such as inhibitory amino acids in de-
decerebrate rats can result in the complete disappearance glutition. Some of the most interesting results in this field
of the SLN-induced deglutition as well as esophageal re- have been those obtained by Wang and Bieger (360), who
flex responses (161, 203). It has also been established observed that microinjections of GABA or GABAA agonist
using immunohistochemical or retrograde tritiated aspar- such as muscimol inhibited the motor events associated
tate transport methods that glossopharyngeal and vagal with swallowing and esophageal peristalsis. It has also
afferent fibers in addition to other neurotransmitters may been reported that local application of bicuculline at the
use EAA as transmitters (251, 286, 287, 290, 291). More- NTS level induced either rhythmic swallowing or rhyth-
over, results obtained by combining retrograde transport mic esophageal peristalsis, which suggests that a tonic
of tritiated aspartate with peroxidase immunohistochem- inhibitory action is exerted by GABA neurons on the
istry or fluorogold histofluorescence have suggested that swallowing pattern generator. Some other features rele-
SLN afferent fibers may use EAA as transmitters (N. vant to the coupling between the oropharyngeal stage of
Schaffar and A. Jean, unpublished results). As is the case swallowing and esophageal peristalsis have been consis-
for baroreceptors and some vagal pulmonary afferent tently described in these experiments. When swallows
fibers (33, 168, 274, 351), it is therefore likely that at least consist of oropharyngeal stages alone, local application of
some of the afferent fibers involved in the initiation of subthreshold doses of bicuculline can render the swal-
swallowing may use EAA as transmitters. In addition, lows complete, i.e., the oropharyngeal phase is followed
glutamatergic NTS neurons have been found to exist and by primary peristalsis (Fig. 7B). Moreover, during fast
may be activated by the afferent fibers (179, 286, 324). The rhythmic swallowing, which normally consists of a series
possibility that EAA receptors may be involved in pattern- of oropharyngeal stages alone, application of bicuculline
ing swallowing has been strongly supported by the results can release the inhibition, preventing the occurrence of
of experiments where an oscillatory behavior, i.e., rhyth- esophageal phases, and complete rhythmic swallows oc-
mic swallowing or rhythmic esophageal contractions, was cur. Among the many possible explanations, the most
induced by locally applying EAA (Fig. 7, A and B) (124, plausible one seems to be that GABAergic mechanisms
178). Studies on brain stem slices have shown that NTS may be involved in the inhibition of the esophageal phase
neurons exhibit EAA-induced rhythmic patterns of activ- of swallowing that occurs during the oropharyngeal phase
ity that paralleled those of swallowing neurons and have (Fig. 7D and Table 2). The exact origin of these GABA-
pacemaker properties that were activated via NMDA-re- mediated inhibitory phenomena is unknown, but local
ceptor associated channels (Fig. 9A). These studies sug- GABAergic NTS neurons are probably involved (32, 144,
gest that EAA receptors may play a critical role in the 209, 216, 325). In addition, recent results have shown that
motor patterning of swallowing behavior (332, 333). neurons within the subnucleus centralis, which are
EAA receptors are involved in swallowing not only thought to be esophageal premotor neurons, express
within the DSG, but also at the level of the VSG and the GABAA receptor subunits (38). These results therefore
motoneurons (Table 2). However, the effects of EAA at suggest that inhibitory amino acids probably play an im-

portant role in the inhibitory mechanisms at work within sors or agonists can either induce the swallowing motor
the swallowing network (133). At the ambigual level, stim- pattern or facilitate the effects of laryngeal stimulation or
ulation of GABAA receptors has been found to modulate the occurrence of spontaneous swallows (24). On the
the excitatory action of EAA and acetylcholine. Thus it other hand, results obtained by performing microinjec-
seems highly probable that the inhibitory amino acids also tions of monoamines into the swallowing NTS area have
intervene at this level (24). shown that monoamines have mainly depressant effects
Cholinergic neurotransmission has been also found on swallowing, i.e., they resulted in reversible, dose-re-
to play a role in swallowing mechanisms, particularly lated decreases in both the number and strength of the
those underlying esophageal peristalsis (23, 204). At the rhythmic swallows elicited by ipsilateral SLN stimulation
level of the NTS, esophageal contractions can be induced (175–177). This inhibitory action is not a side effect due to
by locally applying acetylcholine or muscarinic receptor the perturbation of homeostatic parameters such as re-
agonists. Moreover, the esophageal stage of a swallowing spiratory rhythm or blood pressure, since the swallowing
sequence can be blocked after local application of mus- elicited by stimulating the SLN contralateral to the injec-
carinic antagonists, such as methscopolamine, within the tion site remained unaffected.
NTS (Fig. 7C). These results suggest that a cholinergic With regard to the catecholamines, the inhibitory
mechanism probably participates in the linkage between action of norepinephrine can be mimicked by clonidine
the oropharyngeal and esophageal stages of swallowing microinjection and reduced by pretreatment with phen-
(Fig. 7D and Table 2). Systemic injections of atropine tolamine, but not with metitepin, a serotoninergic blocker
have also been found to block the esophageal stage of (176). It is therefore likely to result at least partly from
swallowing in sheep (376). However, the cholinergic link activation of ␣-adrenergic receptors. The nature of the
between the oropharyngeal and esophageal activity might receptor involved in the effects of dopamine is still
be species dependent and requires further investigation. unknown. It should, however, be noted that microin-
In cats and humans, atropine injection does not block the jections of the dopaminergic agonist apomorphine also
esophageal peristalsis of the striated portion of the esoph- inhibit swallowing (176). These data indicate that cat-
agus, which suggests that central muscarinic receptors echolamines exert an inhibitory influence on the NTS
are not involved in the pharyngo-esophageal coupling (31, neural components involved in deglutition, and as yet,
114, 262). The source of cholinergic inputs to NTS has not there is no direct evidence available that any excitatory
yet been clearly identified. Cross-innervation and immu- effects may be exerted at this level. It is likely that the
nohistochemical data have suggested that vagal afferent facilitatory effects elicited by systemic administration
fibers may use acetylcholine as a transmitter and that might originate from the drugs acting on supramedullary
some of these fibers might be esophageal afferent fibers structures, as suggested by experiments in which cat-
(97, 261). It has also been demonstrated that NTS neurons echolamines, in particular dopamine, locally applied to
receive a cholinergic input from neurons in the interme- several forebrain regions, were found to have a facilita-
diate zone of the parvicellular reticular formation. Ana- tory action (26, 27, 29, 366). Results show that apomor-
tomical and electropharmacological data suggest that this phine exerts a facilitatory influence on swallowing when
projection may be involved in esophageal motility (25, injected into the internal carotid artery, but an inhibitory
203). The cholinergic input may also arise from intrinsic effect when injected via the vertebral artery. It can there-
neurons that have been identified within the NTS using fore be postulated that by acting on forebrain sites, cat-
choline acetyltransferase imunohistochemical proce- echolamines have facilitatory effects on swallowing,
dures (285). Cholinergic transmission has also been found whereas they have inhibitory effects when released lo-
to take place via esophageal motoneurons. Acetylcholine cally at brain stem levels, particularly in the NTS. Iono-
applied to the ventrolateral medulla induces esophageal phoretic application of catecholamines within this region
contractions, probably as the result of depolarization of has a mainly depressant effect on neuronal activity (54).
esophageal motoneurons tentatively identified in brain Local applications of serotonin have been reported to
stem slices (25). The acetylcholine-induced effects on have either inhibitory or excitatory effects on swallowing
esophageal motoneurons are resistant to muscarinic an- (123, 175). One should note, however, that ionophoretic
tagonists and depend on nicotinic receptors (362, 375), application of serotonin or serotonergic agents to NTS
which have been shown to participate in esophageal peri- neurons, particularly the reflex neurons, consistently in-
stalsis (114). hibits the neuronal activity (100, 297, 298). The antagonis-
The role played by monoamines in central swallow- tic effects on swallowing are certainly due to differences
ing mechanisms was first investigated by means of indi- in the neuronal sensitivity to serotonin and are therefore
rect methods such as those based on the use of systemic likely to have resulted from different receptor subsets
injections or the intracerebroventricular application of being activated. The excitatory effects may be mediated
drugs (24). Under these experimental conditions, excita- by 5-HT2 receptors, since they are abolished by intrave-
tory effects of monoamines have been observed. Precur- nous injection of either ketanserin, methysergide, or

metergoline (24). The nature of the receptor(s) mediating vasopressin, oxytocin, and somatostatin (24). In the latter
the depressant action of serotonin has not yet been case, anatomical studies have shown that a somatostatin-
clearly established. This effect is mimicked by quipazine ergic connection runs between the NTS subnucleus cen-
and 8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT) tralis, where esophageal neurons are assumed to be lo-
and can be partially prevented by local pretreatment with cated, and the compact rostral formation of the nucleus
metitepin, but not by intravenous injections of methyser- ambiguus, which contains esophageal motoneurons (36,
gide and metergoline. These results suggest that 5-HT1 71). It has been established moreover that somatostatin
receptors are involved (161), which is in line with the regulates neurotransmission mechanisms at the level of
recent finding that 5-HT1A binding sites exist in high den- ambigual motoneurons by facilitating glutamate-induced
sities in NTS areas involved in deglutition (210, 334). The excitation and depressing acetylcholine-induced excita-
question as to what exact factors determine the effects of tion, two excitatory effects which are thought to be in-
serotonin, i.e., excitation versus inhibition, have not yet volved in the swallowing mechanisms (363, 364). Soma-
been elucidated. Due to serotoninergic receptors having tostatin therefore probably has neuromodulatory effects
differential affinities, the amount of agent microinjected on the swallowing network. The inhibitory effects of pep-
may be a critical factor. The neural components involved tides on swallowing have been found to involve opioid
in these opposite effects may also be different. The re- receptors such as the ␮, ␦, and ␬ binding sites (24). The
spective distributions of the injection sites involved in opiates may act at the DSG, VSG, and motoneuron levels,
excitatory and inhibitory effects only partly overlap. The where a high density of enkephalinergic terminals has
inhibitory sites are located in the NTS regions known to been found to exist, particularly within the compact ros-
contain swallowing neurons receiving laryngeal inputs, tral formation of the nucleus ambiguus (232).
i.e., at the level of the interstitial subnucleus, whereas the More recent results, based on chemical neuroana-
excitatory sites are located more rostrally and more me- tomical techniques, have shown that neurons, in the NTS
dially (161). subnucleus centralis, which project to the rostral com-
The effects of monoamines on swallowing may be pact formation of the nucleus ambiguus and which are
mediated by intrinsic catecholaminergic NTS neurons be- probably premotor esophageal neurons, can synthesize
longing to groups A2 and C2 and a population of seroto- nitric oxide (37, 103, 370). The role of these neurons in
nin-containing neurons identified in the rostromedial NTS central swallowing mechanisms now is required to be
(134, 135, 165, 166). Indeed, vagal afferent fibers have investigated.
been found to impinge on catecholaminergic neurons in
the NTS (312). In addition, some vagal afferents have been V. NEURAL MECHANISMS
found to use serotonin as a transmitter (104, 250). One
relevant finding in this connection was that when electri-
cal stimulation was applied to several brain stem regions A. Central Pattern Generation
containing either catecholaminergic or serotoninergic cell
groups, such as the raphe magnus, the ventrolateral retic- The central mechanisms that generate the bursting
ular formation at the pontine and bulbar level, and the activity of swallowing neurons and their sequential or
locus coeruleus, it inhibited reflex deglutition (177). The rhythmic firing behavior are still unknown. In the light of
existence of catecholamine- or serotonin-containing pro- the latest mechanisms found to be responsible for pattern
jections arising from some of these regions and terminat- generation in several other CPGs, it seems likely however
ing in the NTS has been established in several anatomical that the shaping and timing of the deglutitive motor pat-
studies (289, 335). It can therefore be postulated that the tern is based on the connectivity and the synaptic inter-
swallowing inhibition observed in response to stimulation actions between the various groups of neurons in the
of brain stem monoaminergic nuclei may at least partly network, and the intrinsic properties of neurons (77, 107,
result from a release of catecholamines or serotonin 108, 115–117, 197, 265, 292). Although little direct evi-
within the NTS. It is worth pointing out that when applied dence is available as to the exact nature of the swal-
to the locus coeruleus and the raphe magnus, electrical lowing patterning mechanisms, the body of data which
stimulation also depolarizes the laryngeal afferent fibers has been built up in this field over the past 25 years
(205). This suggests that the inhibition of reflex degluti- provides valuable information about the functional
tion, whether it results from brain stem stimulation or is mechanisms possibly underlying the central organiza-
induced by monoamine microinjection into the NTS, may tion of swallowing.
at least partly depend on a blockade of peripheral inputs.
1. Network properties: role of excitatory and
Preliminary evidence is now available which sug-
inhibitory phenomena
gests the existence of excitatory or inhibitory peptidergic
mechanisms affecting swallowing. An excitatory action The fundamental act of swallowing, in particular its
has been observed with thyrotropin-releasing hormone, oropharyngeal stage, is a stereotyped motor behavior, and

the swallowing CPG has been viewed classically like a inhibitory connections between the various links in the
dedicated circuit, i.e., like a specific network of neurons chain. It has been reported that when the neurons respon-
which is hardwired so as to produce a sequence of exci- sible for the beginning of the swallowing sequence fire,
tation and inhibition that is always the same (51, 87, 152, the cells controlling the more distal parts of the tract are
154, 226, 277). The CPG must be able to perform a wide inhibited, and their activity is delayed (149, 152). In this
range of tasks, such as converting the repetitive messages way, inhibition is also successively transmitted through-
conveyed by central or peripheral afferent inputs into a out the network. Inhibitory phenomena play an important
bursting activity, transmitting bursting activity after a role in the shaping and timing of the sequence, since the
variably long delay depending on the nature (oropharyn- neurons controlling more distal parts of the swallowing
geal or esophageal) of the neuron in the network, ensur- canal are subjected to longer periods of inhibition than
ing via a rostrocaudal inhibitory mechanism that the later those controlling rostral parts (149, 152). Because no
neurons cannot fire before or during the activity of the neurons have ever been observed that start to discharge
earlier neurons, and generating a rhythmic bursting pat- at the onset of swallowing and fire for longer periods
tern, at least in the case of the oropharyngeal neurons. when they control more distal parts of the tract, the
The bursting pattern of the swallowing neurons may long-lasting inhibition exerted on the late and very late
be built up as the result of either reexcitation phenomena neurons may result from the successive additional peri-
or excitatory feedback mechanisms (107, 108). The cen- ods of inhibition triggered within the chain by the neuron
trally generated bursting pattern of swallowing NTS neu- that is active (Fig. 8A). The inhibitory message that no
rons suggests that these mechanisms may well take place doubt occurs before the excitatory transfer of the burst-
within the DSG. Neurons with preswallowing activity pre- ing discharge seems to play an important role in the
sumably possess these reexcitation loops so that the neu- central mechanisms. In fact, leaving aside the neurons
ronal firing will increase until reaching the critical level at with preswallowing activity, recordings of the motor
which the swallowing burst is generated (Fig. 4, C and D) events and the central neuronal activity have suggested
(149, 152). The rhythmic firing pattern of the oropharyn- that the inhibitory phenomena may be the first events
geal neurons may rely either on a specific network ar- initiated in the network (87). In the absence of intracel-
rangement, which still remains to be determined, and/or lular recordings, it is not yet possible to state whether or
on cellular properties of the neurons (see sect. VA2). not hyperpolarization may occur before the bursting dis-
In addition to the mechanims by which is generated charge of the swallowing neurons. Extracellular record-
the burst firing of the swallowing neurons, the swallowing ings have shown, however, that the activity of distal neu-
network can be viewed as a linear-like chain of neurons rons is inhibited before the motor activity is initiated (see
based on the rostrocaudal anatomy of the swallowing Fig. 6A). In addition, a subliminal SLN stimulation that
tract. Because there exist, within the NTS, neurons which does not induce swallowing has been found to, neverthe-
fire sequentially during swallowing, each neuron or group less, induce inhibitory phenomena such as relaxation of
of neurons in this chain may control more and more distal the lower esphageal sphincter (263). Recent studies in
regions of the swallowing canal and be responsible for the humans, using an artificial high-pressure zone created by
successive firing behavior (Fig. 8A) (152, 154, 277). Exci- inflating an intraesophageal balloon, suggest that a wave
tatory connections between neurons may provide the ba- of inhibition occurs before the esophagus contracts (303,
sis for the successive excitation of the cells via increas- 304). Furthermore, IX stimulation, which activates the
ingly numerous polysynaptic connections. There is no preswallowing neurons to a subcritical level as far as the
direct evidence available so far about connections be- initiation of swallowing is concerned, nevertheless inhib-
tween identified swallowing NTS neurons. However, re- its the esophageal neurons (61). Recent intracellular stud-
cent anatomical data show that such connections may ies on esophageal motoneurons have confirmed these
exist between neurons located in the interstitial and cen- assumptions. Their authors have demonstrated that these
tralis subnuclei of the NTS (39). In addition to the central inhibitory phenomena are also present at the motoneuro-
connections, each DSG neuron in the chain may be syn- nal level, which means that not only excitatory inputs but
aptically activated via peripheral afferent fibers originat- also inhibitory messages are transferred from the NTS to
ing in the corresponding part of the tract which is under the motoneuronal level (Fig. 6D) (376, 377).
their control. Whether or not this linear pattern of orga- Inhibitory mechanisms may not only be responsible
nization in the form of a chain of neurons exists at the for delaying the onset of neuronal firing, but they may also
VSG level also has not yet been ascertained. This actually contribute directly to the sequential excitation of the
seems rather unlikely, since central stimulation experi- neurons. In fact, via mechanisms such as disinhibition or
ments and those involving the application of EAA in the postinhibitory rebounds, the inhibitory connections may
ventrolateral medulla have failed so far to elicit an orga- be at least partly responsible for the progression of the
nized swallowing motor pattern (24, 161). contraction wave. With the assumption that there exist
In addition to excitatory connections, there also exist only inhibitory connections between swallowing neurons

FIG. 8. Possible mechanisms involved in pattern generation. A: the swallowing network can be viewed as a chain of
neurons (1-4) that parallels the rostrocaudal anatomy of the swallowing tract. When triggered by peripheral or central
inputs, the neurons at the beginning of the chain (1) generate, on the basis of network and/or cellular properties, a burst
firing which starts the sequence; they also exert inhibitory effects on the more caudal neurons in the chain (2, 3, and 4)
through central inhibitory connections (lines with black dots). The swallowing drive may be transferred by central
excitatory connections (white triangles) to the subsequent neuron in the chain (2), which also inhibits the more caudal
neurons, etc. The sequential firing behavior therefore results from the successive excitation of the neurons paralleled by
a rostrocaudal inhibition, which lasts longer when the neuron is more distal in the chain. This network may function
without any sensory feedback, but the peripheral inputs may modulate the sequence (broken lines). Intrinsic properties
of the neurons such as pacemaker, postinhibitory rebound, and delayed excitation properties may intervene in the
functioning of the chain (see text). Given this scheme of organization, it can be postulated to account for the differences
between primary and secondary peristalsis, that the strength of the central excitatory connections decreases in the
caudal direction, while the afferent feedback inputs then become more important (see text for comments). [Adapted
from Jean (155).] B: the chain may also function mainly on the basis of inhibitory connections. In this case, the sequential
firing of the neurons may be produced mainly by mechanisms such as postinhibitory rebounds. In this case again, these
mechanisms will presumably decrease as they occur more caudally. As suggested by field potential recordings, it can be
postulated that the neurons generating the oropharyngeal stage can also induce, in addition to the inhibition, a
long-lasting excitatory influence on neurons of the esophageal network, indicated here by the dotted line with striped
triangles (see text for further information). The sequential firing is therefore dependent on both the inhibitory
connections and the properties of the neurons and on a facilitatory influence exerted on the esophageal network in the
case of the primary peristalsis. This tentative mechanism of intrinsic modulation may account for the differences
between primary and secondary peristalsis. The traces below the diagrams give the membrane potential of oropharyn-
geal (1) and esophageal neurons (2, 3, and 4). The upward deflection corresponds to a depolarization of the neuron and
the downward deflection to an hyperpolarization. The dotted lines in B show a possible long-lasting excitatory or
facilitatory influence exerted by the oropharyngeal neurons on the esophageal ones.
(Fig. 8B), the sequential excitation of neurons may result on the esophageal network, resulting in the sequential
from postinhibitory rebounds involving in this case cellu- discharge of the neurons (Fig. 8B). Results obtained at the
lar properties of the neurons in addition to network con- network level support both of these hypotheses. It has
nections (see sect. VA2). It is also possible that the strong been reported that a subthreshold distension of the
inhibition generated during the oropharyngeal stage of esophagus, which gives rise to no contractions of the
swallowing may be followed by long-lasting excitatory or tract, can elicit a contraction at the segmental level when
facilitatory effects exerted by the oropharyngeal neurons electrical stimulation applied to the IX nerve is withdrawn

(61). In this case, the IX nerve exerts only inhibitory of the duration of the discharges and their bursting fre-
effects at the level of the esophageal neurons, and the quency, some of these discharge patterns look like those
contraction therefore results from postinhibitory rebound of swallowing neurons (161, 327). Results obtained with
mechanisms; it is the inhibition that renders the sub- bath application of EAA have shown that specific activa-
threshold distension effective. Field potentials recorded tion of NMDA receptors can induce rhythmic bursting
at the level of esophageal neurons in the NTS may be patterns in NTS neurons (330, 331). Here again, some of
composed of either a single wave of potential reflecting the patterns resemble those of swallowing neurons in
the inhibition of these neurons during the oropharyngeal terms of the bursting discharge and bursting frequency.
phase of swallowing, or a biphasic wave of potential There is admittedly no definite evidence available so far
indicating that the esophageal neuronal population is un- that these neurons may be swallowing neurons, but at
dergoing an excitatory or a facilitatory influence follow- least it can be said that within the swallowing-related NTS
ing the inhibition (Fig. 6, B and C) (152). Therefore, the regions, there are neurons present that respond in vitro
biphasic wave of potential reflects an inhibitory-excita- just like the swallowing neurons respond to afferent stim-
tory sequence occurring at the level of the esophageal ulation and NMDA application in vivo.
neurons during swallowing. It is of interest that the wave Intrinsic neuronal properties have been thoroughly
of excitation is not systematically present, like the esoph- documented in slice preparations by performing intracel-
ageal stage in anesthetized preparations. Moreover, it lular recordings. Like most of the neurons in the central
gradually becomes stronger during rhythmic swallowing, nervous system of mammals, NTS neurons have been
which is known to facilitate complete esophageal peristal- found to have several endogenous properties, some of
sis in experimental animals (Fig. 6B). The wave of exci- which seem to be relevant to swallowing pattern genera-
tation reflecting the activity of esophageal neurons may tion (161, 327). NTS neurons possess an early transient
depend on some rebound phenomena or result from a outward potassium current (IKA) that is responsible, in
state of excitation that may be induced by the release of addition to its role in frequency adaptation, for the de-
a neurotransmitter with a long-lasting action during the layed firing of the neurons that occurs when they are
oropharyngeal phase. Consequently, the oropharyngeal depolarized from negative membrane potentials (75, 332,
stage of swallowing may trigger phenomena such as in- 333). IKA might therefore be involved in the sequential
trinsic neuromodulation (170), i.e., the activity within the activity of swallowing neurons. If there exist any cells
network of oropharyngeal neurons may facilitate that of with an IKA conductance within the swallowing network,
other neurons within the network, namely, the esopha- it is possible that inhibition of these neurons might abol-
geal neurons. ish the steady-state inactivation of IKA, and therefore
delay the onset of their firing. It should be noted that the
2. Cellular properties: intrinsic and delay induced by IKA is dependent on the inhibitory ef-
transmitter-induced properties fects: the stronger the hyperpolarization of the neuron, or
the longer its duration, the longer this delay will be. A
Most of the data on the intrinsic properties of neu- neuron subjected to a short inhibition will therefore fire
rons liable to be involved in swallowing have been ob- earlier than one influenced by long-lasting inhibition (Fig.
tained in studies on brain stem slices. The data indicate 9B) (327). The pattern of activity of esophageal neurons
that neurons located in dorsal and ventral medullary re- fits this picture very well. Within the swallowing net, IKA
gions and in cranial motor nuclei that are involved in conductances might therefore contribute to the delayed
swallowing, such as V, VII, X, and XII motor nuclei and the activation of the neurons. It should be pointed out, how-
nucleus ambiguus, possess various ionic conductances ever, that the neurons must receive excitation to be able
that may be involved in patterning the swallowing motor to produce their burst firing activity. Within a network of
event (55, 56, 58, 74, 75, 118, 332, 333, 340, 354, 355, 374). neurons with excitatory connections between them, ex-
The linkage between the endogenous properties of neu- citation is sequentially transferred, and the IKA conduc-
rons studied under these in vitro conditions and their tances may adjust the sequential firing of neurons. If the
possible role in swallowing pattern generation is far from excitation results mainly from long-lasting excitatory ef-
having been elucidated at present. The most relevant data fects developed during the oropharyngeal stage, i.e., from
in this connection have been obtained in studies on NTS the hypothetical intrinsic system of modulation, the IKA
neurons, in particular those located in the peri-interstitial conductances will play a key role in the delayed firing of
region of the NTS where are situated swallowing-related the neurons. In this case, it is of interest to note that the
neurons (330 –333). network may function mainly with inhibitory connections
Extracellular recordings on neurons in the rat NTS (Fig. 8B). It has also been reported that some NTS neu-
region have shown that repetitive stimulation applied to rons possess low-threshold activated calcium currents,
afferent fibers within the tractus solitarius can elicit burst- IT(Ca), which are responsible for postinhibitory rebounds
ing discharges in some NTS neurons (329, 331). In terms (Fig. 9C) (56, 328). If some neurons in the swallowing

FIG. 9. NTS neuronal activities re-

corded in vitro on rat brain stem slices.
A: two types of rhythmic bursting dis-
charges elicited in NTS neurons by bath
application of NMDA (60 ␮M). 1: Typical
rhythmic burst firing superimposed on
cyclic depolarization of membrane po-
tential. Note that the burst of spikes may
be followed by depolarizing after-poten-
tials and that the frequency of the rhyth-
mic activity depends on the membrane
potential value. 2: Depending on the
membrane potential, NMDA application
induces different types of discharge in
this neuron. A depolarization associated
with repetitive firing, various rhythmic
busting patterns, or a single rhythmic dis-
charge at more negative potentials. Note
that the rhythmic patterns are driven by
cyclic membrane potential depolariza-
tions characterized by an initial ramp-
shaped phase. [Adapted from Tell and
Jean (332).] B: delayed excitation in
a NTS neuron. A control depolarizing
pulse elicited repetitive firing (top trace)
when it was preceded by a conditional
hyperpolarizing pulse; the first spike in
the burst was delayed (middle and bot-
tom traces). Note that the delay was
longer when the duration of the hyper-
polarizing pulse increased. [From Tell
(327).] C: postinhibitory rebound in a
NTS neuron. Depending on the ampli-
tude of the hyperpolarizing pulse, the
neuron showed either a subliminar depo-
larization or burst firing pattern. [Adapted
from Tell and Bradley (328).] D: model for
the generation of NMDA-induced oscilla-
tions in NTS neurons. These ionic conduc-
tances were identified in NTS neurons that
fire under NMDA application as shown in
A2. [From Tell and Jean (333).]
network do have these calcium conductances, it is there- like properties (Fig. 9, A and D) (332, 333, 356). In addi-
fore likely that they will be involved in their burst firing tion to mechanisms such as those involving reexcitation
activity. As stated above, most of the neurons in the phenomena, if swallowing neurons possess these pace-
swallowing CPG probably undergo inhibitory influences maker-like properties, it is very likely that they may par-
before their burst firing is initiated. These inhibitory in- ticipate in burst generation, as has been found to occur in
puts may therefore activate the IT(Ca) and participate in several other CPGs (11, 117, 358). Interestingly, the
the bursting activity. Moreover, as postulated above, with NMDA-induced bursting pattern is dependent on the
properties of this kind, the swallowing network will be membrane potential and occurs in a high membrane po-
able to function only if there are inhibitory connections tential range (333, 356); this feature is in keeping with
between the neurons. Whether or not this is the case, the results suggesting that the bursting swallowing pattern is
sequential firing of the neurons will therefore rely mainly preceded by an inhibitory phase. It is therefore likely that
on the postinhibitory rebound properties of the neurons. NMDA-gated conductances may participate in the burst
Moreover, the responses of NTS neurons to activation of formation within the swallowing network. Because
NMDA receptors have shown that they have pacemaker- NMDA receptors are actually involved in generating de-

glutition, or more specifically, rhythmic swallowing and in ageal phase may show some lability and also suggest that
eliciting pacemaker-like properties in NTS neurons, it is the central program controlling this phase may be less
furthermore likely that the oscillatory properties of the robust than that responsible for the oropharyngeal phase
swallowing network may involve conditional bursters lo- (see sects. II and III). The size of the neuronal population
cated within the NTS. In fact, two types of NMDA-induced involved during these two phases is also different. De-
bursting patterns have been recorded among NTS neu- pending on the number of muscles involved, the number
rons (Fig. 9A) (332). The one pattern probably corre- of active neurons during the oropharyngeal phase of swal-
sponds to a typical pacemaker bursting activity, in which lowing has been found to be far larger than that involved
the firing of the neuron is superimposed on a bell-shaped in the esophageal phase (149, 152). The bursting activity
depolarization of the membrane potential. Due to the of the oropharyngeal neurons is also very different from
limited samples of this type of neuron available, the con- that of the esophageal neurons. Among the motoneurons,
ductances involved in the burst firing have yet not been the only respect in which the two types differ is the
specified, however. The other pattern of pacemaker-like duration of the discharge, whereas among the interneu-
oscillations results in the activation of NMDA-gated rons, the discharge frequency also differs conspicuously,
conductances and in interactions with other voltage-de- since it can be 10-fold higher in the case of the oropha-
pendent conductances at work in NTS neurons, such as ryngeal neurons. It is also worth noting that even when
high-threshold calcium conductances, calcium-activated the discharge frequencies were in the same range of mag-
potassium currents, and IKA (Fig. 9D). In this case, the nitude, as in the case of the late and very late neurons,
burst firing is subtended by a wave of depolarization with there was also a significant difference between the fre-
a characteristic ramp-shaped phase, the duration of which quencies, the higher frequency being that observed in the
increases with the hyperpolarization and thus delays the neurons controlling the proximal parts of the esophagus
firing. These interactions between chemo- and voltage- (149, 152). A clear-cut discharge frequency gradient can
gated conductances have been found to play a key role therefore be said to exist within the swallowing network,
in the expression and shaping of the cell discharge and the elements subserving these two stages are clearly
pattern (333). quite separate. Whatever mechanisms may be involved in
the sequential firing, their strength therefore obviously
decreases along the chain of neurons. These differences
B. Mechanisms of Deglutition and Secondary may reflect differences in the strength of the synaptic
Peristalsis connections along the chain of neurons, possibly due to
the existence of increasing numbers of synapses, and/or
In species with an entirely striated esophagus, it has to the properties of the cells. In fact, data obtained in the
by now been clearly established that deglutition, i.e., the case of secondary peristalsis have suggested that the
oropharyngeal phase followed by primary peristalsis, is a swallowing CPG can be subdivided into two subnetworks:
centrally patterned motor activity and that the central an oropharyngeal and an esophageal net of neurons, each
program is modulated by central or peripheral inputs so of which mediates the patterning of the respective phase
that the motor contraction is adapted to the size of the of deglutition, but that the esophageal net is likely to have
bolus (see sect. IV). In species with a smooth muscle less robust central mechanisms and be more dependent
esophagus, intrinsic peripheral mechanisms of both neu- on afferent inputs.
ral and muscular origin are obviously involved in the The mechanisms underlying secondary peristalsis
organization of the smooth muscle motor pattern (78, 79, have not yet been completely elucidated. In some species,
80, 110, 111, 280). Even in this case, however, several data no clear-cut differences have been observed between the
have suggested that under physiological conditions the primary and secondary peristalstic processes (141, 147,
central nervous system may also contribute to the orga- 148, 199, 302), whereas in others, striking differences have
nization of the sequential motor pattern (145–148, 336). A been noted, since the secondary peristalsis hardly de-
good example of this central intervention has been pro- pends at all on afferent feedback (152, 219, 220, 277).
vided by experiments showing that sequential activity Whatever mechanisms may be involved, secondary peri-
occurs in vagal preganglionic fibers during swallowing stalsis functions most efficiently with continuous feed-
(109, 281). It is therefore to be expected that when acti- back. In sheep, for example, the fact that secondary peri-
vated, the CPG will always organize the whole sequence stalsis is obviously dependent on feedback phenomena
from the oropharynx to the esophagus. The hypothesis suggests that there is little if any central programming and
that the network consists of a chain of neurons would that the sequential contractions rely on peripheral feed-
account for how this sequence is generated. However, back mechanisms (152). This also supports the view that
there exist some differences between the oropharyngeal the esophageal net is completely separate from the oro-
and esophageal phases of swallowing. In fact, results pharyngeal one. However, authors performing microelec-
indicate that unlike the oropharyngeal phase, the esoph- trode recordings failed to detect any differences between

the neurons involved or their discharge parameters: a that mechanisms found to operate mainly in the central
given neuron was found to be involved in both primary nervous system of lower species are equally valid in the
and secondary peristalsis, and the duration of discharge case of mammalian central nervous system (197). The
and the frequency were the same in both cases, or even swallowing CPG is not an automatic, continuously func-
more paradoxically, were larger during secondary peri- tioning CPG, and the question arises as to whether the
stalsis (149, 152). This is puzzling from the patterning swallowing neurons are completely inactive when no
point of view. Why are afferent inputs necessary under swallowing occurs, or whether these neurons may have
these conditions, and why is the central program ineffec- other functions. This question is especially interesting,
tive? In fact, when the same elements are involved in both since we have established that swallowing neurons in-
cases without there being any difference between their clude NTS neurons, and it has by now emerged that the
discharge patterns, the sole difference between primary NTS is far from being simply a sensory relay (157, 161).
and secondary peristalsis is that the latter lacks an oro- NTS neurons are involved in many activities, such as the
pharyngeal phase, and consequently is not accompanied autonomic ones, as well as in endocrine processes and in
by any oropharyngeal network activity. Therefore, the several integrated behaviors such as emotional processes,
activity of the oropharyngeal net might be an important hunger, thirst, control of pain mechanisms, regulation of
factor in the central programming of primary peristalsis. the level of consciousness, and probably many other
That is to say that the esophageal net may program esoph- yet nonidentified functions (157). This is particularly
ageal peristalsis only when triggered by the oropharyn- striking given that the NTS is quite a small structure
geal net. In this way, the oropharyngeal net may serve as containing only a small population of neurons, numbering
an intrinsic modulatory system (Fig. 8B), a mechanism around 40,000 in the case of the rat caudal NTS (259).
which seems to play an important role in several CPGs Are all the NTS neurons in this very small population
(170). When it is present, the esophageal net can program each devoted to a single fixed function, or do there exist
the peristaltic wave, whereas when it is absent, as in the within the NTS one or several populations of neurons that
case of secondary peristalsis, the program requires pe- are flexible and participate in several functions, depend-
ripheral influences. Whatever the case may be, the previ- ing on the inputs they receive? It has been observed by the
ous oropharyngeal phase will facilitate or trigger central group of Maurice Moulins that in invertebrates, swallow-
esophageal programming mechanisms, such as those in- ing depends on a pattern generator that is temporarily
volving the powerful inhibitory phenomena which induce formed preparatory to the production of the motor activ-
postinhibitory rebounds and/or long-lasting facilitatory in- ity (222, 223). That is to say that when a given stimulus is
fluences. delivered, a pool of appropriate neurons is activated and
forms the swallowing CPG, whereas these neurons are
involved in other tasks when no swallowing activity is
C. Nature of the Swallowing CPG required.
In keeping with the new principles involving flexible
Classically, the swallowing CPG has always been circuits, recent results have suggested that within the
taken to be a specific network of neurons dedicated to swallowing CPG, some neurons may participate in activ-
this function alone. However, this view has by now been ities other than just swallowing-related ones. It has been
challenged in the light of numerous data obtained mainly established that not only motoneurons, but also interneu-
on the central nervous system of invertebrates. In addi- rons can be involved in at least two different tasks, such
tion to being a classical dedicated network, most of the as swallowing and respiration, swallowing and mastica-
CPGs seem in fact to be either reorganizing or distributed tion, or swallowing and vocalization.
circuits, and a single neural circuit can combine features With regard to the swallowing motoneurons, some
typical of each of these different architectures (82, 169, recent results have indicated that ambigual, trigeminal,
237, 265). In any case, it has been established in particular and hypoglossal motoneurons can fire both in phase with
in the case of the crustacean pyloric pattern generator respiration and during deglutition, as well as with swal-
that various pattern generators exhibit a high degree of lowing and mastication, swallowing and vocalization, and
flexibility, resulting in considerable functional plasticity even during swallowing, vocalization, and respiration (3,
(82). This is a particularly relevant point in the case of the 190, 300, 313, 317, 318, 323, 346, 376). Therefore, common
swallowing CPG for the following reasons. Although the motoneurons may be involved in these activities. By driv-
flexibility of the motor pattern generators has been clearly ing muscles that can participate in two or more activities,
demonstrated in invertebrates, several examples have by these motoneurons probably participate in the fine tuning
now come to light which suggest that in vertebrates, of the muscular activity during the motor behavior. These
particularly in mammals, pattern generators also show motoneurons presumably receive a drive from separate
some flexibility (237, 265). Previous results relating, for CPGs, and their activity no doubt depends on synaptic
example, to the cellular properties of neurons have shown interactions between the two networks.

Some recent results have indicated that interneurons for great functional flexibility. Despite the progress made
localized in the dorsal (DSG) or ventral (VSG) regions of as far as invertebrates are concerned, the exact role of
the swallowing network also fire during several motor these neurons in the mammalian CPGs during swallowing
behaviors such as swallowing, respiration, mastication, or other activities is difficult to assess, and further exper-
and vocalization (Fig. 10, A and B) (7, 22, 59, 106, 172, 190, iments are now required to elucidate this point in the
252, 253, 373). The common motoneurons might therefore various CPGs.
be triggered by common pools of interneurons. These The mechanisms that make it possible for the same
results indicate that in mammals, the neurons liable to be neuron to participate in several sometimes antagonistic
involved in pattern generation can belong to different activities still remain to be determined. In invertebrates,
CPGs. Multifunctional neurons of this kind would make the flexibility of the CPGs is conferred by the inputs,
FIG. 10. Multifunctional activities in

swallowing neurons and diagram of the pos-
sible flexibility of the swallowing CPG. A:
extracellular recordings on decerebrate rats
of the activity of a VSG neuron. In 1, the
neuron (SwN) exhibited the typical burst
firing pattern during swallowing (SHm: su-
prahyoid muscles EMG) evoked by SLN
stimulation. Without any swallowing motor
event, a pattern of rhythmic activities (in 2),
associated with the respiratory cycle (not
recorded), was elicited by ionophoretic ap-
plication of kainate, showing the presence
of a subliminal respiratory drive. [Adapted
from Kessler (172).] B: intracellular record-
ings of the activity of a cat NTS neuron (N).
In 1, this neuron exhibited cyclic depolariza-
tion of its membrane potential in phase with
the inspiratory activity recorded from the
phrenic nerve (Phr). In 2, during fictive swal-
lowing (bursting activities recorded in the
XII nerve) elicited by stimulating the SLN,
the respiratory neuron became a swallowing
neuron, since its burst firing activity was in
phase with the swallowing. [Adapted from
Bianchi and Grélot (22).] C: the swallowing
CPG may be a dedicated circuit (1) with
neurons subserving only this function. This
CPG has connections with other CPGs, such
as those involved in ingestive behavior (lick-
ing, sucking, mastication), speech, protec-
tive reflexes (emesis, coughing), rumination,
and respiration, to ensure functional inter-
actions under physiological conditions. Al-
ternatively, the swallowing CPG may be a
reorganizing circuit (2) consisting of pools
of flexible neurons, i.e., neurons which can
function in several CPGs involved in the
organization of various kinds of motor be-
havior.

which both restructure a CPG by changing the influences sequence. The sequential burst firing of the swallowing
exerted on the synaptic connections between neurons neurons probably depends on the pattern of intrinsic
and alter the intrinsic properties of the neurons compos- connections within the swallowing network. Within this
ing the CPGs (82). It is worth noting that in the case of the network, central inhibitory connections, in particular,
NTS neurons, in vitro data on brain stem slice prepara- play a major role, resulting in a rostrocaudal inhibition
tions have provided evidence that there is a cellular basis within the network which parallels the rostrocaudal anat-
underlying the flexibility. The same NTS neuron can ex- omy of the swallowing tract and acts in such a way that
hibit either tonic firing, burst firing, or a beating-like firing when the neurons controlling the proximal parts of the
depending on the balance between excitatory and inhibi- tract are active, those which command more distal parts
tory inputs, which may modulate the interactions be- are inhibited. Intrinsic properties of the neurons, in par-
tween several ionic conductances (Fig. 9A2) (162, 332, ticular those of NTS neurons, probably also contribute to
333). If the same properties are preserved in vivo, it is determine the shaping and timing of the swallowing mo-
possible that the role of each neuron is not in fact fixed tor pattern. In particular, pacemaker-like properties of
once and for all. A neuron may function flexibly within a NTS neurons are also thought to greatly contribute to
network and thereby participate in several behaviors patterning the bursting neuronal firing and generating
(197). Whatever the case may be, the evidence available to their oscillatory behavior during rhythmic swallowing. As
date indicates that within the dorsal and ventral medulla, clearly demonstrated in the case of invertebrate pattern
there exists a common pool of neurons that might have a generators, it now seems likely in the light of several
multifunctional role. It can therefore be postulated that at recent results that the swallowing CPG may show some
least some of the components of the swallowing network flexibility. These results suggest that at least some of the
are not dedicated to swallowing alone but can also serve swallowing neurons may be multifunctional neurons and
some purpose in other central networks (Fig. 10C). belong to pools of neurons that are common to several
CPGs.
It will obviously be a long and difficult task to further
VI. CONCLUSION AND PROSPECTS increase our knowledge about the neuronal mechanisms
involved in swallowing in mammals. Several possible
Swallowing is a vital motor activity that serves ali- lines of research can nevertheless be indicated as means
mentary purposes and protects the upper airway. This of answering questions yet unsolved, using new ap-
complex motor sequence involves the coordinated and proaches to the neurophysiology of swallowing. One of
synchronized contraction of more than 25 pairs of mus- the most important questions that remains to be answered
cles in the oropharynx, larynx, and esophagus, which are about the neural control of swallowing is whether the
active during an all-or-none oropharyngeal phase, fol- central nervous system of the species with a smooth
lowed by the primary esophageal peristalsis. Swallowing muscle esophagus may include a network of neurons that
is also a rhythmic motor event, at least as far as its is similar to that of the species with a striated esophagus,
oropharyngeal stage is concerned. Swallowing depends and if so, how this network functions. The supramedul-
on a CPG located in the medulla oblongata, which in- lary influences on swallowing, which have been only
volves several brain stem motor nuclei (V, VII, IX, X, XII) sparsely documented so far, require more thorough inves-
and two main groups of interneurons: a dorsal DSG in the tigation. In particular, this would make it possible to
NTS and a VSG located in the ventrolateral medulla above specify the role of these central influences in several
the nucleus ambiguus. Within the CPG, neurons in the pathological situations. Interestingly, it is now possible in
DSG play the leading role in generating the swallowing studies of this kind to use new approaches such as cor-
pattern, while neurons in the VSG act as switching neu- tical evoked potential, transcranial magnetic stimulation,
rons, distributing the swallowing drive to the various and magneto-encephalographic recordings, not only on
motoneuronal pools. It is quite remarkable that a CPG for experimental animals but also on humans (14, 15, 53, 119,
a fundamental motor activity should be located within a 122, 339, 348). To further elucidate the working of the
primary sensory nucleus, namely, the NTS. As in the case CPG, it will also be necessary to identify at the cellular
of other CPGs, the functioning of the central network can level the action of neurotransmitters and neuromodula-
be influenced by both peripheral and central inputs, tors and the types of receptors involved. This would
which serve in particular to adapt the swallowing drive to provide valuable information about the possible sites of
the size of the bolus to be swallowed. action for therapeutic agents. It seems to be quite impos-
Little is known so far about the mechanisms at work sible at present to definitely elucidate the intrinsic mech-
in the CPG. Among the various neurotransmitters that are anisms underlying swallowing pattern generation in mam-
known to intervene in swallowing, the EAA receptors, in mals. However, these basic mechanisms can be studied in
particular those of the NMDA type, play an important role networks consisting of limited populations of neurons,
in triggering the motor event and patterning the motor such as those with which invertebrates are endowed, or

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Brain Stem Control of Swallowing: Neuronal Network and Cellular Mechanisms

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PHYSIOLOGICAL REVIEWS

Vol. 81, No. 2, April 2001

Brain Stem Control of Swallowing:

Laboratoire de Neurobiologie des Fonctions Végétatives, Département de Physiologie et Neurophysiologie,

I. INTRODUCTION also protects the upper respiratory tract by cleaning the

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inhibition of their spontaneous discharge during swallow-

Motoneurons active in swallowing have been identi-

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1. Comparison of discharge characteristics and localization between oropharyngeal and esophageal

Oropharyngeal Neurons Esophageal Neurons

DSG VSG Motoneurons DSG VSG Motoneurons

Burst duration, ms 90–400 80–300 50–200 150–1200 150–800

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FIG. 5. Diagram of the swallowing

TABLE 2. Connections between medullary swallowing neurons

Oropharyngeal VSG Oropharyngeal Esophageal DSG Esophageal

Oropharyngeal DSG neurons E (EAA) ? I (GABA)/E (ACh) I (?)

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FIG. 9. NTS neuronal activities re-

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FIG. 10. Multifunctional activities in

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