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
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I. Introduction
II. Motor Activity
A. The sequential swallowing pattern: oropharyngeal deglutition and primary peristalsis
of the esophagus
B. Rhythmic swallowing movements
C. Motility of the esophagus: secondary and autonomic peristalsis
D. Other types of movements
III. The Neuronal Network Generating Swallowing
A. Localization and functional significance of the swallowing center neurons
B. Organization of the neuronal network
IV. Activation of the Neuronal Network and Modulation of Network Activity
A. Role of sensory inputs
B. Supramedullary influences on swallowing
C. Action of brain stem neurotransmitter systems
V. Neural Mechanisms
A. Central pattern generation
B. Mechanisms of deglutition and secondary peristalsis
C. Nature of the swallowing CPG
VI. Conclusion and Prospects
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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
The act of swallowing is a fundamental motor activity
in mammals, since it serves two vital functions. By propulsing food from the oral cavity into the stomach via the
pharynx and the esophagus, swallowing subserves an
alimentary function and thus constitutes the first, irreversible step in feeding behavior. The swallowing reflex
http://physrev.physiology.org
also protects the upper respiratory tract by cleaning the
naso- and oropharynx and closing the nasopharynx and
the larynx, to prevent the pulmonary aspiration of food
particles (34, 87, 90, 110, 226, 248).
Swallowing is known to be a complex but stereotyped motor sequence, with the implication that it involves a fixed behavioral pattern. It constitutes, however,
one of the most elaborate motor functions, even in hu-
0031-9333/01 $15.00 Copyright © 2001 the American Physiological Society
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lowing is a suitable model not only for the neurophysiological analysis of sequential motor events, but also for
that of rhythmic motor behaviors. However, it should be
stressed that the rhythmic motor pattern is mainly associated with the oropharyngeal phase of swallowing, and
the uppermost part of the cervical esophagus when the
rhythmic frequency is low. No esophageal peristalsis occurs during the successive oropharyngeal sequences, and
only the last oropharyngeal event in the series is followed
by the complete esophageal stage (79, 111, 279, 350, 353).
In mammals, all the muscles involved in the oropharyngeal stage are striated and are therefore driven by
several pools of motoneurons located in various cranial
motor nuclei in the brain stem and the uppermost levels
of the cervical spinal cord (51, 87, 156, 226). The esophageal muscle is entirely composed of striated fibers in
species such as rat, guinea pig, rabbit, dog, sheep, and
cow and is therefore controlled by cranial motoneurons.
In some species however, e.g., cats, opossums, and primates, a variable portion of the lower esophagus is composed of smooth muscle fibers, controlled by the autonomic nervous system (60, 79, 110, 111, 280).
It has by now been clearly established, as originally
postulated in the pioneering work by Meltzer (218 –220),
that the sequential and rhythmic patterns of swallowing
are formed and organized by a central pattern generator
(CPG). The CPG was previously described as a swallowing center that can be subdivided into three systems: an
afferent system corresponding to the central and peripheral inputs to the center; an efferent system corresponding to the outputs from the center, consisting of the
various motoneuron pools involved in swallowing; and an
organizing system corresponding to the interneuronal network that programs the motor pattern (51, 87, 156, 280).
In fact, the concept of a swallowing center implies the
idea of an anatomical localization, whereas that of a CPG
is based on a more functional principle focusing on the
activity of the various pools of neurons, i.e., motoneurons
and interneurons, involved in the motor activity. The
swallowing CPG is located within the medulla oblongata
(156, 161). Swallowing is indeed a primitive reflex, which
means that it is present in all animals with organs serving
differentiated functions and that it emerges early during
development. The normal human fetus can swallow by
the 12th gestational week, before the cortical and subcortical structures have developed (139). It has also been
reported that swallowing is still possible in human anencephalic fetuses (266, 269). Experimental studies have
shown, moreover, that the destruction of several nervous
structures such as the forebrain, cerebellum, and pons
does not alter swallowing (34). In fact, the basic sequential motor pattern seems to remain nearly normal as long
as the nervous structures located between the C1 level
and the trigeminal motor nuclei are intact (86, 89, 150,
152, 231).
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mans, since it requires coordinating an extraordinary bilateral sequence of activation and inhibition among more
than 25 pairs of muscles in the mouth, pharynx, larynx,
and esophagus (70, 87, 226). One of the most striking
characteristics of swallowing is that the motor sequence
can be readily initiated by stimulating a nerve, namely, the
internal branch of the superior laryngeal nerve (SLN) (61,
87, 149, 225, 279). Swallowing therefore probably constitutes, as Doty (87) has said, one of “the most complex
stereotyped pattern of behavior that can be consistently
evoked by electrical stimulation of a peripheral nerve.”
Because the motor event elicited by stimulating the SLN
includes all the components of the physiological motor
pattern, swallowing provides a suitable model for studying the neurophysiological mechanisms underlying motor
pattern generation.
Since Magendie (208), the act of swallowing has generally been described as having three phases or stages
(34, 51, 70, 87, 89, 226). As regards the motor pattern
occurring during feeding behavior, swallowing has been
subdivided into an oral, preparatory phase, followed by a
pharyngeal phase, and then by an esophageal phase, corresponding to the primary peristalsis of the esophagus
(78, 110, 142, 164, 280). In fact, the oral, preparatory phase
during which the alimentary bolus is formed is almost
entirely voluntary and can be interrupted at any time,
whereas the pharyngeal and esophageal phases are involuntary. Moreover, once it has been initiated, the pharyngeal phase of swallowing constitutes an irreversible motor event. The same irreversible motor sequence is
observed both during the swallowing, which is not associated with food consumption, but serves to clear the
oropharynx of small amounts of saliva, and during the
reflex swallowing elicited by stimulation of the SLN (87).
Under these swallowing conditions, the pharyngeal phase
of deglutition involves not only pharyngeal and laryngeal
muscles, but also muscles in the oral cavity such as the
tongue and suprahyoid muscles. Therefore, the actual
motor event of swallowing can be best described as being
composed of an oropharyngeal stage and a subsequent
esophageal stage. It is this overall motor pattern, corresponding to the basic or fundamental swallow, which has
been mainly studied in neurophysiological investigations
(154 –156).
Classically, swallowing has been taken to be a sequential motor event and not a rhythmic motor behavior
like mastication, respiration, or locomotion. Deglutition
can occur repeatedly during feeding, but this is generally
regarded as simply involving the repetition at a low frequency of a single sequential motor performance (87, 164,
194). However, under the appropriate stimulus, some
components of the swallowing act can take on the properties of a rhythmic motor behavior (51, 87, 149, 161, 279).
A typical rhythmic pattern of swallowing is elicited during
long-lasting repetitive stimulation of the SLN. Thus swal-
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BRAIN STEM CONTROL OF SWALLOWING
II. MOTOR ACTIVITY
A. The Sequential Swallowing Pattern:
Oropharyngeal Deglutition and Primary
Peristalsis of the Esophagus
The motor activity of the two stages of swallowing
shows different features. The oropharyngeal stage of the
basic or fundamental swallowing is a complex, stereotyped sequence of excitatory and inhibitory events (87). It
involves a set of muscles that always participate in this
fundamental motor pattern, and therefore, these muscles
have been termed obligate muscles (87, 90). In addition to
the obligate muscles, other muscles, such as extrinsic
tongue muscles, facial muscles, lip muscles, and levator
mandible muscles, may or may not participate in swallowing, depending on either the species or the swallowing
conditions, and therefore constitute facultative deglutition muscles (90).
The onset of the oropharyngeal stage of swallowing
starts in most species with the contraction of the mylohoid muscle, which can be taken to be the first muscle to
become active in swallowing (87, 88). At the same time or
after a very short delay of 30 – 40 ms, a contraction also
begins in the anterior digastric and internal pterygoid
muscles, concurrently with that occurring in the geniohyoid, stylohyoid, styloglossus, posterior tongue, superior
constrictor, palatoglossus, and palatopharyngeus. All
these muscles constitute, along with the mylohyoid, the
“leading complex” that invariably initiates the act of swallowing (Fig. 1A) (88). The sequence continues with a
pattern of excitation and inhibition in pharyngeal and
laryngeal muscles. The middle and inferior pharyngeal
constrictors fire in an overlapping sequence, and the inhibitory phenomena are particularly striking in laryngeal
muscles such as the posterior crycoarytenoid, which becomes silent for several hundred of milliseconds (87). The
oropharyngeal phase ends when the wave of contraction
reaches the upper esophageal sphincter. At rest, the
sphincter is closed by the tonic contraction of the cricopharyngeal muscle, which plays the main role in the
sphincteric function (8, 9, 13, 49, 129, 301). Inhibition of
the tonic contraction, resulting in the relaxation and
opening of the sphincter, starts at the onset of swallowing
and lasts until the cricopharyngeal muscle becomes active and propels the bolus into the esophageal body (Fig.
1, A and B) (110, 111, 164, 226).
The duration of the whole oropharyngeal sequence is
in the range of 0.6 –1 s and remarkably constant in all the
mammals studied, including humans (87, 110). The electromyographic activity in each individual muscle consists
of a phasic discharge, in the form of a burst of spikes,
which ranges in general between 200 and 600 ms, depending on the muscle (88, 140, 171). The wave of contraction
travels down the oro- and hypopharynx at a speed of
⬃10 –20 cm/s before reaching the upper esophageal
sphincter. This wave of contraction develops a force with
a peak amplitude in the range of 100 mmHg in the oropharynx, reaching up to 200 mmHg in the human hypopharynx (Fig. 1B) (110, 353). When initiated by stimulation of the SLN, swallowing does not start immediately
but occurs after a variable delay. Depending on the species, this delay ranges from 100 ms in sheep to 40 – 60 ms
in rats (Fig. 4) (149, 152, 174). The presence of this delay
suggests that the central nervous system comes into play
during this period and participates in organizing the swallowing motor pattern.
In addition to the firing activity, when background
activity is present in the muscles, it is abruptly inhibited
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Swallowing, which can be triggered by stimulating a
peripheral nerve and involves limited regions of the central nervous system, is an attractive model for the neurophysiological analysis of sequential and rhythmic motor
behaviors. However, it has received less attention than
other fundamental motor activities such as locomotion,
mastication, or respiration (65). This is probably due to
the complexity of the motor pattern along with the great
number of muscles and cranial nerves involved, which
renders neurophysiological studies difficult. In addition,
the whole swallowing sequence is difficult to initiate in
anesthetized animals (149, 152).
Since the extensive review by Doty (87), several reviews on swallowing and its various aspects, such as
those relating to esophageal motility, have been published
(51, 70, 72, 78, 79, 84, 90, 110, 111, 129, 132, 154 –156, 161,
164, 226 –228, 278, 280, 353). However, the brain stem
mechanisms contributing to the sequential and rhythmic
motor events involved in swallowing have not been analyzed so far in detail. This review therefore focuses on the
brain stem CPG responsible for swallowing. It deals with
the results obtained over the last 25 years, first using
classical electrophysiological techniques and then pharmacological approaches, as well as neuroanatomical
methods, such as tract-tracing techniques. These results
have been mainly obtained on anesthetized or decerebrate animals, and in some cases on in vitro brain stem
slices. The brain stem CPG will be analyzed here in terms
of its location, the firing behavior of the neurons, the
patterns of connectivity and the neurotransmitters involved. The regulation of the central program by central
or peripheral inputs and some tentative mechanisms possibly underlying CPG activity will also be examined. Although a detailed analysis of the swallowing motor pattern is beyond the scope of this review, the various motor
patterns correlated with swallowing, which are relevant
to the interpretation of central nervous mechanisms, will
be briefly described before the neurophysiological analyses are discussed.
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Volume 81
with the onset of firing in the leading complex, and this
inhibition is maintained until the actual swallowing contraction begins (Fig. 1A) (87, 88, 140, 171). Inhibition can
also be detected in muscles of the leading complex just
before they contract during swallowing (88). A strong
inhibition of the background activity is also observed
after the cessation of the firing activity. Therefore, the
oropharyngeal stage comprises an extraordinary sequence of inhibition and activation in pairs of muscles,
which have to be synchronized during the motor sequence (70, 87). It is particularly striking that this complex motor sequence constitutes an “all or none” motor
activity, just like simpler reflexes. In other words, once it
has been initiated, the sequence invariably reaches the
pharyngo-esophageal junction (87, 231).
In comparison with the extraordinary complexity of
the oropharyngeal phase, the esophageal phase of swallowing is quite simple. It consists of a peristaltic wave of
contraction, which propagates down the esophagus, enabling the alimentary bolus to be transported from the
pharynx to the stomach (111, 128, 129, 142, 164). At rest,
the esophagus is electromyographically silent, i.e., there
is no tonic or rhythmic activity. The peristaltic contraction moves from the proximal to the distal part of the
esophagus at a speed that may show a fairly high degree
of variability, depending on the species and the nature of
the muscles, i.e., on whether an esophagus is composed of
striated muscle alone or of both striated and smooth
muscle. For example, the whole esophageal phase can
last less than 2 s in anesthetized sheep and exceed 10 s in
conscious humans (79, 87, 110, 149, 152, 353). Among all
the species combined, the mean velocity of the peristaltic
wave can be evaluated at between 2 and 4 cm/s, a value
conspicuously lower than that obtained in the case of the
oropharyngeal sequence. The amplitude of the peristaltic
wave is more variable than in the oropharynx. It may be
lower, ranging between 35 and 70 mmHg, but may reach
upper values of 180 –200 mmHg (Fig. 1B) (110, 111, 275,
353). The duration of the contraction at the segmental
level is longer than that observed in the oropharyngeal
muscles. It generally exceeds 1 s and can reach values of
up to 4 s, depending on the level of the esophagus and the
nature of the muscle (129, 336). The esophageal phase
ends when the contraction wave reaches the lower esoph-
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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.
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BRAIN STEM CONTROL OF SWALLOWING
B. Rhythmic Swallowing Movements
Rhythmic swallowing behavior can occur during
physiological activities such as drinking, which involves a
train of closely spaced swallows. It has been reported that
depending on the amount of liquid being drunk, several
successive swallows occur, numbering up to 100 in horses
(87). Under experimental conditions, the best way of
inducing rhythmic swallowing is to apply long-lasting repetitive stimulation to the SLN (Fig. 3) (86, 149, 225, 279).
Under repetitive stimulation of the SLN, at 20 –30 Hz,
swallowing rates of 1–2/s can be readily induced in species such as rats and sheep during short periods of time
(4 –10 s) (149, 152, 174). Even during very long-lasting
stimulation, the rhythmic pattern can continue, although
obviously with a lower frequency. Under urethane anesthesia for example, a dog can swallow repetitively for 1 h
at a rate of 0.4 Hz (87). In fact, as long as there is a bolus
to swallow, or at least saliva, it is possible to observe
sustained swallowing at a rapid rate with only slight signs
of fatigue.
When swallows occur at a fast rate, the motor pattern
consists of a series of complete oropharyngeal phases,
whereas the esophagus remains quiescent and the lower
esophageal sphincter is relaxed. A normal peristaltic contraction wave does not occur until after the last swallow
in the series (Fig. 3A) (12, 221, 350). That is to say that
during repetitive swallowing, the so-called deglutitive inhibition continuously blocks the esophageal activity.
When the rate of the oropharyngeal swallowing is slow,
the esophageal peristalsis is initiated but then interrupted
or modified depending on when the subsequent swallow
occurs during the peristalsis and on the nature of the
muscle (striated or smooth) (350). When striated muscle
only is involved, a second swallow initiated during the
primary peristalsis results in the immediate and complete
inhibition of the contractile activity induced by the first
swallow, and the first wave progresses no further (Fig.
3A) (129, 152, 277, 279). In the species with smooth muscle distal esophagus, the pattern may be different, probably due to intricate interactions between central and
peripheral effects. When the first swallowing wave has
reached the smooth muscle segment of the esophagus,
the peristaltic wave is not interrupted at this segment by
the next swallow, but can proceed distally, although it
decreases gradually in amplitude until it disappears (350).
In these species, a previous swallow or the presence of a
swallowing wave within the esophagus can dramatically
alter the nature of the subsequent esophageal wave by
decreasing its amplitude, modifying its velocity, and
sometimes rendering it nonperistaltic (350). Whatever the
case may be, depending on the duration of the whole
swallowing sequence and the frequency of the rhythmic
activities, the rhythmic swallowing motor pattern mainly
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ageal sphincter and propels the bolus down into the stomach. At rest, the lower sphincter is the site of a high
pressure zone that prevents the reflux of food from the
stomach. The factors contributing to the basal sphincter
tone are multiple (78, 79, 110, 111, 164). In most species,
the tonic contraction is mediated by a tonic depolarization of the smooth muscle fibers, without any action
potentials (111, 280). During swallowing, the sphincteric
tone is inhibited at the beginning of a swallow or after a
short delay. That is to say that this tone is inhibited during
the whole swallowing sequence until a phasic contraction
of the sphincter occurs, as at the upper sphincteric level
(Fig. 1, A and B) (79, 110, 164).
Because there is no basal tone in the esophagus at
rest, esophageal peristalsis has been thought of as just a
sequence of excitatory events corresponding to the propagation of the contraction wave. However, several lines of
evidence suggest that the esophageal peristaltic contraction, like the oropharyngeal sequence, not only consists of
a single sequential contraction but that this contraction is
preceded by an inhibitory input, which has been called
deglutitive inhibition. The lower sphincter relaxation is a
component of the deglutitive inhibition. At the other levels of the esophagus, the inhibition is not usually detectable in the absence of basal tone, but becomes clearly
visible during repetitive swallowing (79, 110, 353). By
artifically setting up a high pressure zone in the human
esophagus by inserting an intraluminal balloon and inflating it to a critical level, Sifrim et al. (303, 304) have also
observed the occurrence of a deglutitive-induced inhibitory influence before the esophageal contraction. This
inhibition begins simultaneously at various levels of the
esophagus but lasts progressively longer as it reaches the
more distal segments. In addition, in vivo recordings on
the opossum smooth muscle have shown that even without any pressure changes in the esophageal body, a membrane hyperpolarization of variable amplitude and duration precedes the muscular contraction (273, 311).
Therefore, it seems very likely that, as in the oropharynx,
the sequential pattern occurring in the esophagus is a
sequence of inhibitory and excitatory events.
Upon comparing the duration of the contractions, the
velocity of the contraction waves and the pressures developed, it becomes quite obvious that the esophageal
phase has quite different characteristics from the oropharyngeal phase. In addition, unlike the oropharyngeal
phase, esophageal peristalsis shows some degree of variability. The contraction wave can stop before reaching the
sphincter, even in awake animals (9, 86, 149, 152, 218, 302,
353). Esophageal peristalsis is therefore not an all or none
sequence, which suggests that some differences may exist
between the central mechanisms involved in the esophageal versus the oropharyngeal sequence.
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involves the oropharyngeal phase, which suggests that an
oscillatory activity may take place at the central level.
C. Motility of the Esophagus: Secondary and
Autonomic Peristalsis
D. Other Types of Movements
Some of the muscles that are involved in the motor
performance of swallowing also participate in several
other types of motor behavior. These motor activities can
be subdivided into simple motor events, called elementary reflexes, and more complex motor patterns such as
mastication, respiration, speech, and several protective
reflexes.
1. Elementary reflexes
Electrical or natural stimulation of either the oropharyngo-laryngeal area or the esophagus can evoke in
the same musculature a variety of simple reflexes. These
responses can also be elicited by stimulating central end
of nerves which innervate these regions such as the trigeminal, lingual, glossopharyngeal, vagal, superior laryngeal, and recurrent laryngeal nerves (Fig. 4A) (87, 88, 90,
212, 279). The reflex response evoked by nerve stimulation is generally ipsilateral, or at least it is much stronger
ipsilaterally. The motor responses evoked consist of short
electromyographic activities, lasting for ⬃10 ms. The latency of the responses is also short, since the minimal
latency is in the range of 6 –10 ms, depending on the
muscle and the afferent fibers involved (87, 90). The reflex
pathway may be monosynaptic, as in the case of the jaw
closing muscles, but most of these elementary reflexes
are mediated via oligosynaptic circuits (90).
With regard to the swallowing muscles, the elementary reflexes evoked by stimulating the SLN can also
involve many nonlaryngeal muscles such as the geniohyoid, palatopharyngeus, and thyrohyoid muscles, the pharyngeal constrictors, and muscles of the tongue and upper
cervical esophagus (87, 90, 279). All these muscles are
obligate swallowing muscles, which means that the SLN
strongly influences the motoneurons that innervate these
muscles. The elementary reflex responses interact with
the more complex swallowing behavior. The latter exerts
the most powerful control on the motoneuronal pool and
to a large degree overrides the effects of the elementary
reflexes (Fig. 4A) (88). These findings indicate that the
circuitry involved in the elementary reflexes, or at least
part of this circuitry, also participates in swallowing.
2. Involvement of swallowing muscles in other
motor behaviors
Swallowing muscles in the oropharynx and larynx
are also involved in several other integrated behaviors,
such as the activities involved in the preparatory oral
phases of ingestive behavior, i.e., lapping, licking, sucking, and mastication (90, 296, 326, 368). Muscles innervated by the trigeminal motor nucleus, such as the mylohyoid, anterior digastric, and lateral pterygoid, are
involved in jaw opening and chewing, during which they
have a typical rhythmic activity (90, 215, 322, 326, 368).
Muscles innervated by the facial motor nucleus, such as
the stylohyoid and posterior digastric muscles, intervene
in jaw movements (90). Tongue muscles controlled by the
hypoglossal nucleus, such as the genioglossus and styloglossus, which are involved in protrusion and retrusion of
the tongue, respectively, are also among those mainly
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Part of the swallowing sequence, namely, an esophageal peristalsis, can also be induced in the absence of the
oropharyngeal phase of swallowing and is called secondary peristalsis (219). Secondary peristalsis occurs in response to stimulation of sensory receptors in the esophagus. For example, the transient esophageal distension
induced by rapidly inflating an intraluminal balloon can
induce peristaltic contractions in the esophagus. This may
correspond to the distensions produced when the esophageal content is not completely cleared by the first swallow, or when reflux of the gastric contents occurs into
the esophagus. Secondary peristalsis may be initiated
at the level of either the striated or the smooth muscle.
The wave of contraction usually begins at the level of
the distension or just above it (79, 110, 111, 280, 353).
Once initiated, the secondary peristaltic wave
progresses distally through the esophagus, like the primary peristalsis (101, 129, 280). The amplitude and velocity of the peristaltic contractions induced by esophageal
distension are similar to those observed during primary
peristalsis. Secondary peristalsis can also be either complete or interrupted at a variable distance from the level at
which it has been initiated. It should be noted, however,
that whether or not a transient distension suffices to
induce secondary peristalsis in the smooth muscle esophagus, the presence of a bolus may be required for the
peristaltic wave to be propagated down the whole esophagus in species with a striated muscle esophagus (147,
149, 152, 276, 277). Secondary peristalsis also involves a
sequence of inhibitory and excitatory events, as shown by
the relaxation of the lower esophageal sphincter, which
begins when the wave of contraction is initiated and
lasts until the contraction reaches the sphincteric level
(111, 263).
Finally, a peristaltic contraction can still be obtained
in the smooth muscle segment of the esophagus in the
absence of any extrinsic innervation. This peristaltic contraction is called tertiary or autonomic peristalsis because
of the peripheral nature of the underlying mechanisms
(60, 78, 79, 111, 280).
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tagonistic pairs of activities as respiration and swallowing, speaking and swallowing, or jaw opening and swallowing. They constitute an example subscribing to the
general rule whereby motoneurons serve as a common
final pathway.
III. THE NEURONAL NETWORK GENERATING
SWALLOWING
A. Localization and Functional Significance of the
Swallowing Center Neurons
Primary lesion experiments as well as electrophysiological and more recent pharmacological and neuroanatomical experiments have generally yielded fairly concordant results as regards the swallowing CPG (24, 51, 87,
156, 226, 280). It was on the basis of microelectrode
recordings, however, that the swallowing-related neurons
were identified and the structures where they are located
were mainly established, and a general picture of the
organization and functional principles of the swallowing
CPG was built up (154, 156, 161). Most of the data obtained in this connection were obtained in experiments
performed on anesthetized or decerebrate animals. In
addition, under these experimental conditions, swallowing was frequently reflexively elicited by applying electrical stimulation to the SLN, in many cases in paralyzed
animals, thus resulting in a fictive swallowing pattern.
Therefore, these results relate more to the stereotyped
basic swallowing movement than to the physiological
motor activity involved in alimentary and drinking behavior, which shows greater variability and a higher degree of
complexity (87, 90, 164).
As regards the swallowing CPG, microelectrode data
have been obtained on several species, such as the cat,
dog, monkey, rat, and sheep (59, 149, 174, 246, 255, 314,
345), but the most extensive studies have been carried out
on anesthetized sheep (5, 46, 47, 61, 62, 149, 151, 152, 159,
160). In addition, most of these results have been obtained
by performing extracellular recordings. Only recently
have intracellular recordings been successfully obtained
on swallowing neurons, focusing mainly on the activity of
motoneurons (337, 376, 377), whereas few intracellular
recordings have been carried out so far on swallowing
interneurons (106). When recorded extracellularly, the
vast majority of the swallowing-related neurons, which
will be referred to hereafter as swallowing neurons, are
phasic neurons that are usually silent but produce a burst
of spikes, which has been called “swallowing activity”
(Fig. 2) (149), the timing of which is correlated with the
swallowing motor activity. Spontaneously active neurons
have also been found to participate in swallowing. Depending on the neuron, they can exhibit either a temporary increase in their discharge frequency or a phasic
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involved in all oral activities such as chewing, licking, and
sucking (83, 200, 296, 326, 342).
Several swallowing muscles in the mouth, pharynx,
and larynx exhibit either an inspiratory or an expiratory
activity. This respiratory activity in oro-pharyngo-laryngeal muscles ensures the patency of the upper airway and
regulates the airflow during the respiratory cycle (19, 81,
143, 352). Adductor muscles of the larynx are active during the expiratory phase of the respiratory cycle and
regulate the rate of airflow during expiration, whereas
abductor muscles become active during inspiration, thus
ensuring airway patency (19, 87). In addition to participating in swallowing and respiration, laryngeal muscles
obviously participate strongly in the various types of phonation (105, 239, 241, 369). Intrinsic and extrinsic tongue
muscles, such as the genioglossus, also contribute to the
respiratory activity and may be active during either inspiration or expiration (200, 201, 372). The tongue tonus, in
particular, is important in the maintenance of the appropriate airway aperture. Pharyngeal muscles can also be
active during one or the other phase of the respiratory
cycle (112, 299, 352). With regard to the relationships
between swallowing and respiration, in early asphyxia,
most or all of the muscles active in deglutition are recruited and participate in the respiratory effort. In these
cases, the muscles are active only in respiration (88).
Under these conditions, the respiratory drive therefore
overrides the swallowing drive.
Emesis is a complex sequential and coordinated motor activity, which involves some of the muscles which
participate in swallowing (187, 188). During emesis, an
opening of both the lower and upper esophageal sphincters occurs and antiperistaltic contractions of the esophagus are generated, particularly in its cervical portion
(187–189). Several oropharyngeal muscles also contract,
especially the laryngeal muscles acting as glottis closers,
pharyngeal dilator muscles, geniohyoid, genioglossus, and
digastric muscles (113, 347). Most of these muscles are
also active during retching, which may precede the expulsion phase of the emetic reflex. Rumination is a reflex
motor sequence whereby animals such as cow and sheep
regurgitate food from the stomach back to the mouth,
where it is chewed again and then reswallowed (52, 91,
110, 276, 277, 308). During rumination, the esophageal
sphincters relax and an antiperistaltic wave occurs concomitantly, in this case involving the whole esophagus.
Swallowing muscles are also activated during activities
such as coughing, belching, eructation, regurgitation,
and several other rather particular types of behavior
(110).
This brief survey shows the extraordinary diversity
of the behavior in which the muscles participating in
swallowing are also involved. These muscles can participate in reverse motor activities, such as rumination or
vomiting compared with deglutition, or even in such an-
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Volume 81
1. Motoneurons
FIG. 2. Sequential firing of dorsal medullary neurons during swallowing. A: firing patterns of oropharyngeal (early) neurons. MHm
gives the EMG of the mylohyoid, indicative of the onset of swallowing, and SwN is the activity of various neurons recorded at the
nucleus tractus solitarii (NTS) level during swallowing triggered by
stimulating the superior laryngeal nerve. Recordings have been
aligned on the onset of the mylohyoid EMG (t0, broken line). Only the
burst firing (“swallowing activity”) or the cessation of neuronal activity is shown; the initial activity induced by each laryngeal stimulation is not represented (see Fig. 4). Note the large overlap between
the sequential burst firing. The neuronal activity shown in the first
trace is that of a neuron with a preswallowing discharge; in this case,
continuous firing occurred from the superior laryngeal nerve (SLN)
stimulation up to the swallowing burst. [Adapted from Jean (149,
152).] B: activity of esophageal (late and very late) neurons. Note the
differences between the discharge duration and burst firing frequency
in esophageal versus oropharyngeal neurons. [Adapted from Jean
(149).]
Motoneurons active in swallowing have been identified 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 electrophysiological studies have been carried out so far on swallowing 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 motor 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
experiments have shown for example that abolishing the
V motor nuclei does not affect the swallowing sequence
(87, 89, 152). Trigeminal motoneurons mainly involved in
swallowing innervate the mylohyoid, anterior digastric,
lateral pterygoid, and tensor veli palatini (87). Within the
VII motor nucleus, motoneurons greatly involved in swallowing control the posterior digastric and stylohyoid (87).
Other muscles innervated by these two motor nuclei, such
as the medial pterygoid, temporal, and masseter are more
facultative swallowing muscles (70, 90). In fact, the main
motor nuclei involved in swallowing are the XII motor
nucleus and the nucleus ambiguus. Most, if not all, of the
motoneurons within these nuclei, which innervate the
intrinsic and extrinsic muscles of the tongue, such as the
genioglossus, geniohyoid, styloglossus and hyoglossus,
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inhibition of their spontaneous discharge during swallowing (Fig. 2A) (149, 152, 174, 345). Depending on the temporal relationship between their activity and the onset of
swallowing, these swallowing neurons have been classified into three categories: “early” or oropharyngeal neurons, firing before or during the oropharyngeal phase of
swallowing, and “late” and “very late” esophageal neurons, discharging during the esophageal peristalsis, that is
to say during the cervical or thoracic esophageal contractions, 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 neurons can furthermore be subdivided into motoneurons
and interneurons.
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BRAIN STEM CONTROL OF SWALLOWING
April 2001
neurons have also been identified in the nucleus ambiguus (66, 247). Unlike the striated motoneurons, which
are located compactly in a single region, the preganglionic
esophageal neurons consist of two separate groups: the
one located in the rostral part of the X motor nucleus and
the other in its caudal portion (66, 284).
Extracellular recordings have shown that within V
and XII motor nuclei and the nucleus ambiguus (46, 47,
149, 151, 152, 174), the oropharyngeal motoneurons,
which are generally silent at rest, exhibit during swallowing a short burst of low-frequency (40 –50 Hz) spikes with
a duration in the 50- to 200-ms range and considerable
overlapping between the discharge of the various neurons. The bursting discharge can either precede the beginning of swallowing by a few milliseconds or lag between 0 and 200 ms behind the onset of the sequence. The
firing behavior of esophageal motoneurons is somewhat
different (152, 183, 377). However, the results published
to date on these motoneurons are mainly restricted to
sheep. The bursting discharge has a longer duration (up to
800 ms) and a very low frequency (10 –20 Hz) and lags
from 200 –300 ms to 2 s behind the onset of swallowing.
Therefore, the swallowing activity has a longer duration
and a lower frequency in the esophageal than in the
oropharyngeal motoneurons; the later the neuron becomes active during swallowing, the longer it will fire and
the lower its discharge frequency will be (see Table 1).
In addition to the burst firing that occurs in motoneurons during swallowing, they can exhibit a short-latency
(7–12 ms) synaptic activation, which is also called initial
activity. This initial activity consists of one spike elicited
in oropharyngeal or esophageal neurons by stimulating
the afferent fibers present in the SLN or the vagus nerve,
respectively (46, 47, 149, 151, 152, 174, 317). This initial
activity has been observed only in response to ipsilateral
1. Comparison of discharge characteristics and localization between oropharyngeal and esophageal
medullary neurons
TABLE
Oropharyngeal Neurons
Esophageal Neurons
Interneurons
Burst duration, ms
Firing mean frequency, Hz
Latency of synaptic activity, ms
Peripheral afferent fibers
Cortex
Localization
Interneurons
DSG
VSG
Motoneurons
90–400
50–250
80–300
40–250
50–200
40–50
1–4
(SLN/IX)
5–8
NTS subnuclei
(interstitial,
intermediate, ventral,
and ventrolateral)
6–12
(SLN/IX)
10–16
Ventrolateral
reticular
formation
7–12
(SLN/IX)
10–16
V, VII, XII
nerve nuclei
nA (IX/X)
For further explanations and references, see text (sects.
III
and
IV,
DSG
VSG
150–1200
10–40
3–4 (SLN)
6–10 (cervical X)
10–12
NTS subnuclei
(centralis,
intermediate)
Motoneurons
150–800
10–40
(3–8 for preganglionic
fibers)
7–12 (SLN)
?
nA (X) (X dorsal
motor nucleus for
preganglionic
neurons)
A and B). nA, nucleus ambiguus; NTS, nucleus tractus solitarii.
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and the pharynx, larynx, and esophagus, participate in
swallowing (87, 226).
Data have shown the existence of a myotopic pattern
of organization within the motor nuclei. This pattern of
organization is based on a series of dorsoventral and
mediolateral subdivisions in V, VII, and XII motor nuclei
(341), i.e., the mylohyoid and anterior digastric motoneurons are situated in the ventromedial region of V motor
nucleus, and tongue protrudor motoneurons are located
in XII ventrolateral nucleus, whereas the tongue retractors are to be found more dorsolaterally (102, 181, 182,
196, 207, 234, 256, 344). The myotopic organization of the
nucleus ambiguus corresponds to the well-known rostrocaudal pattern of organization of the motoneurons innervating the esophagus, pharynx, and larynx (28, 191–193),
where the esophageal motoneurons are localized in the
rostral compact formation of the nucleus, the pharyngeal
and soft palate motoneurons in the intermediate semicompact formation, and most of the laryngeal motoneurons in the caudal loose formation of the nucleus. This
scheme of organization results in the sequential firing of
nucleus ambiguus motoneurons during swallowing. However, the various pools of motor nuclei are not involved in
any ordered sequence during swallowing, since the contraction of muscles in the leading complex involves motoneurons in V, VII, and XII motor nuclei and the nucleus
ambiguus (88).
With regard to the innervation of the smooth muscle
esophagus, the majority of the preganglionic neurons are
located within the X motor nucleus. It has been reported
that experimental lesion of this nucleus in the cat impairs
the motility of the smooth muscle esophagus (131). Moreover, after injecting tracer into the cat esophagus and
lower esophageal sphincter, most of the labeled cells have
been observed in the X motor nucleus, although some
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2. Interneurons
Extensive microelectrode recordings, first performed
on sheep (5, 61, 62, 149, 151, 152, 159) and subsequently
on the rat, dog, cat, and monkey (59, 94, 174, 190, 202, 246,
345), have shown that the swallowing neurons are located
in two main brain stem areas: 1) in the dorsal medulla
within the nucleus tractus solitarii (NTS) and in the adjacent reticular formation, where they form the dorsal swallowing group (DSG), and 2) in the ventrolateral medulla,
just above the nucleus ambiguus, where they form the
ventral swallowing group (VSG). Swallowing neurons are
therefore located in the same medullary sites where are
situated neurons that belong to CPGs involved in respiration and cardiovascular regulation (21, 73, 99, 163). In
addition, other swallowing-related neurons have been
identified within or very close to the motor nuclei and in
the pons, at the level of the sensory nucleus of the trigeminal nerve (46, 47, 152, 160, 174, 254).
The results of microelectrode recording studies have
not corroborated the lesion and anatomical data, suggesting that the swallowing CPG might be located rostrally in
the medial reticular formation. Doty et al. (89) postulated
that the interneuronal network that organizes swallowing
might be located within the medial reticular formation,
between the posterior pole of the facial nucleus and the
rostral pole of the inferior olive. This assumption was
based on lesion experiments performed on various species (e.g., on cats, dogs, and monkeys), which severely
affected the motor pattern. The anatomical results obtained on the cat by Holstege et al. (137) have suggested
that part of the “swallowing center” might be present in
the pontine tegmental area just dorsomedial to the superior olivary complex. In fact, the latter data were obtained
with tracing techniques, which can be used to demonstrate connections between neurons but not to identify
the function of any such connections. Moreover, there is
no direct evidence that any swallowing-related neurons
exist within these regions: their possible role in swallowing still remains to be determined.
A) DORSAL SWALLOWING GROUP: THE INTERNEURONAL POPULATION IN THE NTS. Within the NTS, there exist neurons that
fire during either the oropharyngeal or the esophageal
phase of swallowing (149, 152). These neurons exhibit a
typical sequential firing pattern that parallels the sequential motor pattern typical of deglutition (Fig. 2). When
rhythmic oropharyngeal phases of swallowing are elicited, NTS neurons involved in the oropharyngeal sequence produce rhythmic bursting discharges that are
closely linked to the motor pattern (Fig. 3). Because these
neurons are still active during fictive swallowing elicited
in paralyzed animals, their bursting discharge cannot be
due to peripheral afferent inputs generated by the muscular contraction and actually correspond to a central
swallowing activity (149, 152, 174). These results have
amply confirmed that swallowing is a centrally patterned
motor activity, as suggested in the pioneer study by Meltzer (218), and demonstrate that NTS medullary neurons
form part of the neuronal network that generates swallowing. In previous studies on the cat, Sumi (314) failed to
detect any bursting activity in the NTS during fictive
swallowing. However, recent studies have provided evidence that in the cat also, there exist NTS neurons involved in swallowing that have a centrally patterned activity (106, 345).
Most of the oropharyngeal neurons are active either
just a few milliseconds before or during the oropharyngeal phase of swallowing. The firing pattern of these
neurons is characterized by a short burst of spikes, with a
duration in the range of 100 –300 ms, a steady or an
increasing-decreasing frequency with a mean value in the
range of 100 Hz, and an instantaneous frequency that can
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stimulation applied to afferent fibers. Several pulses are
generally required to initiate the spike, the latency of
which is variable and suggests the existence of a polysynaptic pathway.
No central recordings have been performed so far on
the activity of the preganglionic vagal neurons that innervate the smooth muscle esophagus. The data available on
this subject were obtained in cross-innervation experiments and by directly recording the activity of vagal fibers
(109, 281). They show that these neurons operate an
ordered sequence during swallowing, which suggests that
a central control may be at work even in the case of the
smooth muscle esophagus. The burst firing of the preganglionic vagal neurons driving the smooth muscle esophagus has a long duration, in the range of 1 s, and a very low
frequency, i.e., 3– 8 Hz (109, 281). Recordings of the vagal
efferent fibers innervating the opossum esophagus and
the dog lower esophageal sphincter, both of which are
composed of smooth muscle, indicate that both the vagal
excitatory and inhibitory pathways are involved in swallowing (109, 233). These results therefore show that the
CPG exerts both an excitatory and an inhibitory drive on
the smooth musculature.
Recent intracellular recordings on hypoglossal and
nucleus ambiguus motoneurons (337, 376, 377) have
shown that, during swallowing, the firing of motoneurons
was superimposed on a bell-shaped membrane depolarization. This simple bell-shaped depolarization of the
membrane potential is not the only event that has been
found to accompany the firing of these motoneurons. In
some cases, complex depolarizing-hyperpolarizing or hyperpolarizing-depolarizing waves of membrane potential
are evoked in motoneurons during swallowing (Fig. 6D).
This indicates that in addition to an excitatory drive, these
motoneurons may also receive inhibitory inputs or have
complex intrinsic properties that are activated by the
swallowing drive.
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BRAIN STEM CONTROL OF SWALLOWING
939
be as high as 400 Hz (Figs. 2A and 4B) (149, 152, 174).
Recent intracellular studies on cats have shown that the
bursting activity of oropharyngeal NTS neurons is superimposed on a high-amplitude depolarizing wave, between
15 and 20 mV, which indicates that a strong central drive
is exerted during swallowing (Fig. 3C) (106). As in the
case of the muscular pattern, considerable overlaps occur
between the sequential burst firing of the various neurons.
The esophageal neurons obviously fire later on during
swallowing, with a phase lag of 200 –300 ms to 2 s after the
onset of the motor activity, at least in sheep (149, 151,
152). As we saw above with the motoneurons, the firing
behavior of the esophageal neurons differs from that of
the oropharyngeal neurons. The duration of the bursts of
spikes is longer (between 200 ms and 1 s), and the firing
frequency is much lower, since it does not exceed 40 Hz
in the case of the late neurons and is as low as 10 –20 Hz
in that of the very late neurons (Fig. 2B). At the level of
the interneurons, one can also observe an increase in the
duration of the discharge and a decrease in the firing
frequency when the neuron is active later during swallowing (Table 1). No central recordings have been performed
so far on esophageal neurons in species with a smooth
muscle esophagus.
When stimulation is applied to afferent fibers, both
types (oropharyngeal and esophageal) of interneurons
produce a synaptic response (initial activity) in the form
of a single spike. This initial activity can be elicited by
stimulating the ipsilateral SLN in all the oropharyngeal
NTS neurons and in the late esophageal neurons, the
firing behavior of which is linked to the activity of the
upper cervical esophagus (Figs. 4B and 6A). In the very
late esophageal neurons, an initial activity can be elicited
by stimulating the cervical vagus (149, 152). The synaptic
response may occur with a very short, stable latency of
1–2 ms, indicating that, at least some, of these neurons are
monosynaptically connected to afferent fibers (149, 152,
255, 294). In these types of neurons, the synaptic response
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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).]
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Volume 81
and the burst firing activity are clearly separated by an
interval of variable length, depending on the order at
which the neuron is recruited in the sequence (Figs. 4B
and 6A).
Among NTS oropharyngeal neurons, some exhibit a
particular pattern of bursting activity starting before the
onset of the swallowing motor sequence. Unlike those
neurons, where the swallowing burst occurs with a phase
lag after stimulation and only when a swallow is initiated,
these neurons exhibit a continuous discharge in response
to the stimulus. This discharge, called “preswallowing
activity,” starts long before the beginning of the muscular
contraction. It decreases and stops quite rapidly when no
swallowing occurs, but continues and increases, turning
into a swallowing activity, when swallowing is initiated
(Figs. 2 and 4, C and D). This pattern of discharge suggests that these neurons are involved in the initiation of
swallowing, and it has been postulated that they may
constitute the trigger neurons in deglutition (149, 152).
As regards the location of NTS swallowing neurons,
most of the relevant data were obtained before the cytoarchitectonic subdivisions of the nucleus were established on the basis of anatomical studies (1, 17, 157, 167).
Therefore, their location has not been specified in relation
to these subdivisions. However, in all the species studied,
it has emerged that the oropharyngeal neurons are situated rostrocaudally at the level of the intermediate-subpostremal portion of the NTS (17), within the medial part
of the lateral NTS which overlaps the interstitial, intermediate, ventral, and, to some extent, the ventrolateral sub-
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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 oropharyngeal 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).]
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BRAIN STEM CONTROL OF SWALLOWING
C) INTERNEURONS IN THE MOTONEURONAL POOLS. Apart from
the VSG in the ventrolateral medulla, which probably
plays an important role within the swallowing CPG (see
sect. IIIB), swallowing interneurons have been identified
within V and XII motor nuclei or in their close vicinity.
These neurons produce a high-frequency discharge, and
when tested by stimulating the motor nerves, they failed
to respond antidromically (46, 47, 149, 174). These neurons may play the role of premotor neurons or be involved
in the organization of the swallowing drive to the various
motoneurons involved in swallowing within a single motor nucleus (254). Electrophysiological and neuroanatomical data also suggest that they might be involved in
the bilateral coordination of the motoneuronal pools (5,
46, 47, 158, 235). The exact function of these neurons has
not yet been elucidated, however, and further experiments will be required before this is possible.
D) PONTINE INTERNEURONS. In sheep, a population of
neurons exhibiting burst firing in phase with the oropharyngeal stage of swallowing has been found to exist more
rostrally in the pons, in a region extending rostrally to the
exit of the facial nerve, above the V motor nucleus, at the
level of the principal sensory trigeminal nucleus (160).
These neurons, which are spontaneously active, present a
swallowing activity in the form of a burst of spikes lasting
some 40 –380 ms, with a similar discharge frequency to
that of the medullary interneurons, ranging between 60
and 340 Hz. In addition, they can be synaptically activated
by applying stimulation to the ipsilateral SLN with a latency of 1.5– 4 ms resembling that of the NTS neurons.
However, there are two striking differences between
these and the NTS neurons. In the pons, the swallowing
burst always occurs after the beginning of swallowing and
is abolished after motor paralysis of the animal. In addition, unlike NTS neurons, the pontine neurons are antidromically activated when stimulation is applied to the
ventro-postero-medial nucleus of the thalamus (160). On
the basis of these results, these pontine neurons have
been classified as sensory relay neurons and are thought
to be involved in providing information from the oropharyngeal receptors to the higher nervous centers. They
therefore do not belong to the swallowing CPG.
B. Organization of the Neuronal Network
The detailed connections between the various groups
of neurons within the swallowing CPG still remain to be
mapped. However, the results of electrophysiological and
anatomical experiments have provided some information
about the organization of the DSG, VSG, and motoneurons
(2, 152, 154, 156).
1. Connections between the various neuronal groups
The latency of the synaptic response (initial activity)
is shorter among the neurons of the DSG than those of the
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divisions of the nucleus (149, 152, 161, 174). The esophageal neurons, which to date have been clearly identified
only in sheep, are also situated at the level of the intermediate-subpostremal part of the nucleus, between the
tractus solitarius and the X motor nucleus (149, 152), a
region which may correspond to the centralis subdivision
of the NTS in the rat (1, 202). Interestingly, anatomical
results have shown that both laryngeal and pharyngeal
afferent fibers project mainly to the interstitial subdivision of the NTS in all the species studied and that the
esophageal afferent fibers end within the NTS subnucleus
centralis, at least in the rat (1, 238). Therefore, within the
NTS, there are these two subnuclei that are mainly concerned with swallowing (see Table 1).
B) VSG. In the ventrolateral medulla above the nucleus
ambiguus, there also exists a large population of oropharyngeal swallowing neurons (59, 94, 149, 151, 152, 174,
252, 345). These neurons have been identified as interneurons on the basis of criteria, such as the lack of antidromic activation by vagus nerve stimulation and a high
discharge frequency. In addition, several neurons in this
region fire during the leading phase of swallowing, before
most of the motoneurons in the nucleus ambiguus become active. The burst firing behavior of the VSG neurons
is very similar to that of the DSG neurons in terms of the
sequential firing pattern, in which there is considerable
overlap, discharge duration, and frequency. This population has, however, a lower instantaneous discharge frequency, which never reaches the higher instantaneous
values (400 Hz) observed in the DSG neurons (149, 152,
174). The main difference lies in the synaptic response to
stimulation of the SLN. The initial activity is not readily
triggered in these VSG neurons with a single pulse, and
several pulses are generally required to initiate the response. Moreover, the fact that the latency is visibly
longer (between 7 and 12 ms) and shows some degree of
variability suggests the existence of a polysynaptic connection between the afferent fibers and the neurons (149,
174, 255; see Table 1).
The existence of a large population of esophageal
interneurons in the ventrolateral medulla is less clear.
Bursting discharges in phase with esophageal peristalsis
have been recorded in the medullary region above the
nucleus ambiguus (152). However, in the case of esophageal neurons, applying stimulation to the vagus nerve
systematically induces an antidromic field potential. Without any intracellular evidence, it is therefore not possible
in the case of esophageal neurons to clearly distinguish
between motoneurons and actual interneurons (151, 152).
Whatever the case may be, swallowing neurons
within the ventrolateral medulla are still active during
fictive swallowing. Their bursting activity is therefore actually a central discharge, and these neurons, like those in
the NTS, belong to the neuronal network that generates
swallowing.
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is also connected to the homologous contralateral medullary region and to VII, X, and XII motor nuclei, all of
which are also involved in swallowing (158). The ventrolateral medulla, which contains swallowing neurons, is
therefore connected to all the various groups of motoneurons involved in swallowing: this conclusion is in
complete agreement with other anatomical data (138,
195, 343).
These results suggest that within the swallowing network, VSG neurons are activated via DSG neurons and
that motoneurons are driven by neurons of the VSG (Fig. 5
and Table 2). If we therefore consider the swallowing
CPG, there exist simple circuits linking together the afferent fibers, the DSG neurons, the VSG neurons, and the
motoneurons. At each level obviously, i.e., within the
NTS, the ventrolateral medulla and the motoneuronal
pools, circuits more complex than a simple monosynaptic
connection may exist. However, the trisynaptic circuits
are probably basic elements in the functioning of the
CPG. Such reflex loops are also probably basic in the
elementary reflexes.
Recent results obtained with retrograde tract tracing
techniques or by performing transneuronal labeling with
pseudorabies virus indicate that a direct connection may
exist between swallowing regions in the NTS and motoneurons in the nucleus ambiguus, at least in the rat (16,
18, 39, 125, 126). These studies show that NTS neurons,
which are supposed to be esophageal neurons, since they
are located in the subnucleus centralis where esophageal
afferent fibers project, send axon terminals in the rostral
compact formation of the nucleus ambiguus where esophageal motoneurons are situated. A direct connection between NTS esophageal neurons and esophageal motoneurons may exist, since the existence of an interneuronal
pool of esophageal neurons has not been clearly demonstrated in the ventrolateral medulla. However, it seems
unlikely that a direct connection of this kind exists in the
case of oropharyngeal neurons (see sect. IIIA2). All the
results available to date on functionally identified swallowing neurons have shown that motoneurons are driven
by oropharyngeal neurons within the VSG. Therefore, it is
puzzling that the oropharyngeal population of interneurons within the ventrolateral medulla, i.e., the VSG, was
not determined in the anatomical studies. Recordings will
have to be made on functionally identified neurons to be
able to ascertain whether there exists a monosynaptic
link between neurons in the DSG and motoneurons.
2. Role of the various interneuronal groups in the CPG
It has been established in several networks involved
in basic motor behavior, such as locomotion, that within
a given CPG all the neurons are not equal since some of
them play a preeminent role (10, 117). As regards swallowing, data already obtained suggest that neurons in the
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VSG. In the case of SLN stimulation, the latency is 1– 4 ms
in the DSG and 7–12 ms in the VSG (149, 151, 152, 159,
174, 255). A synaptic response can also be initiated in
swallowing neurons by stimulating a specific cortical
area, which induces swallowing (see sect. IV). Here again,
the latency of the response is shorter in the NTS swallowing neurons (5– 8 ms) than in the neurons in the ventrolateral medulla (10 –16 ms) (152, 159). These results suggest that the neurons of the VSG are probably activated
via neurons of the DSG. Indeed, regardless of which afferent pathway is stimulated, the initial response of the
VSG neurons is abolished after lesion of the DSG (152,
159). Although no direct evidence is available at the single
cell level that a connection of this kind exists between the
DSG and VSG, connections between the NTS region and
the ventrolateral reticular formation surrounding the nucleus ambiguus, where swallowing neurons are located,
have been found to exist in several anatomical experiments (57, 69, 236, 249, 257, 258, 283, 288). Other anatomical results have shown that the ventrolateral medulla also
projects to the NTS region (20, 126, 198, 282, 349). However, whether or not these possible reciprocal connections are involved in swallowing still remains to be established.
Electrophysiological experiments on sheep have
shown that only the swallowing neurons within the VSG
could be antidromically activated by stimulating the swallowing region of V motor nucleus, i.e., that region where
swallowing motoneurons are located, while none of the
neurons within the DSG exhibited any antidromic activation under the same conditions (5). These results indicate
that the V motor nucleus is connected to only one of the
medullary regions involved in swallowing, namely, the
VSG. Similar results have also been obtained on the XII
motor nucleus, the stimulation of which evoked an antidromic potential in swallowing neurons of the VSG (4). In
addition, more recent electrophysiological studies on
sheep and cats have established that within the VSG, the
same identified swallowing neuron can project to more
than one motor nucleus. It has been shown, for example,
that the same neuron can project either to V and XII
motor nuclei, or to the XII motor nucleus and the nucleus
ambiguus (6, 94). Some data also suggest that the same
neuron might project to V and XII motor nuclei and the
nucleus ambiguus (94), which are all motor nuclei involved in swallowing. These electrophysiological data fit
in well with those coming from anatomical studies. It has
been shown that retrograde transport of peroxidase, injected under electrophysiological control into the region
of the V motor nucleus where swallowing motoneurons
are situated, resulted in labeling of neurons in the ventrolateral medulla. Control experiments with tritiated
leucine, injected in the VSG region, show labeling in the
ventromedial region of the V motor nucleus. In addition,
these experiments showed that the ventrolateral medulla
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BRAIN STEM CONTROL OF SWALLOWING
DSG are likely candidates to act as generator neurons in
the initiation and organization of the sequential or rhythmic motor pattern (149, 152). The swallowing network in
mammals therefore provides a unique example of neurons located within a primary sensory relay, i.e., the NTS,
which nevertheless play the role of generator neurons.
Several lines of evidence support the idea that NTS neurons play a leading role in swallowing. NTS neurons exhibit a sequential or rhythmic firing pattern that parallels
the motor pattern (149, 152, 174). As this firing remains
unaltered after complete motor paralysis, it is clear that it
is actually a centrally generated premotor activity. Moreover, most of the neurons, if not all those which have a
preswallowing activity, are located within the NTS (149,
152). In addition, systematic exploration of the brain stem
with concentric bipolar electrodes to determine which
central structures responded to stimulation by triggering
deglutition have shown that the active points are situated
only in the region of the solitary complex (50, 174, 225). It
may be that deglutition results from the stimulation of
TABLE
afferent fibers belonging to the solitary tract. The wide
dispersion of the active points suggests, however, that not
only afferent fibers were stimulated but also neurons in or
very close to the NTS. The assumption that NTS neurons
may trigger swallowing was fully confirmed by more recent pharmacological experiments using fine microinjections of excitatory amino acids (EAA), which are thought
to stimulate neuronal cell bodies and not passing fibers. It
was established in these experiments that activating specific EAA receptors within the NTS elicit both the sequential and rhythmic motor swallowing patterns, whereas
microinjections of the same drugs into the ventrolateral
medulla failed to induce the swallowing motor pattern
(124, 173, 178). Furthermore, electrolytic lesion of the
NTS results in the abolition of not only the swallowing
elicited by stimulating the SLN but also that elicited by
stimulating the swallowing cortical area (152, 159). Finally, fine lesions performed on sheep in the NTS region,
which contains neurons that control esophageal motility,
abolished the esophageal phase of swallowing without
2. Connections between medullary swallowing neurons
Inputs From
Inputs to
Oropharyngeal DSG neurons
Oropharyngeal VSG neurons
Esophageal DSG neurons
Oropharyngeal VSG
neurons
Oropharyngeal
motoneurons
Esophageal DSG
neurons
Esophageal
motoneurons
E (EAA)
?
E (EAA)
I (GABA)/E (ACh)
I (?)
E (EAA)
Connections have been established on the basis of electrophysiological and anatomical tract tracing techniques (see text and sects. IIIB and
for references). DSG, dorsal swallowing group; VSG, ventral swallowing group; E, excitatory connection; I, inhibitory connection; EAA,
excitatory amino acids; ACh, acetylcholine.
IVC
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FIG. 5. Diagram of the swallowing
central pattern generator (CPG). The
CPG includes two main groups of neurons located within the medulla oblongata: a dorsal swallowing group (DSG)
located within the nucleus tractus solitarii (NTS) and the adjacent reticular formation and a ventral swallowing group
(VSG) located in the ventrolateral medulla (VLM) adjacent to the nucleus ambiguus (nA). The DSG contains the generator 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 afferent fibers, neurons in the DSG and VSG,
and motoneurons forms an oligosynaptic
loop involved in swallowing and the elementary reflexes (see text for additional
information). [Adapted from Jean (153).]
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3. Synchronization of the two swallowing CPGs
In fact, the CPG for swallowing consists of two hemiCPGs, each located on one side of the medulla (87). The
existence of two hemi-CPGs was established by making
longitudinal midline sections of the medulla. After this
splitting, stimulation applied to the SLN on one side triggered a “unilateral swallowing,” i.e., a swallowing sequence involving only the ipsilateral oropharyngeal muscles, except for the middle and inferior pharyngeal
constrictors in some species (87, 89, 150, 152). These
results indicate that under physiological conditions, the
two hemi-CPGs are tightly synchronized and organize
the coordinated contraction of the bilateral muscles of
the oropharyngeal region.
The mechanisms underlying the synchronization of
the two hemi-CPGs are not known, and this matter has
not yet been well documented. It is likely that the peripheral afferent fibers do not play an important role in the
coordination of the CPGs, since lesion experiments have
shown that splitting the medulla caudal to the obex,
which interrupts the vagal afferent fibers crossing the
midline through the solitary tract, does not affect swallowing, i.e., a bilateral deglutition still occurs in response
to unilateral stimulation of the SLN (87). Moreover, microelectrode recordings have shown that the synaptic
activity of swallowing neurons induced by stimulating the
ipsilateral SLN is absent when it is the contralateral nerve
that is stimulated (Fig. 4C). This finding indicates that the
swallowing neurons receive a direct input only via the
ipsilateral afferent fibers. There probably therefore exist
connections between central neurons that play the key
role in the coordination between the two hemi-CPGs.
Anatomical connections mediated by fibers crossing the
midline have been found to exist between the two medullary regions where swallowing neurons are located, i.e.,
the DSG and VSG (41, 158, 268).
The mechanisms involved in synchronization seem to
include all the swallowing neurons, i.e., motoneurons as
well as dorsal and ventral interneurons. Microelectrode
recordings have shown that in each case, a particular
swallowing neuron produces a swallowing bursting discharge in response to stimulation of the ipsilateral as well
as to that of the contralateral afferent fibers, regardless of
the type of swallowing neuron tested. This indicates that
at each step in the network operation, the entire population of neurons within the NTS, the ventrolateral medulla,
or the motoneuronal pools is active. Here again, however,
the neuronal population within the NTS seems to play a
particularly important role in the synchronization processes. The results of lesion experiments performed on
the NTS esophageal neuronal population have shown that
upon stimulating the ipsilateral SLN, only an oropharyngeal stage of swallowing is elicited, whereas upon stimulating the contralateral nerve, a complete process of deglutition including the esophageal stage is initiated (150,
152). These results also suggest that, at each step, the
appropriate coordination must take place between each
NTS interneuronal populations for the drive to be distributed to the motoneurons.
These results suggest in addition that under ipsilateral stimulation conditions, the swallowing motor sequence is mainly generated in the ipsilateral hemi-CPG
and that this CPG transfers the swallowing premotor
signal to the contralateral CPG. This assumption is also
supported by recordings showing the activity of neurons
with preswallowing activity. These neurons displayed a
clear-cut preswallowing discharge before the swallowing
burst only when the ipsilateral SLN was stimulated. Upon
stimulating the contralateral nerve, only the swallowing
burst was recorded, which suggests that the preswallowing discharge occurs only in the corresponding neurons
on the ipsilateral side and that only the swallowing drive
is transmitted to the contralateral side (Fig. 4C) (152).
Further experiments are required to elucidate the mechanisms underlying the synchronization of the two hemiCPGs. The lesion and electrophysiological data available
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affecting the oropharyngeal phase, which indicates that
some of the neurons actually involved in the generation of
esophageal motility had been destroyed within the NTS
(150, 152).
As regards the swallowing neurons in the ventrolateral medulla, the results available are consistent with the
view that during swallowing these neurons are driven by
NTS neurons. As neurons of the VSG are connected to
motoneurons, one of their functions probably consists of
activating the motoneuronal pools during swallowing.
The existence of neurons with collaterals to several pools
of motoneurons also suggests that they may also participate in the coordination of the motoneuronal pools during
swallowing (6, 94, 158). Within the swallowing CPG, the
ventral swallowing neurons can therefore be said to act as
switching neurons that distribute and coordinate the sequential or rhythmic drive generated in the dorsal group
to the various pools of motoneurons involved in swallowing. It may well be that these neurons are also concerned
in the coordination of the activity of motor nuclei (V, VII,
IX, X, and XII) that are involved in several other types of
motor behavior (see sect. II).
This scheme of organization of the diverse groups of
swallowing neurons does not mean that the connections
between the dorsal group and the ventral group and those
between the ventral group and the motoneurons include
only excitatory connections. Indeed, recent results obtained in intracellular studies on swallowing motoneurons in XII motor nucleus and the nucleus ambiguus (337,
376, 377) have suggested that during the functioning of
the network, both excitatory and inhibitory drives can be
exerted along the anatomical pathways.
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BRAIN STEM CONTROL OF SWALLOWING
indicate, however, that swallowing NTS neurons play a
crucial role in these synchronization processes.
IV. ACTIVATION OF THE NEURONAL
NETWORK AND MODULATION OF
NETWORK ACTIVITY
A. Role of Sensory Inputs
of swallowing. Within the SLN, there exist some fibers
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
can initiate part of the swallowing sequence, that is,
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
initiating or facilitating swallowing converge in the solitary tract and end in the NTS (67, 68, 167, 270, 338). The
solitary tract and the NTS therefore constitute the main
afferent central structures involved in swallowing, particularly the intermediate-subpostremal part of the solitary
system, which receives vagal afferent fibers including
those from the SLN (17, 87, 156). Indeed, stimulation
applied to the solitary tract and its nucleus (NTS) can
induce a very similar swallowing pattern to that obtained
in response to SLN stimulation (50, 174, 225, 231, 244,
367). Furthermore, lesion of the solitary tract abolishes
the swallowing induced by SLN stimulation (89, 152, 367).
Results obtained at the cellular level on swallowingrelated neurons have supported the idea that SLN afferent
fibers play a major role in the initiation of swallowing. In
all the species studied, the results have shown that almost
all the NTS swallowing neurons are synaptically activated
by the SLN (149, 152, 174, 255, 345). In addition, it is very
likely that in most cases, the swallowing neurons may
receive a direct, i.e., monosynaptic, input from SLN afferent fibers (149, 174, 255). The arrangement of the SLN
terminals in the interstitial NTS subnucleus, in the form of
rosettes or glomeruli, also suggests that laryngeal afferent
fibers may exert strong synaptic effects on postsynaptic
elements (238). Electrophysiological results have indicated that most of the NTS oropharyngeal neurons can be
activated also via IX afferent fibers (61, 255). It has been
observed, in sheep and cats, that IX afferent fibers activated ⬃90% of the oropharyngeal neurons studied. However, the IX fibers seem to have less impact than SLN
fibers on the swallowing neurons. Although the latency of
the synaptic response to IX stimulation is in the same
range as that recorded following SLN stimulation, it
seems most likely that it is not monosynaptic, judging
from the conduction distance and the variable latency (30,
61, 255, 294). These findings probably explain why the IX
afferent fibers are relatively inefficient at initiating swallowing. It is still puzzling, however, that, at least in sheep,
all the NTS neurons that display preswallowing activity
have been found to be synaptically activated by both the
SLN and the IX nerve (61). SLN afferent fibers can nevertheless induce a swallowing burst in these neurons upon
receiving either a single stimulating pulse or repeated
stimulation, whereas the IX can induce only preswallowing activity even when undergoing repetitive stimulation,
which indicates that the activation of IX afferent fibers
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Sensory inputs from peripheral areas play an essential part in inducing the whole swallowing motor sequence or parts of this motor sequence such as esophageal peristalsis (51, 87, 90, 156, 226). They play the prime
role in reflex swallowing or secondary peristalsis, and
they are also involved in voluntary swallowing. It is obviously very difficult to perform deglutition without having
anything to swallow, and this is also the case when the
oropharyngeal mucosa is anesthetized (87, 211, 267).
Moreover, sensory inputs modulate the central network
activity to adapt the forthcoming motor sequence to the
information arising from peripheral receptors (155, 156).
It is generally assumed that the afferent fibers involved in the initiation of swallowing are those running
within the maxillary branch of the trigeminal nerve, the
glossopharyngeal nerve, and the vagus nerve, especially
its SLN (87, 90, 224, 226). These nerves innervate peripheral areas such as the dorsum of the tongue, the epiglottis,
pillars of the fauces, and walls of the posterior pharynx,
the tactile or chemical stimulation of which induces swallowing (87, 90, 226, 231). Electrical stimulation of these
nerves can also trigger swallowing. In fact, all the results
obtained so far show that only stimulation applied to the
SLN induces the highly specific swallowing pattern without any additional orofacial activity, i.e., “pure” swallowing, with a minimal latency. Interestingly, among the various patterns of stimulation used for this purpose and
whatever the species under investigation, repetitive stimulation applied to the SLN at a frequency of around 30 Hz
(in the 20- to 40-Hz range) acts like “magic” by producing
pure swallowing at the lowest stimulus threshold (86, 87,
149, 174, 225, 279). Applying stimulation to the other
afferent fibers is less effective, and the results obtained
have been variable and often conflicting, depending on
the species studied (61, 62, 86, 87, 255, 305, 306, 309, 310).
Frequently, the motor pattern was very different from that
of pure swallowing and induced only at high stimulation
intensities and after a long latency (87). It has been observed in a comparative study on sheep that IX nerve
stimulation can facilitate swallowing but does not suffice
to trigger the motor pattern, and stimulation applied to
the maxillary branch of the V nerve cannot induce swallowing (61, 62). Therefore, although SLN afferent fibers
are involved in triggering several other reflexes, they constitute the main afferent pathway involved in the initiation
945
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ANDRÉ JEAN
217). Studies on the activity of vagal sensory fibers in
anesthetized cats and rats or conscious sheep have indicated that these fibers are strongly excited by the presence of a bolus or the passage of the peristaltic wave. All
these results suggest that continuous sensory feedback
may influence the neurons of the CPG and thus modulate
the central program (95, 155). In fact, results obtained at
the cellular level have shown that applying continuous
stimulation to peripheral receptors by means of an inflated balloon can either induce a permanent activity in
the neurons that are active during swallowing or modify
the bursting activity occurring during swallowing (Fig.
6A). The early neurons can be activated by locally distending the pharyngeal cavity, whereas the late and very
late neurons respond to local distension of the proximal
and distal esophagus, respectively (149, 152). To be efficient, 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).]
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alone does not suffice for the swallowing threshold to be
reached (Fig. 4D) (61).
Although the swallowing motor sequence is centrally
organized, it can change as the result of peripheral afferent information (155). Studies on the swallowing motor
sequence have strongly suggested that it is controlled by
a peripheral feedback mechanism. It has been established
that the amplitude and duration of the electromyographic
activity of oropharyngeal muscles partly depends on the
consistency of the bolus (140). The importance of sensory
feedback for esophageal peristalsis was shown by experiments in which “wet” swallows (with various volumes of
water) were found to be associated with a contraction
wave with a slower speed and a greater amplitude and
duration than “dry” swallows (85, 136). Direct evidence
that sensory feedback intervenes during swallowing has
been provided by afferent nerve recordings (9, 64, 98,
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BRAIN STEM CONTROL OF SWALLOWING
B. Supramedullary Influences on Swallowing
Experimental data have shown that the basic swallowing pattern can be induced without any supramedullary structures being involved. Under physiological conditions, however, the swallowing network receives inputs
from higher centers, and several cortical and subcortical
structures also influence swallowing (51, 87, 119, 156, 214,
226). The fact that an individual can swallow voluntarily
without the existence of any need to ingest food or to
protect the upper airways shows that the medullary swallowing network can be activated at least by inputs from
the cerebral cortex. In addition, several clinical reports
have indicated that cortical dysfunction of the kind resulting from cerebrovascular accidents, cerebral palsy, or
neurological diseases such as Parkinsonism, may result in
dysphagia or swallowing impairments or may affect
esophageal peristalsis (127, 153, 180, 214, 260, 365). These
observations point to the involvement of supramedullary
influences, although the peripheral afferent pathway and
the CPG, which is localized in the caudal brain stem, seem
to remain unaltered in these patients.
Supramedullary structures may be responsible for
various effects on swallowing such as initiating the motor
activity, or modulating reflex swallowing. However, most
of the data available were obtained in stimulation experiments and were difficult to interpret, since it is generally
not a pure swallowing motor activity that is initiated in
this way, but more complex feeding behavior, i.e., mastication and swallowing, or lapping, mastication and swallowing, or licking and swallowing, etc. (42, 316). In addition, it is difficult to identify among these effects those
which are due to the afferent feedback and to distinguish
between centrally organized movements and motor activities involving feedback phenomena. Moreover, the presumed centrally induced effects may actually arise from
the stimulated site or from passing fibers.
There exist a number of subcortical sites, including
the corticofugal swallowing pathway, which can trigger
or modify swallowing, in particular the internal capsule,
subthalamus, amygdala, hypothalamus, substantia nigra,
mesencephalic reticular formation, and monoaminergic
brain stem nuclei (27, 43, 44, 90, 177, 319 –321). These
influences can be either excitatory or inhibitory. It has
been reported that several forebrain regions, including
the amygdala and the lateral hypothalamus, may facilitate
swallowing by means of dopaminergic mechanisms (26,
27, 132, 366). Inhibitory effects can be evoked by stimulating brain stem structures such as the periaqueductal
gray, the ventrolateral pontine reticular formation, and
some monoaminergic cell groups (177, 295, 320, 321).
Results suggest that these inhibitory effects probably involve 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
complex central pathway is not known. Few studies have
in fact dealt with these central effects on the neurons of
the CPG. As far as the supramedullary influences on
swallowing and their action at the cellular brain stem
level are concerned, all the results available so far have
been obtained in studies on the cortical influences on
swallowing.
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distally as the neuronal discharge occurs later and later
during swallowing. Furthermore, the swallowing activity
of medullary neurons increases either when a bolus is
swallowed or during a subliminal distension of the corresponding region of the tract (149, 152). The burst firing
activity of the neuron increases in terms of both its duration and frequency. The changes resulting from peripheral
stimulation are more striking in the case of the esophageal than the oropharyngeal neurons: depending on the
volume of the balloon inserted, a twofold increase in the
duration and a fivefold increase in the frequency can be
observed (152). The activation of peripheral receptors
during swallowing therefore results in a decrease in the
velocity of the peristalsis, which makes the duration of
the whole sequence longer and the muscular contraction
more powerful. Sensory feedback can therefore be said to
modify the central program, by adjusting the motor outputs depending on the contents of the tract (155).
In addition to these excitatory phenomena, the sensory inputs can also trigger inhibitory effects via central
connections, as suggested by electromyographic data and
vagal motor fiber recordings (129, 276, 281). The occurrence of these inhibitory phenomena has been fully confirmed by microelectrode recordings showing that all the
esophageal neurons are strongly inhibited during the oropharyngeal stage of swallowing; they were also inhibited
during a pharyngeal distension that stimulated the peripheral receptors (Fig. 6A) (149, 152, 155). Oropharyngeal
distension excites the early interneurons, which results in
an inhibition of the late and very late neurons via central
inhibitory connections. The inhibitory effect depends on
the size of the inflated balloon; when it is greatly inflated,
swallowing activity is completely abolished, whereas during a slight inflation, this activity is only weakened and
delayed (149, 152). The discharge of the very late neurons
is also inhibited during the activation of the cervical
esophageal receptors. The strength of this inhibition is
variable depending on the size of the inflated balloon.
These data indicate that the swallowing neurons controlling the distal regions of the swallowing tract are
inhibited when neurons controlling the more proximal
regions are excited. They support the idea that there
may exist a rostrocaudal inhibition within the swallowing network, as suggested by the blockade of the esophageal peristalsis that occurs during rhythmic swallowing (149, 152, 155, 277).
947
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pathway from the cortex to motoneuronal pools involved
in swallowing has been mapped using tracing techniques
(184 –186), these results indicate that the cortical input to
identified swallowing neurons mainly focuses on swallowing neurons in the DSG and involves the same circuit
as the afferent fibers do, at least in sheep (Fig. 5). The
DSG neurons therefore receive convergent information
from both cortical and peripheral inputs that trigger swallowing.
On the basis of the finding that during swallowing
sensory feedback is conveyed to the cortical area via a
first relay in the pons, the swallowing cortical area may
have a further function (48, 160, 320, 321). Neurons in this
area may belong to a ponto-cortico-medullary loop so that
upon receiving sensory information, they might control
the activity of the CPG swallowing neurons as they fire
successively, just as peripheral afferent fibers do (159). It
has been shown that cortical neurons in the swallowing
cortical area of sheep are activated or inhibited during
swallowing (45). More recent findings on monkeys indicate that cortical areas associated with feeding behavior
are involved in swallowing (213, 214, 242, 243, 245). However, changes in the firing activity of cortical neurons
during swallowing have been shown to depend on sensory feedback, since it is abolished in paralyzed animals.
Because only early and a few late neurons respond to
cortical stimulation, the control of swallowing may be
restricted to the oropharyngeal phase and the beginning
of the esophageal phase. Therefore, the cortical swallowing area may serve mainly to trigger deglutition and control the beginning of the motor sequence, after which the
sequence might be carried out without any further cortical control (159).
C. Action of Brain Stem Neurotransmitter Systems
Some pharmacological results relating to swallowing
have been reviewed previously (24, 25). The present review focuses mainly on local effects that can be clearly
linked to the initiation and programming of the swallowing motor sequence. In this connection, data have been
obtained using in situ ejection of drugs by ionophoresis or
application of pressure, and most of these results have
been obtained at the level of the DSG in rats (24, 25, 161).
To date there has been only one study dealing with the
action of drugs on functionally identified neurons, i.e.,
swallowing-related neurons (172). However, other experiments on “reflex” interneurons in the NTS, i.e., neurons
which can be synaptically activated via SLN or IX nerves,
or on neurons studied in vitro in swallowing medullary
regions, have provided some complementary information
at the cellular level (161, 298).
At the level of the NTS, i.e., the DSG, experiments
based on intracerebral microinjections have yielded deci-
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In several species, swallowing can be initiated by
stimulating a limited area of the cortical surface. In rabbits, an efficient region of this kind has been detected
within the anterolateral frontal cortex (316). A specific
swallowing zone, i.e., one inducing pure swallowing, is
situated anterior to the orbital gyrus in sheep (42). It is
worth noting that as in the case of peripheral afferent
stimulation, swallowing is best initiated by applying repetitive stimulation to the cortex at a frequency in the 20to 40-Hz range. Recent results have shown, however, in
the conscious dog, that a single stimulus applied by transcutaneous magnetic stimulation can induce swallowing
(348). Moreover, with the use of this technique, it has
been shown in humans that cortical stimulation can produce, as does stimulation of the afferent fibers (see sect.
IID1), short-latency electromyographic responses in several oropharyngeal muscles and in the cervical esophagus
(119). The corticofugal swallowing pathway, which includes structures such as the internal capsule, the pyramidal pathway, and the mesencephalic reticular formation,
ends within the solitary system (43, 44, 159). Lesion of the
NTS area involved abolishes the swallowing evoked by
cortical stimulation, which further indicates that the solitary system is the main central system responsible for
swallowing (152, 159).
Results obtained on anesthetized sheep (152, 159)
indicate that most of the early neurons in the DSG can be
activated by applying cortical stimulation. This is in agreement with the idea that one of the functions of the cortical
area may be to trigger the “voluntary” swallowing motor
sequence. Cortically induced swallowing, however, requires repetitive stimulation, whereas a single pulse applied to SLN is generally effective under identical experimental 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
fact that the pathway from the cortical area to the CPG is
polysynaptic (42, 43). Moreover, although all the swallowing neurons with preswallowing activity tested so far have
been found to be activated by the cortex, this was so in
the case of only 79% of the remaining oropharyngeal
neurons studied (152, 159). In line with what occurs with
SLN stimulation, cortical stimulation induces an initial
activity followed by the swallowing burst that accompanies the onset of swallowing. Both the latency and the
number of neurons activated depend on the neuronal
group involved. Early neurons in the DSG were cortically
activated with a shorter latency than those in the VSG
(5– 8 ms vs. 10 –16 ms), and only 32% of all the neurons in
the ventrolateral medulla were cortically activated. Late
neurons in the DSG also responded to cortical stimulation, but in small numbers (38%) and with a longer latency
of 10 –12 ms. None of the late neurons in the VSG nor the
very late neurons either in the DSG or the VSG was
activated by cortical stimulation (159). Although a direct
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induce either a single motor event or series of rhythmic
swallowing events similar to those elicited by long repetitive stimulation of the SLN. Microinjections of glutamate
are likely to have resulted in generalized neuronal excitation within the area covered by the agent. The fact that
these injections into the NTS can produce a patterned
response instead of a disorganized muscular activity is
quite remarkable and indicates that this region contains
neurons that play a prime role in initiating and patterning
deglutition and esophageal peristalsis (161). Results obtained using EAA receptor agonists and antagonists have
clearly demonstrated that deglutition and esophageal contractions can be triggered by activating either N-methylD-aspartate (NMDA) or non-NMDA receptors (124, 173,
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: intrapharyngeal 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 acetylcholine, in the case of inhibitory and excitatory connections respectively (see text for comments).
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sive information about the involvement of EAA receptors
in swallowing mechanisms. In both anesthetized and decerebrate rats, glutamate microinjections performed
within the swallowing area of the NTS elicited swallows
that were very similar to those triggered by either electrical stimulation of the SLN or mechanical stimulation of
the pharyngeal mucosa (Fig. 7A) (124, 173, 178). Both the
oropharyngeal stages of swallowing and complete swallowing, i.e., the oropharyngeal stage followed by esophageal persistalsis, can be obtained by performing microinjections into the interstitial NTS subnucleus (173).
Specific esophageal peristaltic contractions can be initiated by injecting glutamate and EAA agonists into the
region of the subnucleus centralis (23, 124). Furthermore,
depending on the dose, glutamate microinjections can
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the ventral level have been less fully documented. Microinjections performed in vivo failed to elicit the oscillatory
behavior characteristic of rhythmic swallowing (24). Results obtained by Kessler (172) have indicated that the
swallowing activity of neurons in the VSG depends on the
activation of EAA receptors, that is to say that the swallowing drive set up in the DSG and transferred to the
swallowing neurons in the VSG involves at least the EAA
(Fig. 7D). This result is in keeping with anatomical data
showing the existence of glutamatergic connections between NTS and ventrolateral medulla (307). Here again,
both types of EAA receptors, i.e., NMDA and non-NMDA
receptors, are involved. In studies on brain stem slices, it
has been established that the NMDA receptors play a
critical but paradoxical role, since they are involved in the
rising phase of the excitatory postsynaptic potentials elicited in these neurons in response to stimulation applied to
the solitario-ambigual pathway (361).
Inhibitory phenomena are thought to play an important role in the swallowing mechanisms (see sect. V).
However, little is known so far about the function of
neurotransmitters such as inhibitory amino acids in deglutition. Some of the most interesting results in this field
have been those obtained by Wang and Bieger (360), who
observed that microinjections of GABA or GABAA agonist
such as muscimol inhibited the motor events associated
with swallowing and esophageal peristalsis. It has also
been reported that local application of bicuculline at the
NTS level induced either rhythmic swallowing or rhythmic esophageal peristalsis, which suggests that a tonic
inhibitory action is exerted by GABA neurons on the
swallowing pattern generator. Some other features relevant to the coupling between the oropharyngeal stage of
swallowing and esophageal peristalsis have been consistently described in these experiments. When swallows
consist of oropharyngeal stages alone, local application of
subthreshold doses of bicuculline can render the swallows complete, i.e., the oropharyngeal phase is followed
by primary peristalsis (Fig. 7B). Moreover, during fast
rhythmic swallowing, which normally consists of a series
of oropharyngeal stages alone, application of bicuculline
can release the inhibition, preventing the occurrence of
esophageal phases, and complete rhythmic swallows occur. Among the many possible explanations, the most
plausible one seems to be that GABAergic mechanisms
may be involved in the inhibition of the esophageal phase
of swallowing that occurs during the oropharyngeal phase
(Fig. 7D and Table 2). The exact origin of these GABAmediated inhibitory phenomena is unknown, but local
GABAergic NTS neurons are probably involved (32, 144,
209, 216, 325). In addition, recent results have shown that
neurons within the subnucleus centralis, which are
thought to be esophageal premotor neurons, express
GABAA receptor subunits (38). These results therefore
suggest that inhibitory amino acids probably play an im-
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this agent can elicit long series of rhythmic swallows,
including more than 100 motor events (178). At esophageal sites, activation of NMDA receptors seems to be
more potent than that of non-NMDA receptors (24). This
is in keeping with the existence of large numbers of
NMDA receptors within the subnucleus centralis (40). At
the cellular level, it has been reported that glutamate
activated almost all the reflex neurons tested (130, 298).
With the use of brain stem slices, it has been found
that neurons located in NTS regions known to contain
swallowing neurons possess both types of EEA receptors (330).
Within the DSG, EAA mechanisms may contribute to
initiating the motor sequence and to building up the swallowing pattern. EAA may be released either by afferent
fibers involved in swallowing or by intrinsic NTS neurons,
or both (Fig. 7D). Although there is no direct evidence
that swallowing afferent fibers actually use EAA as a
transmitter, microinjections of either DL-2-amino-5phosphonovalerate (APV), a NMDA receptor antagonist,
or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a nonNMDA receptor antagonist, performed within the NTS of
decerebrate rats can result in the complete disappearance
of the SLN-induced deglutition as well as esophageal reflex responses (161, 203). It has also been established
using immunohistochemical or retrograde tritiated aspartate transport methods that glossopharyngeal and vagal
afferent fibers in addition to other neurotransmitters may
use EAA as transmitters (251, 286, 287, 290, 291). Moreover, results obtained by combining retrograde transport
of tritiated aspartate with peroxidase immunohistochemistry or fluorogold histofluorescence have suggested that
SLN afferent fibers may use EAA as transmitters (N.
Schaffar and A. Jean, unpublished results). As is the case
for baroreceptors and some vagal pulmonary afferent
fibers (33, 168, 274, 351), it is therefore likely that at least
some of the afferent fibers involved in the initiation of
swallowing may use EAA as transmitters. In addition,
glutamatergic NTS neurons have been found to exist and
may be activated by the afferent fibers (179, 286, 324). The
possibility that EAA receptors may be involved in patterning swallowing has been strongly supported by the results
of experiments where an oscillatory behavior, i.e., rhythmic swallowing or rhythmic esophageal contractions, was
induced by locally applying EAA (Fig. 7, A and B) (124,
178). Studies on brain stem slices have shown that NTS
neurons exhibit EAA-induced rhythmic patterns of activity that paralleled those of swallowing neurons and have
pacemaker properties that were activated via NMDA-receptor associated channels (Fig. 9A). These studies suggest that EAA receptors may play a critical role in the
motor patterning of swallowing behavior (332, 333).
EAA receptors are involved in swallowing not only
within the DSG, but also at the level of the VSG and the
motoneurons (Table 2). However, the effects of EAA at
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sors or agonists can either induce the swallowing motor
pattern or facilitate the effects of laryngeal stimulation or
the occurrence of spontaneous swallows (24). On the
other hand, results obtained by performing microinjections of monoamines into the swallowing NTS area have
shown that monoamines have mainly depressant effects
on swallowing, i.e., they resulted in reversible, dose-related decreases in both the number and strength of the
rhythmic swallows elicited by ipsilateral SLN stimulation
(175–177). This inhibitory action is not a side effect due to
the perturbation of homeostatic parameters such as respiratory rhythm or blood pressure, since the swallowing
elicited by stimulating the SLN contralateral to the injection site remained unaffected.
With regard to the catecholamines, the inhibitory
action of norepinephrine can be mimicked by clonidine
microinjection and reduced by pretreatment with phentolamine, but not with metitepin, a serotoninergic blocker
(176). It is therefore likely to result at least partly from
activation of ␣-adrenergic receptors. The nature of the
receptor involved in the effects of dopamine is still
unknown. It should, however, be noted that microinjections of the dopaminergic agonist apomorphine also
inhibit swallowing (176). These data indicate that catecholamines exert an inhibitory influence on the NTS
neural components involved in deglutition, and as yet,
there is no direct evidence available that any excitatory
effects may be exerted at this level. It is likely that the
facilitatory effects elicited by systemic administration
might originate from the drugs acting on supramedullary
structures, as suggested by experiments in which catecholamines, in particular dopamine, locally applied to
several forebrain regions, were found to have a facilitatory action (26, 27, 29, 366). Results show that apomorphine exerts a facilitatory influence on swallowing when
injected into the internal carotid artery, but an inhibitory
effect when injected via the vertebral artery. It can therefore be postulated that by acting on forebrain sites, catecholamines have facilitatory effects on swallowing,
whereas they have inhibitory effects when released locally at brain stem levels, particularly in the NTS. Ionophoretic application of catecholamines within this region
has a mainly depressant effect on neuronal activity (54).
Local applications of serotonin have been reported to
have either inhibitory or excitatory effects on swallowing
(123, 175). One should note, however, that ionophoretic
application of serotonin or serotonergic agents to NTS
neurons, particularly the reflex neurons, consistently inhibits the neuronal activity (100, 297, 298). The antagonistic effects on swallowing are certainly due to differences
in the neuronal sensitivity to serotonin and are therefore
likely to have resulted from different receptor subsets
being activated. The excitatory effects may be mediated
by 5-HT2 receptors, since they are abolished by intravenous injection of either ketanserin, methysergide, or
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portant role in the inhibitory mechanisms at work within
the swallowing network (133). At the ambigual level, stimulation of GABAA receptors has been found to modulate
the excitatory action of EAA and acetylcholine. Thus it
seems highly probable that the inhibitory amino acids also
intervene at this level (24).
Cholinergic neurotransmission has been also found
to play a role in swallowing mechanisms, particularly
those underlying esophageal peristalsis (23, 204). At the
level of the NTS, esophageal contractions can be induced
by locally applying acetylcholine or muscarinic receptor
agonists. Moreover, the esophageal stage of a swallowing
sequence can be blocked after local application of muscarinic antagonists, such as methscopolamine, within the
NTS (Fig. 7C). These results suggest that a cholinergic
mechanism probably participates in the linkage between
the oropharyngeal and esophageal stages of swallowing
(Fig. 7D and Table 2). Systemic injections of atropine
have also been found to block the esophageal stage of
swallowing in sheep (376). However, the cholinergic link
between the oropharyngeal and esophageal activity might
be species dependent and requires further investigation.
In cats and humans, atropine injection does not block the
esophageal peristalsis of the striated portion of the esophagus, which suggests that central muscarinic receptors
are not involved in the pharyngo-esophageal coupling (31,
114, 262). The source of cholinergic inputs to NTS has not
yet been clearly identified. Cross-innervation and immunohistochemical data have suggested that vagal afferent
fibers may use acetylcholine as a transmitter and that
some of these fibers might be esophageal afferent fibers
(97, 261). It has also been demonstrated that NTS neurons
receive a cholinergic input from neurons in the intermediate zone of the parvicellular reticular formation. Anatomical and electropharmacological data suggest that this
projection may be involved in esophageal motility (25,
203). The cholinergic input may also arise from intrinsic
neurons that have been identified within the NTS using
choline acetyltransferase imunohistochemical procedures (285). Cholinergic transmission has also been found
to take place via esophageal motoneurons. Acetylcholine
applied to the ventrolateral medulla induces esophageal
contractions, probably as the result of depolarization of
esophageal motoneurons tentatively identified in brain
stem slices (25). The acetylcholine-induced effects on
esophageal motoneurons are resistant to muscarinic antagonists and depend on nicotinic receptors (362, 375),
which have been shown to participate in esophageal peristalsis (114).
The role played by monoamines in central swallowing mechanisms was first investigated by means of indirect methods such as those based on the use of systemic
injections or the intracerebroventricular application of
drugs (24). Under these experimental conditions, excitatory effects of monoamines have been observed. Precur-
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vasopressin, oxytocin, and somatostatin (24). In the latter
case, anatomical studies have shown that a somatostatinergic connection runs between the NTS subnucleus centralis, where esophageal neurons are assumed to be located, and the compact rostral formation of the nucleus
ambiguus, which contains esophageal motoneurons (36,
71). It has been established moreover that somatostatin
regulates neurotransmission mechanisms at the level of
ambigual motoneurons by facilitating glutamate-induced
excitation and depressing acetylcholine-induced excitation, two excitatory effects which are thought to be involved in the swallowing mechanisms (363, 364). Somatostatin therefore probably has neuromodulatory effects
on the swallowing network. The inhibitory effects of peptides on swallowing have been found to involve opioid
receptors such as the ␮, ␦, and ␬ binding sites (24). The
opiates may act at the DSG, VSG, and motoneuron levels,
where a high density of enkephalinergic terminals has
been found to exist, particularly within the compact rostral formation of the nucleus ambiguus (232).
More recent results, based on chemical neuroanatomical techniques, have shown that neurons, in the NTS
subnucleus centralis, which project to the rostral compact formation of the nucleus ambiguus and which are
probably premotor esophageal neurons, can synthesize
nitric oxide (37, 103, 370). The role of these neurons in
central swallowing mechanisms now is required to be
investigated.
V. NEURAL MECHANISMS
A. Central Pattern Generation
The central mechanisms that generate the bursting
activity of swallowing neurons and their sequential or
rhythmic firing behavior are still unknown. In the light of
the latest mechanisms found to be responsible for pattern
generation in several other CPGs, it seems likely however
that the shaping and timing of the deglutitive motor pattern is based on the connectivity and the synaptic interactions between the various groups of neurons in the
network, and the intrinsic properties of neurons (77, 107,
108, 115–117, 197, 265, 292). Although little direct evidence is available as to the exact nature of the swallowing patterning mechanisms, the body of data which
has been built up in this field over the past 25 years
provides valuable information about the functional
mechanisms possibly underlying the central organization of swallowing.
1. Network properties: role of excitatory and
inhibitory phenomena
The fundamental act of swallowing, in particular its
oropharyngeal stage, is a stereotyped motor behavior, and
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metergoline (24). The nature of the receptor(s) mediating
the depressant action of serotonin has not yet been
clearly established. This effect is mimicked by quipazine
and 8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT)
and can be partially prevented by local pretreatment with
metitepin, but not by intravenous injections of methysergide and metergoline. These results suggest that 5-HT1
receptors are involved (161), which is in line with the
recent finding that 5-HT1A binding sites exist in high densities in NTS areas involved in deglutition (210, 334). The
question as to what exact factors determine the effects of
serotonin, i.e., excitation versus inhibition, have not yet
been elucidated. Due to serotoninergic receptors having
differential affinities, the amount of agent microinjected
may be a critical factor. The neural components involved
in these opposite effects may also be different. The respective distributions of the injection sites involved in
excitatory and inhibitory effects only partly overlap. The
inhibitory sites are located in the NTS regions known to
contain swallowing neurons receiving laryngeal inputs,
i.e., at the level of the interstitial subnucleus, whereas the
excitatory sites are located more rostrally and more medially (161).
The effects of monoamines on swallowing may be
mediated by intrinsic catecholaminergic NTS neurons belonging to groups A2 and C2 and a population of serotonin-containing neurons identified in the rostromedial NTS
(134, 135, 165, 166). Indeed, vagal afferent fibers have
been found to impinge on catecholaminergic neurons in
the NTS (312). In addition, some vagal afferents have been
found to use serotonin as a transmitter (104, 250). One
relevant finding in this connection was that when electrical stimulation was applied to several brain stem regions
containing either catecholaminergic or serotoninergic cell
groups, such as the raphe magnus, the ventrolateral reticular formation at the pontine and bulbar level, and the
locus coeruleus, it inhibited reflex deglutition (177). The
existence of catecholamine- or serotonin-containing projections arising from some of these regions and terminating in the NTS has been established in several anatomical
studies (289, 335). It can therefore be postulated that the
swallowing inhibition observed in response to stimulation
of brain stem monoaminergic nuclei may at least partly
result from a release of catecholamines or serotonin
within the NTS. It is worth pointing out that when applied
to the locus coeruleus and the raphe magnus, electrical
stimulation also depolarizes the laryngeal afferent fibers
(205). This suggests that the inhibition of reflex deglutition, whether it results from brain stem stimulation or is
induced by monoamine microinjection into the NTS, may
at least partly depend on a blockade of peripheral inputs.
Preliminary evidence is now available which suggests the existence of excitatory or inhibitory peptidergic
mechanisms affecting swallowing. An excitatory action
has been observed with thyrotropin-releasing hormone,
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inhibitory connections between the various links in the
chain. It has been reported that when the neurons responsible for the beginning of the swallowing sequence fire,
the cells controlling the more distal parts of the tract are
inhibited, and their activity is delayed (149, 152). In this
way, inhibition is also successively transmitted throughout the network. Inhibitory phenomena play an important
role in the shaping and timing of the sequence, since the
neurons controlling more distal parts of the swallowing
canal are subjected to longer periods of inhibition than
those controlling rostral parts (149, 152). Because no
neurons have ever been observed that start to discharge
at the onset of swallowing and fire for longer periods
when they control more distal parts of the tract, the
long-lasting inhibition exerted on the late and very late
neurons may result from the successive additional periods of inhibition triggered within the chain by the neuron
that is active (Fig. 8A). The inhibitory message that no
doubt occurs before the excitatory transfer of the bursting discharge seems to play an important role in the
central mechanisms. In fact, leaving aside the neurons
with preswallowing activity, recordings of the motor
events and the central neuronal activity have suggested
that the inhibitory phenomena may be the first events
initiated in the network (87). In the absence of intracellular recordings, it is not yet possible to state whether or
not hyperpolarization may occur before the bursting discharge of the swallowing neurons. Extracellular recordings have shown, however, that the activity of distal neurons is inhibited before the motor activity is initiated (see
Fig. 6A). In addition, a subliminal SLN stimulation that
does not induce swallowing has been found to, nevertheless, induce inhibitory phenomena such as relaxation of
the lower esphageal sphincter (263). Recent studies in
humans, using an artificial high-pressure zone created by
inflating an intraesophageal balloon, suggest that a wave
of inhibition occurs before the esophagus contracts (303,
304). Furthermore, IX stimulation, which activates the
preswallowing neurons to a subcritical level as far as the
initiation of swallowing is concerned, nevertheless inhibits the esophageal neurons (61). Recent intracellular studies on esophageal motoneurons have confirmed these
assumptions. Their authors have demonstrated that these
inhibitory phenomena are also present at the motoneuronal level, which means that not only excitatory inputs but
also inhibitory messages are transferred from the NTS to
the motoneuronal level (Fig. 6D) (376, 377).
Inhibitory mechanisms may not only be responsible
for delaying the onset of neuronal firing, but they may also
contribute directly to the sequential excitation of the
neurons. In fact, via mechanisms such as disinhibition or
postinhibitory rebounds, the inhibitory connections may
be at least partly responsible for the progression of the
contraction wave. With the assumption that there exist
only inhibitory connections between swallowing neurons
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the swallowing CPG has been viewed classically like a
dedicated circuit, i.e., like a specific network of neurons
which is hardwired so as to produce a sequence of excitation and inhibition that is always the same (51, 87, 152,
154, 226, 277). The CPG must be able to perform a wide
range of tasks, such as converting the repetitive messages
conveyed by central or peripheral afferent inputs into a
bursting activity, transmitting bursting activity after a
variably long delay depending on the nature (oropharyngeal or esophageal) of the neuron in the network, ensuring via a rostrocaudal inhibitory mechanism that the later
neurons cannot fire before or during the activity of the
earlier neurons, and generating a rhythmic bursting pattern, at least in the case of the oropharyngeal neurons.
The bursting pattern of the swallowing neurons may
be built up as the result of either reexcitation phenomena
or excitatory feedback mechanisms (107, 108). The centrally generated bursting pattern of swallowing NTS neurons suggests that these mechanisms may well take place
within the DSG. Neurons with preswallowing activity presumably possess these reexcitation loops so that the neuronal firing will increase until reaching the critical level at
which the swallowing burst is generated (Fig. 4, C and D)
(149, 152). The rhythmic firing pattern of the oropharyngeal neurons may rely either on a specific network arrangement, which still remains to be determined, and/or
on cellular properties of the neurons (see sect. VA2).
In addition to the mechanims by which is generated
the burst firing of the swallowing neurons, the swallowing
network can be viewed as a linear-like chain of neurons
based on the rostrocaudal anatomy of the swallowing
tract. Because there exist, within the NTS, neurons which
fire sequentially during swallowing, each neuron or group
of neurons in this chain may control more and more distal
regions of the swallowing canal and be responsible for the
successive firing behavior (Fig. 8A) (152, 154, 277). Excitatory connections between neurons may provide the basis for the successive excitation of the cells via increasingly numerous polysynaptic connections. There is no
direct evidence available so far about connections between identified swallowing NTS neurons. However, recent anatomical data show that such connections may
exist between neurons located in the interstitial and centralis subnuclei of the NTS (39). In addition to the central
connections, each DSG neuron in the chain may be synaptically activated via peripheral afferent fibers originating in the corresponding part of the tract which is under
their control. Whether or not this linear pattern of organization in the form of a chain of neurons exists at the
VSG level also has not yet been ascertained. This actually
seems rather unlikely, since central stimulation experiments and those involving the application of EAA in the
ventrolateral medulla have failed so far to elicit an organized swallowing motor pattern (24, 161).
In addition to excitatory connections, there also exist
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(Fig. 8B), the sequential excitation of neurons may result
from postinhibitory rebounds involving in this case cellular properties of the neurons in addition to network connections (see sect. VA2). It is also possible that the strong
inhibition generated during the oropharyngeal stage of
swallowing may be followed by long-lasting excitatory or
facilitatory effects exerted by the oropharyngeal neurons
on the esophageal network, resulting in the sequential
discharge of the neurons (Fig. 8B). Results obtained at the
network level support both of these hypotheses. It has
been reported that a subthreshold distension of the
esophagus, which gives rise to no contractions of the
tract, can elicit a contraction at the segmental level when
electrical stimulation applied to the IX nerve is withdrawn
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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 oropharyngeal (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.
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2. Cellular properties: intrinsic and
transmitter-induced properties
Most of the data on the intrinsic properties of neurons liable to be involved in swallowing have been obtained in studies on brain stem slices. The data indicate
that neurons located in dorsal and ventral medullary regions and in cranial motor nuclei that are involved in
swallowing, such as V, VII, X, and XII motor nuclei and the
nucleus ambiguus, possess various ionic conductances
that may be involved in patterning the swallowing motor
event (55, 56, 58, 74, 75, 118, 332, 333, 340, 354, 355, 374).
The linkage between the endogenous properties of neurons studied under these in vitro conditions and their
possible role in swallowing pattern generation is far from
having been elucidated at present. The most relevant data
in this connection have been obtained in studies on NTS
neurons, in particular those located in the peri-interstitial
region of the NTS where are situated swallowing-related
neurons (330 –333).
Extracellular recordings on neurons in the rat NTS
region have shown that repetitive stimulation applied to
afferent fibers within the tractus solitarius can elicit bursting discharges in some NTS neurons (329, 331). In terms
of the duration of the discharges and their bursting frequency, some of these discharge patterns look like those
of swallowing neurons (161, 327). Results obtained with
bath application of EAA have shown that specific activation of NMDA receptors can induce rhythmic bursting
patterns in NTS neurons (330, 331). Here again, some of
the patterns resemble those of swallowing neurons in
terms of the bursting discharge and bursting frequency.
There is admittedly no definite evidence available so far
that these neurons may be swallowing neurons, but at
least it can be said that within the swallowing-related NTS
regions, there are neurons present that respond in vitro
just like the swallowing neurons respond to afferent stimulation and NMDA application in vivo.
Intrinsic neuronal properties have been thoroughly
documented in slice preparations by performing intracellular recordings. Like most of the neurons in the central
nervous system of mammals, NTS neurons have been
found to have several endogenous properties, some of
which seem to be relevant to swallowing pattern generation (161, 327). NTS neurons possess an early transient
outward potassium current (IKA) that is responsible, in
addition to its role in frequency adaptation, for the delayed firing of the neurons that occurs when they are
depolarized from negative membrane potentials (75, 332,
333). IKA might therefore be involved in the sequential
activity of swallowing neurons. If there exist any cells
with an IKA conductance within the swallowing network,
it is possible that inhibition of these neurons might abolish the steady-state inactivation of IKA, and therefore
delay the onset of their firing. It should be noted that the
delay induced by IKA is dependent on the inhibitory effects: the stronger the hyperpolarization of the neuron, or
the longer its duration, the longer this delay will be. A
neuron subjected to a short inhibition will therefore fire
earlier than one influenced by long-lasting inhibition (Fig.
9B) (327). The pattern of activity of esophageal neurons
fits this picture very well. Within the swallowing net, IKA
conductances might therefore contribute to the delayed
activation of the neurons. It should be pointed out, however, that the neurons must receive excitation to be able
to produce their burst firing activity. Within a network of
neurons with excitatory connections between them, excitation is sequentially transferred, and the IKA conductances may adjust the sequential firing of neurons. If the
excitation results mainly from long-lasting excitatory effects developed during the oropharyngeal stage, i.e., from
the hypothetical intrinsic system of modulation, the IKA
conductances will play a key role in the delayed firing of
the neurons. In this case, it is of interest to note that the
network may function mainly with inhibitory connections
(Fig. 8B). It has also been reported that some NTS neurons possess low-threshold activated calcium currents,
IT(Ca), which are responsible for postinhibitory rebounds
(Fig. 9C) (56, 328). If some neurons in the swallowing
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(61). In this case, the IX nerve exerts only inhibitory
effects at the level of the esophageal neurons, and the
contraction therefore results from postinhibitory rebound
mechanisms; it is the inhibition that renders the subthreshold distension effective. Field potentials recorded
at the level of esophageal neurons in the NTS may be
composed of either a single wave of potential reflecting
the inhibition of these neurons during the oropharyngeal
phase of swallowing, or a biphasic wave of potential
indicating that the esophageal neuronal population is undergoing an excitatory or a facilitatory influence following the inhibition (Fig. 6, B and C) (152). Therefore, the
biphasic wave of potential reflects an inhibitory-excitatory sequence occurring at the level of the esophageal
neurons during swallowing. It is of interest that the wave
of excitation is not systematically present, like the esophageal stage in anesthetized preparations. Moreover, it
gradually becomes stronger during rhythmic swallowing,
which is known to facilitate complete esophageal peristalsis in experimental animals (Fig. 6B). The wave of excitation reflecting the activity of esophageal neurons may
depend on some rebound phenomena or result from a
state of excitation that may be induced by the release of
a neurotransmitter with a long-lasting action during the
oropharyngeal phase. Consequently, the oropharyngeal
stage of swallowing may trigger phenomena such as intrinsic neuromodulation (170), i.e., the activity within the
network of oropharyngeal neurons may facilitate that of
other neurons within the network, namely, the esophageal neurons.
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ANDRÉ JEAN
Volume 81
network do have these calcium conductances, it is therefore likely that they will be involved in their burst firing
activity. As stated above, most of the neurons in the
swallowing CPG probably undergo inhibitory influences
before their burst firing is initiated. These inhibitory inputs may therefore activate the IT(Ca) and participate in
the bursting activity. Moreover, as postulated above, with
properties of this kind, the swallowing network will be
able to function only if there are inhibitory connections
between the neurons. Whether or not this is the case, the
sequential firing of the neurons will therefore rely mainly
on the postinhibitory rebound properties of the neurons.
Moreover, the responses of NTS neurons to activation of
NMDA receptors have shown that they have pacemaker-
like properties (Fig. 9, A and D) (332, 333, 356). In addition to mechanisms such as those involving reexcitation
phenomena, if swallowing neurons possess these pacemaker-like properties, it is very likely that they may participate in burst generation, as has been found to occur in
several other CPGs (11, 117, 358). Interestingly, the
NMDA-induced bursting pattern is dependent on the
membrane potential and occurs in a high membrane potential range (333, 356); this feature is in keeping with
results suggesting that the bursting swallowing pattern is
preceded by an inhibitory phase. It is therefore likely that
NMDA-gated conductances may participate in the burst
formation within the swallowing network. Because
NMDA receptors are actually involved in generating de-
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FIG. 9. NTS neuronal activities recorded in vitro on rat brain stem slices.
A: two types of rhythmic bursting discharges elicited in NTS neurons by bath
application of NMDA (60 ␮M). 1: Typical
rhythmic burst firing superimposed on
cyclic depolarization of membrane potential. Note that the burst of spikes may
be followed by depolarizing after-potentials and that the frequency of the rhythmic 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 discharge at more negative potentials. Note
that the rhythmic patterns are driven by
cyclic membrane potential depolarizations characterized by an initial rampshaped 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 bottom traces). Note that the delay was
longer when the duration of the hyperpolarizing pulse increased. [From Tell
(327).] C: postinhibitory rebound in a
NTS neuron. Depending on the amplitude of the hyperpolarizing pulse, the
neuron showed either a subliminar depolarization or burst firing pattern. [Adapted
from Tell and Bradley (328).] D: model for
the generation of NMDA-induced oscillations in NTS neurons. These ionic conductances were identified in NTS neurons that
fire under NMDA application as shown in
A2. [From Tell and Jean (333).]
April 2001
BRAIN STEM CONTROL OF SWALLOWING
B. Mechanisms of Deglutition and Secondary
Peristalsis
In species with an entirely striated esophagus, it has
by now been clearly established that deglutition, i.e., the
oropharyngeal phase followed by primary peristalsis, is a
centrally patterned motor activity and that the central
program is modulated by central or peripheral inputs so
that the motor contraction is adapted to the size of the
bolus (see sect. IV). In species with a smooth muscle
esophagus, intrinsic peripheral mechanisms of both neural and muscular origin are obviously involved in the
organization of the smooth muscle motor pattern (78, 79,
80, 110, 111, 280). Even in this case, however, several data
have suggested that under physiological conditions the
central nervous system may also contribute to the organization of the sequential motor pattern (145–148, 336). A
good example of this central intervention has been provided by experiments showing that sequential activity
occurs in vagal preganglionic fibers during swallowing
(109, 281). It is therefore to be expected that when activated, the CPG will always organize the whole sequence
from the oropharynx to the esophagus. The hypothesis
that the network consists of a chain of neurons would
account for how this sequence is generated. However,
there exist some differences between the oropharyngeal
and esophageal phases of swallowing. In fact, results
indicate that unlike the oropharyngeal phase, the esoph-
ageal phase may show some lability and also suggest that
the central program controlling this phase may be less
robust than that responsible for the oropharyngeal phase
(see sects. II and III). The size of the neuronal population
involved during these two phases is also different. Depending on the number of muscles involved, the number
of active neurons during the oropharyngeal phase of swallowing has been found to be far larger than that involved
in the esophageal phase (149, 152). The bursting activity
of the oropharyngeal neurons is also very different from
that of the esophageal neurons. Among the motoneurons,
the only respect in which the two types differ is the
duration of the discharge, whereas among the interneurons, the discharge frequency also differs conspicuously,
since it can be 10-fold higher in the case of the oropharyngeal neurons. It is also worth noting that even when
the discharge frequencies were in the same range of magnitude, as in the case of the late and very late neurons,
there was also a significant difference between the frequencies, the higher frequency being that observed in the
neurons controlling the proximal parts of the esophagus
(149, 152). A clear-cut discharge frequency gradient can
therefore be said to exist within the swallowing network,
and the elements subserving these two stages are clearly
quite separate. Whatever mechanisms may be involved in
the sequential firing, their strength therefore obviously
decreases along the chain of neurons. These differences
may reflect differences in the strength of the synaptic
connections along the chain of neurons, possibly due to
the existence of increasing numbers of synapses, and/or
to the properties of the cells. In fact, data obtained in the
case of secondary peristalsis have suggested that the
swallowing CPG can be subdivided into two subnetworks:
an oropharyngeal and an esophageal net of neurons, each
of which mediates the patterning of the respective phase
of deglutition, but that the esophageal net is likely to have
less robust central mechanisms and be more dependent
on afferent inputs.
The mechanisms underlying secondary peristalsis
have not yet been completely elucidated. In some species,
no clear-cut differences have been observed between the
primary and secondary peristalstic processes (141, 147,
148, 199, 302), whereas in others, striking differences have
been noted, since the secondary peristalsis hardly depends at all on afferent feedback (152, 219, 220, 277).
Whatever mechanisms may be involved, secondary peristalsis functions most efficiently with continuous feedback. In sheep, for example, the fact that secondary peristalsis is obviously dependent on feedback phenomena
suggests that there is little if any central programming and
that the sequential contractions rely on peripheral feedback mechanisms (152). This also supports the view that
the esophageal net is completely separate from the oropharyngeal one. However, authors performing microelectrode recordings failed to detect any differences between
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glutition, or more specifically, rhythmic swallowing and in
eliciting pacemaker-like properties in NTS neurons, it is
furthermore likely that the oscillatory properties of the
swallowing network may involve conditional bursters located within the NTS. In fact, two types of NMDA-induced
bursting patterns have been recorded among NTS neurons (Fig. 9A) (332). The one pattern probably corresponds to a typical pacemaker bursting activity, in which
the firing of the neuron is superimposed on a bell-shaped
depolarization of the membrane potential. Due to the
limited samples of this type of neuron available, the conductances involved in the burst firing have yet not been
specified, however. The other pattern of pacemaker-like
oscillations results in the activation of NMDA-gated
conductances and in interactions with other voltage-dependent conductances at work in NTS neurons, such as
high-threshold calcium conductances, calcium-activated
potassium currents, and IKA (Fig. 9D). In this case, the
burst firing is subtended by a wave of depolarization with
a characteristic ramp-shaped phase, the duration of which
increases with the hyperpolarization and thus delays the
firing. These interactions between chemo- and voltagegated conductances have been found to play a key role
in the expression and shaping of the cell discharge
pattern (333).
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ANDRÉ JEAN
C. Nature of the Swallowing CPG
Classically, the swallowing CPG has always been
taken to be a specific network of neurons dedicated to
this function alone. However, this view has by now been
challenged in the light of numerous data obtained mainly
on the central nervous system of invertebrates. In addition to being a classical dedicated network, most of the
CPGs seem in fact to be either reorganizing or distributed
circuits, and a single neural circuit can combine features
typical of each of these different architectures (82, 169,
237, 265). In any case, it has been established in particular
in the case of the crustacean pyloric pattern generator
that various pattern generators exhibit a high degree of
flexibility, resulting in considerable functional plasticity
(82). This is a particularly relevant point in the case of the
swallowing CPG for the following reasons. Although the
flexibility of the motor pattern generators has been clearly
demonstrated in invertebrates, several examples have by
now come to light which suggest that in vertebrates,
particularly in mammals, pattern generators also show
some flexibility (237, 265). Previous results relating, for
example, to the cellular properties of neurons have shown
that mechanisms found to operate mainly in the central
nervous system of lower species are equally valid in the
case of mammalian central nervous system (197). The
swallowing CPG is not an automatic, continuously functioning CPG, and the question arises as to whether the
swallowing neurons are completely inactive when no
swallowing occurs, or whether these neurons may have
other functions. This question is especially interesting,
since we have established that swallowing neurons include NTS neurons, and it has by now emerged that the
NTS is far from being simply a sensory relay (157, 161).
NTS neurons are involved in many activities, such as the
autonomic ones, as well as in endocrine processes and in
several integrated behaviors such as emotional processes,
hunger, thirst, control of pain mechanisms, regulation of
the level of consciousness, and probably many other
yet nonidentified functions (157). This is particularly
striking given that the NTS is quite a small structure
containing only a small population of neurons, numbering
around 40,000 in the case of the rat caudal NTS (259).
Are all the NTS neurons in this very small population
each devoted to a single fixed function, or do there exist
within the NTS one or several populations of neurons that
are flexible and participate in several functions, depending on the inputs they receive? It has been observed by the
group of Maurice Moulins that in invertebrates, swallowing depends on a pattern generator that is temporarily
formed preparatory to the production of the motor activity (222, 223). That is to say that when a given stimulus is
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
required.
In keeping with the new principles involving flexible
circuits, recent results have suggested that within the
swallowing CPG, some neurons may participate in activities other than just swallowing-related ones. It has been
established that not only motoneurons, but also interneurons can be involved in at least two different tasks, such
as swallowing and respiration, swallowing and mastication, or swallowing and vocalization.
With regard to the swallowing motoneurons, some
recent results have indicated that ambigual, trigeminal,
and hypoglossal motoneurons can fire both in phase with
respiration and during deglutition, as well as with swallowing and mastication, swallowing and vocalization, and
even during swallowing, vocalization, and respiration (3,
190, 300, 313, 317, 318, 323, 346, 376). Therefore, common
motoneurons may be involved in these activities. By driving muscles that can participate in two or more activities,
these motoneurons probably participate in the fine tuning
of the muscular activity during the motor behavior. These
motoneurons presumably receive a drive from separate
CPGs, and their activity no doubt depends on synaptic
interactions between the two networks.
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the neurons involved or their discharge parameters: a
given neuron was found to be involved in both primary
and secondary peristalsis, and the duration of discharge
and the frequency were the same in both cases, or even
more paradoxically, were larger during secondary peristalsis (149, 152). This is puzzling from the patterning
point of view. Why are afferent inputs necessary under
these conditions, and why is the central program ineffective? In fact, when the same elements are involved in both
cases without there being any difference between their
discharge patterns, the sole difference between primary
and secondary peristalsis is that the latter lacks an oropharyngeal phase, and consequently is not accompanied
by any oropharyngeal network activity. Therefore, the
activity of the oropharyngeal net might be an important
factor in the central programming of primary peristalsis.
That is to say that the esophageal net may program esophageal peristalsis only when triggered by the oropharyngeal net. In this way, the oropharyngeal net may serve as
an intrinsic modulatory system (Fig. 8B), a mechanism
which seems to play an important role in several CPGs
(170). When it is present, the esophageal net can program
the peristaltic wave, whereas when it is absent, as in the
case of secondary peristalsis, the program requires peripheral influences. Whatever the case may be, the previous oropharyngeal phase will facilitate or trigger central
esophageal programming mechanisms, such as those involving the powerful inhibitory phenomena which induce
postinhibitory rebounds and/or long-lasting facilitatory influences.
Volume 81
April 2001
BRAIN STEM CONTROL OF SWALLOWING
Some recent results have indicated that interneurons
localized in the dorsal (DSG) or ventral (VSG) regions of
the swallowing network also fire during several motor
behaviors such as swallowing, respiration, mastication,
and vocalization (Fig. 10, A and B) (7, 22, 59, 106, 172, 190,
252, 253, 373). The common motoneurons might therefore
be triggered by common pools of interneurons. These
results indicate that in mammals, the neurons liable to be
involved in pattern generation can belong to different
CPGs. Multifunctional neurons of this kind would make
959
for great functional flexibility. Despite the progress made
as far as invertebrates are concerned, the exact role of
these neurons in the mammalian CPGs during swallowing
or other activities is difficult to assess, and further experiments are now required to elucidate this point in the
various CPGs.
The mechanisms that make it possible for the same
neuron to participate in several sometimes antagonistic
activities still remain to be determined. In invertebrates,
the flexibility of the CPGs is conferred by the inputs,
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FIG. 10. Multifunctional activities in
swallowing neurons and diagram of the possible 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: suprahyoid 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 application of kainate, showing the presence
of a subliminal respiratory drive. [Adapted
from Kessler (172).] B: intracellular recordings of the activity of a cat NTS neuron (N).
In 1, this neuron exhibited cyclic depolarization of its membrane potential in phase with
the inspiratory activity recorded from the
phrenic nerve (Phr). In 2, during fictive swallowing (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 (licking, sucking, mastication), speech, protective reflexes (emesis, coughing), rumination,
and respiration, to ensure functional interactions under physiological conditions. Alternatively, 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 behavior.
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ANDRÉ JEAN
VI. CONCLUSION AND PROSPECTS
Swallowing is a vital motor activity that serves alimentary purposes and protects the upper airway. This
complex motor sequence involves the coordinated and
synchronized contraction of more than 25 pairs of muscles in the oropharynx, larynx, and esophagus, which are
active during an all-or-none oropharyngeal phase, followed by the primary esophageal peristalsis. Swallowing
is also a rhythmic motor event, at least as far as its
oropharyngeal stage is concerned. Swallowing depends
on a CPG located in the medulla oblongata, which involves several brain stem motor nuclei (V, VII, IX, X, XII)
and two main groups of interneurons: a dorsal DSG in the
NTS and a VSG located in the ventrolateral medulla above
the nucleus ambiguus. Within the CPG, neurons in the
DSG play the leading role in generating the swallowing
pattern, while neurons in the VSG act as switching neurons, distributing the swallowing drive to the various
motoneuronal pools. It is quite remarkable that a CPG for
a fundamental motor activity should be located within a
primary sensory nucleus, namely, the NTS. As in the case
of other CPGs, the functioning of the central network can
be influenced by both peripheral and central inputs,
which serve in particular to adapt the swallowing drive to
the size of the bolus to be swallowed.
Little is known so far about the mechanisms at work
in the CPG. Among the various neurotransmitters that are
known to intervene in swallowing, the EAA receptors, in
particular those of the NMDA type, play an important role
in triggering the motor event and patterning the motor
sequence. The sequential burst firing of the swallowing
neurons probably depends on the pattern of intrinsic
connections within the swallowing network. Within this
network, central inhibitory connections, in particular,
play a major role, resulting in a rostrocaudal inhibition
within the network which parallels the rostrocaudal anatomy of the swallowing tract and acts in such a way that
when the neurons controlling the proximal parts of the
tract are active, those which command more distal parts
are inhibited. Intrinsic properties of the neurons, in particular those of NTS neurons, probably also contribute to
determine the shaping and timing of the swallowing motor pattern. In particular, pacemaker-like properties of
NTS neurons are also thought to greatly contribute to
patterning the bursting neuronal firing and generating
their oscillatory behavior during rhythmic swallowing. As
clearly demonstrated in the case of invertebrate pattern
generators, it now seems likely in the light of several
recent results that the swallowing CPG may show some
flexibility. These results suggest that at least some of the
swallowing neurons may be multifunctional neurons and
belong to pools of neurons that are common to several
CPGs.
It will obviously be a long and difficult task to further
increase our knowledge about the neuronal mechanisms
involved in swallowing in mammals. Several possible
lines of research can nevertheless be indicated as means
of answering questions yet unsolved, using new approaches to the neurophysiology of swallowing. One of
the most important questions that remains to be answered
about the neural control of swallowing is whether the
central nervous system of the species with a smooth
muscle esophagus may include a network of neurons that
is similar to that of the species with a striated esophagus,
and if so, how this network functions. The supramedullary influences on swallowing, which have been only
sparsely documented so far, require more thorough investigation. In particular, this would make it possible to
specify the role of these central influences in several
pathological situations. Interestingly, it is now possible in
studies of this kind to use new approaches such as cortical evoked potential, transcranial magnetic stimulation,
and magneto-encephalographic recordings, not only on
experimental animals but also on humans (14, 15, 53, 119,
122, 339, 348). To further elucidate the working of the
CPG, it will also be necessary to identify at the cellular
level the action of neurotransmitters and neuromodulators and the types of receptors involved. This would
provide valuable information about the possible sites of
action for therapeutic agents. It seems to be quite impossible at present to definitely elucidate the intrinsic mechanisms underlying swallowing pattern generation in mammals. However, these basic mechanisms can be studied in
networks consisting of limited populations of neurons,
such as those with which invertebrates are endowed, or
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which both restructure a CPG by changing the influences
exerted on the synaptic connections between neurons
and alter the intrinsic properties of the neurons composing the CPGs (82). It is worth noting that in the case of the
NTS neurons, in vitro data on brain stem slice preparations have provided evidence that there is a cellular basis
underlying the flexibility. The same NTS neuron can exhibit either tonic firing, burst firing, or a beating-like firing
depending on the balance between excitatory and inhibitory inputs, which may modulate the interactions between several ionic conductances (Fig. 9A2) (162, 332,
333). If the same properties are preserved in vivo, it is
possible that the role of each neuron is not in fact fixed
once and for all. A neuron may function flexibly within a
network and thereby participate in several behaviors
(197). Whatever the case may be, the evidence available to
date indicates that within the dorsal and ventral medulla,
there exists a common pool of neurons that might have a
multifunctional role. It can therefore be postulated that at
least some of the components of the swallowing network
are not dedicated to swallowing alone but can also serve
some purpose in other central networks (Fig. 10C).
Volume 81
April 2001
BRAIN STEM CONTROL OF SWALLOWING
I acknowledge the assistance of Caroline Brocal and Marinette Sellem for secretariat, that of Jocelyne Roman and Yvette
Minguella in preparing the illustrations, and that of Jessica Blanc
for revision of the English.
I take great pleasure in acknowledging my colleagues
who have participated in different phases of the work on
swallowing.
The author’s laboratory is mainly funded by the Ministère
des Universités and the Center National de la Recherche Scientifique (ESA 6034). The support of the Institut National de la
Recherche Agronomique (EA 1033) is gratefully acknowledged.
Parts of the work on swallowing have also been supported by
grants from the Institut National de la Santé et de la Recherche
Médicale.
Address for reprint requests and other correspondence: A.
Jean, Laboratoire de Neurobiologie des Fonctions Végétatives,
ESA CNRS 6034, EA INRA 1033, Département de Physiologie et
Neurophysiologie, Faculté des Sciences St. Jérôme, BP 351,
Avenue Escadrille Normandie Niemen, 13397 Marseille Cedex
20, France (E-mail: [email protected]).
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using computational approaches and modeling natural
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on other experimental models such as the isolated brain
stem preparations may also be useful for this purpose (76,
264). However, depending on the in vitro preparation
used, the developmental aspects, such as possible postnatal changes in the swallowing mechanisms, should not
be overlooked. Interestingly, and somewhat paradoxically, some data have suggested that although swallowing
is a vital function, the underlying mechanisms may be not
fixed at birth (206, 229, 271, 272, 315, 357, 359). Finally,
studies on complex pattern generators such as those operating in mammals will no doubt greatly benefit from the
latest methodological approaches. In particular, it seems
likely that by focusing research on whole populations of
neurons rather than recordings single neurons, it will be
possible to obtain new insights as to how the mammalian
CPGs function. Multiple recordings based on electrophysiological and/or optical methods (92), and the use of
sophisticated functional brain imaging techniques such as
magnetic resonance imaging or positron emission tomography (93) already used in swallowing-related studies
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