Coordination of Pharyngeal and Esophageal Phases of Swallowing

Abstract

Although swallowing has been reviewed extensively, the coordination of the phases of swallowing have not. The phases are controlled by the brainstem, but peripheral factors help coordinate the phases. The occurrence, magnitude, and duration of esophageal phase depends upon peripheral feedback activated by the bolus. The esophageal phase does not occur without peripheral feedback from the esophagus. This feedback is mediated by esophageal slowly-adapting mucosal tension receptors through the recurrent and superior laryngeal nerves. A similar reflex mediated by the same peripheral pathway is the activation of swallowing by stimulation of the cervical esophagus. This reflex occurs primarily in human infants and animals, and this reflex may be important for protecting against aspiration after esophago-pharyngeal reflux. Not only are there inter-phase excitatory processes, but also inhibitory processes. A significant inhibitory process is deglutitive inhibition. When one swallows faster than peristalsis ends, peristalsis is inhibited by the new pharyngeal phase. This process prevents the ongoing esophageal peristaltic wave from blocking the bolus being pushed into the esophagus by the new wave. The esophageal phase returns during the last swallow of the sequence. This process is probably mediated by mucosal tension receptors through the superior laryngeal nerves. A similar reflex exists, the pharyngo-esophageal inhibitory reflex, but studies indicate that it is controlled by a different neural pathway. The pharyngo-esophageal inhibitory reflex is mediated by mucosal tension receptors through the glossopharyngeal nerve. In summary, there are significant peripheral processes that contribute to swallowing, whereby one phase of swallowing significantly affects the other.

Introduction

The physiology of the phases of swallowing has been studied and reviewed for many years.^1-8 While these articles fully reviewed the anatomy and physiology of each phase of swallowing, many provided little information on how these phases of swallowing are coordinated with each other. In addition, over the past thirty years new studies have been published,^9-19 which have added to our understanding of this complex and physiologically important process, and their value in understanding the physiological mechanism of this relationship has not been fully reviewed. This manuscript will review the studies which investigated the physiological mechanisms coordinating the pharyngeal and esophageal phases of swallowing that help to produce the function of swallowing. The esophageal phase of swallowing always begins in the proximal cervical esophagus,^1-8 which in every species is striated muscle.^1-8 Therefore, this review will only consider the coordination of the pharyngeal phase of swallowing with the striated muscle esophageal phase of swallowing.

The role of central pattern generators (CPG) controlling swallowing has been investigated for decades, and the participation of a number of brainstem nuclei has been identified.^20-28 Not only have the possible swallow CPG nuclei been identified, but much information has been obtained about how these CPG’s sequentially activate the pharyngeal and esophageal muscles to produce the effect of bolus propagation through the pharynx and esophagus.^20-28 It is not the purpose of this manuscript to review the identity, actions, and mechanisms of the swallowing CPG’s, the purpose is to present the studies that have investigated how both the CPG’s and peripheral neural reflexes coordinate the functional relationship between the 2 anatomically and functionally different phases of swallowing.

Excitatory Relationships

The swallow CPG studies clearly show that there is an inherent program in the CPG’s which controls the sequential activation of the swallow muscles for each phase,^20-28 but the CNS data does not provide a full understanding of how the phases interact with each other. The concept that initiation of the esophageal phase of swallowing is generated by a central program is based on findings^20,21,25,28 that superior laryngeal nerve (SLN) stimulation in paralyzed animals activated pre-motor neurons associated with the esophageal, as well as pharyngeal, phases of swallowing. Given that in the paralyzed animal no esophageal contractions could occur to stimulate afferent feedback, it was concluded that feedback from peripheral reflexes was not the initiator of the esophageal phase of swallowing. In addition, the swallow CPG data indicates that there is a temporally significant signal that connects the pharyngeal phase to the esophageal phase.²⁸ This was supported by examining the response of neurons of the nucleus tractus solitarius (NTS) after stimulation of the SLN. They found that this stimulus,²⁸ which activates the pharyngeal and esophageal phases of swallowing,²⁹ activated NTS neurons at different delays from the initial stimulus that corresponded to the muscle responses of the pharynx and esophagus during swallowing. It was concluded that there is a CNS connection between the pharyngeal and esophageal phase CPG’s, and that peripheral stimulation is not needed to activate both phases of swallowing.

The SLN studies forming the basis for the concept that a peripheral input is not needed to activate the esophageal phase of swallowing were challenged by numerous animal studies. It was found that the SLN contains afferents not only from the larynx and pharynx, but also from the esophagus.^13,30-32 Therefore, electrical stimulation of the SLN could stimulate peripheral afferents from the esophagus as well as the larynx and pharynx. In addition, while SLN stimulation can initially inhibit activation of the esophageal phase,¹¹ the same stimulus can facilitate activation of the esophageal phase at a later time.¹¹ Therefore, while the central program that governs the esophageal phase of swallowing may be active in paralyzed animals after SLN stimulation, this cannot be used as evidence that the esophageal phase of swallowing is not initiated by a peripheral input under normal conditions. In addition, while the responses of the pharynx-related pre-motor neurons were high frequency, the responses of the esophagus-related pre-motor neurons were low frequency.²⁸ Considering that these responses were in the sensory portion of the swallow CPG, it is unlikely that the responses of the esophagus-related pre-motor neurons were strong enough to activate the motor neurons to obtain a muscle response. Therefore, while the central program that governs the esophageal phase of swallowing may be active in paralyzed animals after SLN stimulation, this cannot be used as evidence that the esophageal phase of swallowing is not initiated by a peripheral input.

There were many CNS studies showing that there was extensive peripheral feedback into brainstem swallow neurons. Both SLN and glossopharyngeal nerve (GPN) afferents innervate swallow-related neurons of the NTS,^20,33,34 and both SLN and GPN afferents can either cause short term activation or longer term inhibition of NTS neurons.³⁵ In addition, afferents from the larynx, pharynx, and esophagus have been shown to have significant excitatory and inhibitory effects on brainstem swallowing neurons at every stage of the swallow process.²¹ However, while these CNS studies defined the specific effects on specific swallow-related neurons of peripheral neural feedback, they could not define the function or importance of these peripheral neural feedbacks.

The function and necessity of peripheral neural feedback for the activation of the esophageal phase of swallowing were established by numerous different types of studies.^36-42 The first indications of the importance of peripheral feedback were the studies on the relationship of the bolus to the esophageal peristalsis. It was found in humans that wet swallows activated the esophageal phase at faster speed, greater amplitude, and greater duration than dry swallows.⁴⁰ In addition, wet swallows initiated esophageal peristalsis > 96% of the time,^37,40 while dry swallows only activated esophageal peristalsis 62%³⁶ or 71%⁴⁰ of the time. In decerebrate cat studies, it was found that the delays between the pharyngeal and esophageal phases of swallowing were much more variable than the delays of muscle activation within the pharyngeal phase.¹³ This indicated that the pharyngeal phase was controlled by a much more well-coordinated system than the connection between the pharyngeal and esophageal phases. These studies indicated that peripheral feedback is very important in the activation of the esophageal phase of swallowing.

The necessity of peripheral feedback to activate the esophageal phase of swallowing was proven using more controlled animal studies. In dog studies³⁹ when the bolus was surgically diverted from the cervical esophagus to outside the body, the esophageal phase of swallowing was almost totally blocked. However, in these studies the bolus did pass through a small section of the cervical esophagus before being diverted. In surgically prepared dog and decerebrate cat studies,^19,38 when the bolus was completely diverted from entering any part of the esophagus, the esophageal phase of swallowing was totally blocked. This was particularly evident when surgical preparation was minimized by insertion of a stopcock between the pharynx and esophagus without transecting the esophagus. In this case simply turning the arm of an implanted stopcock, totally blocked the occurrence of the esophageal phase of swallowing (Fig. 1). While diversion of the bolus at the level of the cervical esophagus blocked the esophageal phase, diversion at the thoracic level did not.³⁹ The results of these studies indicate that bolus activation of the cervical esophagus is necessary for initiation of the esophageal phase of swallowing. However, once the esophageal phase CPG is activated it will control esophageal phase of swallowing without the need of additional peripheral feedback.

Figure 1.

The necessity of a bolus for activation of the esophageal phase of swallowing. This figure shows that under the same conditions and same stimulus when the bolus is diverted there is no change in the pharyngeal phase, but the esophageal phase is totally eliminated. The swallow was activated by water injection by pump into the pharynx through a catheter inserted 7 cm into the nasal cavity. The bolus was diverted by turning the arm of a 3 way stopcock that was inserted into the esophagus just caudal to the upper esophageal sphincter. ESO#, esophageal manometry recording # cm from the lower esophageal sphincter; GH, geniohyoideus; CP, cricopharyngeus; CT, cricothyroideus; EMG, electromyography. Adapted from Lang et al.¹⁹

An argument against the necessity of peripheral feedback back to initiate the esophageal phase based on bolus studies might be that since a dry swallow activated esophageal peristalsis, a bolus is not necessary for activation of the esophageal phase of swallowing. However, a dry swallow is not absent a bolus, as it contains saliva and air. It was also observed in decerebrate cats or surgically prepared dogs that diverting the bolus of a dry swallow also blocked the esophageal phase of swallowing.^19,38 Therefore, while there is a CNS connection between the pharyngeal and esophageal CPG’s, it requires peripheral feedback from esophageal receptors to activate the esophageal phase of swallowing.

The neural pathway, that transmits the stimulus to the CPG’s in order to activate the esophageal phase of swallowing after the pharyngeal phase, was demonstrated to be the afferents of the recurrent laryngeal nerve (RLN). It was observed that transection of the proximal RLN (RLNp) blocked or significantly inhibited initiation of the esophageal phase of swallowing.¹⁴ This effect of RLNp transection was more pronounced in more orad portions of the esophagus, reflecting the innervation pattern of the RLNp.³² Considering that RLNp is purely sensory for the esophagus,^13,41 this observation also provides strong evidence for the essential role of cervical esophageal peripheral inputs, rather than a central program, for the initiation of the esophageal phase of swallowing.

The brain stem studies described above actually strongly support the conclusion that initiation of the esophageal phase of swallowing is dependent upon feedback from peripheral inputs. The finding that sensory feedback from the esophagus greatly enhanced the activation of esophageal phase premotor neurons makes this activity much more likely to activate motor neurons and the esophageal phase of swallowing.^20,21,25,28 Therefore, while the central program of the pharyngeal phase of swallowing may stimulate the esophageal premotor neurons, this stimulation alone is not sufficient to activate the esophageal phase of swallowing. Although the concept that a central program initiates the esophageal phase of swallowing is not supported by most studies, evidence does exist that a central program controls the timing sequence of pharyngeal to esophageal phases of swallowing. That is, the time delays between pharyngeal and esophageal phases of swallowing were not dependent upon peripheral feedback,¹⁵ therefore, they must have been preprogrammed in the CPG’s.

Considering that the esophageal phase of swallowing can be activated by the bolus of a dry swallow,^19,40,42 the receptors that mediate this response must be very sensitive. No direct studies have been conducted to determine the specific receptors that generate the esophageal phase of swallowing. However, there are 3 types of esophageal tension receptors: mucosal rapidly-adapting and slowly-adapting tension receptors and muscular slowly-adapting tension receptors.^43-46 The mucosal receptors are best activated by stimulating the mucosa without distending the esophageal wall. It is likely that the receptors activating the esophageal phase of swallowing are the mucosal slowly-adapting receptors, because it has been shown that this effect can be activated by very small amounts of swallowed bolus and even perhaps by air during a dry swallow.^19,40,42 The receptors are unlikely to be the mucosal rapidly-adapting receptors because these receptors mediate the esophago-upper esophageal sphincter relaxation reflex (EURR) and belching.¹⁹

Not only is esophageal stimulation important for the activation of the esophageal phase during swallowing, but esophageal stimulation can activate the pharyngeal phase of swallowing. Studies^15,17,47,48 have shown that the appropriate stimulation of the cervical esophagus can initiate swallowing beginning with the pharyngeal phase. This esophago-pharyngeal swallow reflex (EPSR) is activated in a probabilistic manner. When swallowing was activated by balloon distension or fluid injection into the esophagus, the probability of activation of swallowing increased the closer the stimulus was to the cervical esophagus, the stronger the esophageal distension, and the longer the length of the distension.^15,17 The more rapid the injection of fluid into the esophagus, the higher the probability of activation of swallowing and the lower the latency to activation of swallowing.¹⁵ This reflex is more commonly observed and easier to activate in animals and human infants than human adults.^12,17,47,48

The afferent neural pathway for this reflex is the RLN just caudal to the cricoid cartilage (RLNc), and stimulation of this nerve activates swallowing.¹⁵ The RLNc connects to the SLN before the SLN merges with the vagus nerve.⁴⁹ Therefore, both pharyngeal and esophageal afferents can activate the pharyngeal and esophageal phases of swallowing.

The receptors that mediate this reflex response are probably the mucosal slowly-adapting tension receptors,¹⁵ because this reflex response was blocked after the application of local anesthetic to the esophageal mucosa. This effect is unlikely to be mediated by the mucosal rapidly-adapting receptors, because these receptors mediate EURR and belching as described above.¹⁹ The receptors and afferents that mediate activation of the esophageal phase of swallowing and the EPSR are the same, and they have very similar effects. They both activate the swallow process from the esophagus rather than the pharynx.

The function or purpose of EPSR is unknown, but a proposed theory is that this effect is a reflex response of airway protection.¹⁵ If a bolus were to lodge in the proximal cervical esophagus, where this reflex is most sensitive,¹⁵ it could be pushed orad as well as caudad if secondary peristalsis were activated. In all cases of secondary peristalsis, the peristaltic wave begins orad of the stimulating object^3,50-52 so that when the wall collapses during peristalsis it does not collapse on the bolus, but orad of it. This guarantees that the bolus will only move distally. However, if the bolus is in the proximal cervical esophagus, there is no way secondary peristalsis could occur orad of the bolus. If the peristalsis collapses on the bolus it could push the bolus in both directions causing esophago-pharyngeal reflux and aspiration. Therefore, in this situation a safer response would be to activate the pharyngeal not esophageal phase of swallowing. The fact that this reflex is much more common in human infants and animals than adult humans is probably related to the position of the larynx in the neck.^17,47,48 In animals and human infants the larynx is high in the neck.⁵³ When the larynx is high in the neck the position of the epiglottis behind the soft palate allows the larynx to open directly into the nasopharynx.⁵⁴ Therefore, both infant humans and animals are more likely to aspirate if they have esophago-pharyngeal reflux during swallowing.^15,54 One of the primary proposed mechanisms of sudden infant death syndrome (SIDS) is aspiration of swallowed boluses,^55-58 and it has been shown in decerebrate cats that the sensitivity of this esophagus-initiated swallow response is dependent upon body position.⁵⁹ Therefore, it is possible that human babies aspirate causing SIDS, because this esophagus initiated swallow response is inhibited when babies are in the prone position.

It is hypothesized that since pharyngeal and esophageal phases of swallowing can be activated by stimulation of receptors in the pharynx and esophagus through the same afferent nerve, ie, SLN, that this is really one reflex mechanism with one motor pathway and a wide range of sensory afferents.

Another pharyngeal excitatory effect on the esophageal phase of swallowing is the biomechanical effect of the pharyngeal phase. During the pharyngeal phase of swallowing the supra-laryngeal muscles contract pulling the larynx orad.¹⁸ The larynx is attached to the proximal esophagus at the cricopharyngeus,⁶⁰ therefore, this laryngeal elevation also pulls the proximal esophagus orad.⁶¹ Both in vitro and in vivo studies^18,62-64 have found that elongation of the esophagus increases the stress-strain ratio of the esophagus causing a significant increase in circumferential tension by a biomechanical process. It has been shown in the decerebrate cat (Fig. 2) that such an effect also occurs in the live animal.^18,65 It has been hypothesized that the function of this effect is to stiffen the proximal esophageal wall during the pharyngeal phase which facilitates the distal movement of the bolus into the esophagus prior to initiation of the esophageal phase.

Figure 2.

The biomechanical increase in esophageal circumferential tension caused by the pharyngeal phase of swallowing. This figure shows the increase in circumferential tension of the proximal cervical esophagus during the pharyngeal phase of swallowing when the esophagus is pulled orad by laryngeal elevation. This is a biomechanical effect in which the circumferential tension increases due to an increase in stress-strain relationship caused by elongation of the esophagus during laryngeal elevation. This effect requires no neural or chemical mediation. It is hypothesized that this effect functions to facilitate the distal movement of the bolus as it is pushed into the esophagus during the pharyngeal phase. TH, thyrohyoideus; TP, thyropharyngeus; CP, cricopharyngeus; E3, esophagus 3 cm from the CP; EMG, electromyography; SG, strain gauge; NasoP, nasopharyngeal induced swallow. Adapted from Lang et al.¹⁸

In summary (Fig. 3), the timing of the activation of the esophageal phase of swallowing after the pharyngeal phase is controlled by CPG’s. While the timing of the transition from pharyngeal to esophageal phase is largely controlled by the CNS, the initiation of the esophageal phase is dependent upon peripheral feedback from the esophagus. Swallowing can be activated from both the pharynx and cervical esophagus. However, esophageal activation occurs more readily in infant humans and animals than in adult humans, which is related to their differences in laryngeal anatomy. The elevated position of the larynx in human infants and animals make them more likely to aspirate as a result of esophago-pharyngeal reflux. The elevation of the larynx during swallowing tightens the proximal esophageal wall which facilitates bolus flow.

Figure 3.

The neural pathway controlling the excitatory relationship between pharyngeal and esophageal phases of swallowing. This figure shows 2 peripheral processes from the pharyngeal phase of swallowing that excites the esophageal phase. After activation of primary peristalsis (1°P) through pharyngeal mucosal tension receptors (McTR) and the super laryngeal nerve (SLN), a CNS pathway from one portion of the pre-motor nucleus tractus solitarius (NTSa) to another (NTSb) activates the esophageal phase. This response takes a few seconds to occur which provides time for the following. During swallowing pharyngeal phase pushes the bolus into the esophagus which stimulates mucosal slowly-adapting tension receptors (McST) through recurrent laryngeal nerve (RLN) and SLN to activate the esophageal phase. This pathway probably also mediates the second peripheral process that excites the esophageal phase, ie, the esophago-pharyngeal stimulatory reflex (EPSR). Stimulation of mucosal slowly-adapting receptors through the RLN and SLN activates primary peristalsis. The final SLN neural pathway may be the same for both effects. Secondary peristalsis (2°P) is activated through muscular slowly-adapting tension receptors (MsST) and the vagus nerve. NTS, nucleus tractus solitarius; CPGp, pharyngeal phase central pattern generator; CPGe, esophageal phase central pattern generator.

Inhibitory Relationships

The swallowing process itself has a significant inhibitory relationship called deglutitive inhibition. Deglutitive inhibition occurs when swallows occur repeatedly close together and at some rate the esophageal phases are blocked and only the pharyngeal phase occurs until the last swallow.^66-74 This response not only inhibits the circumferential propagating muscle contractions, but also the propagating longitudinal contractions of the peristaltic wave.⁶⁸ The pharyngeal phase of swallowing can occur at a faster repetitive rate than the esophageal phase due to its shorter duration and the difference in the type of muscle in many species.^69,70 The pharyngeal phase lasts less than 1 second and many of the muscle responses are simultaneous.^66,74 On the other hand, the esophageal phase lasts about 8 seconds to 10 seconds and it occurs in a very organized propagated fashion.⁷⁰ Given these significant differences, there would be a major functional problem for movement of the bolus from pharyngeal to esophageal phase unless there was some mechanism that ensured that the esophageal phase only occurred when it was able to fully accept a bolus from the pharyngeal phase. The swallowing CPG’s have a built-in mechanism that is part of the swallow program which controls for this possible problem by inhibiting the progression of esophageal peristalsis if it occurs at the same time as the new swallowing response begins.^66-74 A very important part of this esophageal inhibition is that it occurs very early on in the swallow process during activation of the pharyngeal phase of swallowing.^66-74

Another mechanism that has been proposed to account for deglutitive inhibition is esophageal muscle refractoriness.⁶⁹ That is, all muscles require time to relax before they can be activated again. However, while smooth muscles might exhibit significant refractoriness, the refractoriness inherent in striated muscle is simply not extreme enough to account for deglutitive inhibition.

The second pharyngeal generated inhibitory process is the pharyngo-esophageal inhibitory reflex (PEIR). In PEIR, stimulation of the pharynx inhibits the motility of the entire esophagus.¹¹ The afferent nerve mediating the PEIR is the GPN, as transecting the GPN (Fig. 4), but not the SLN (Fig. 5), blocks the PEIR.¹¹ The receptors for the PEIR are the muscular slowly-adapting tension receptors.¹¹ Brainstem neural recording studies²³ found that application of neural antagonists to specific areas of the NTS blocked distal esophageal inhibition caused by pharyngeal stimulation, but had no effect on deglutitive inhibition. Therefore, it is highly unlikely that PEIR is the mechanism of deglutitive inhibition.

Figure 4.

Effect of glossopharyngeal nerve (GPN) transection on the pharyngo-esophageal inhibitory reflex (PEIR). This figure shows transecting the GPN totally blocks the PEIR, showing that the primary afferents for the PEIR are in the GPN. Esophageal peristalsis was activated by injection of air into the esophagus and PEIR was activated by injecting water into the pharynx. #’s, the numbers are the distance in cm of the manometry recording sites from the lower esophageal sphincter; 5752, animal number; 10/4/96, date of the study on Oct 4, 1996; ESO, esophagus. Adapted from Lang et al.¹¹

Figure 5.

Effect of super laryngeal nerve (SLN) transection on the pharyngo-esophageal inhibitory reflex (PEIR). This figure shows transecting the SLN had no effect on the PEIR, showing that the SLN did not transmit afferents for the PEIR. Esophageal peristalsis was activated by injection of air into the esophagus and PEIR was activated by injecting water into the pharynx. LES, lower esophageal sphincter; ESO, esophagus; 5754, animal number; 10/15/96, date of the study on Oct 15, 1996. Adapted from Lang et al.¹¹

In summary (Fig. 6), there are two inhibitory processes that affect the pharyngeal and esophageal swallow process. Deglutitive inhibition prevents esophageal bolus obstruction during rapid swallowing, and in other situations pharyngeal stimulation, ie, the PEIR, shuts down esophageal motility and the esophageal phase for protective purposes.

Figure 6.

The neural pathway controlling the inhibitory relationship between pharyngeal and esophageal phases of swallowing. This figure shows that there are 2 peripheral inhibitory processes from the pharyngeal to esophageal phase of swallowing. The first response is deglutitive inhibition which is a normal part of the swallow process. During activation of the pharyngeal phase, while there is a built-in delay in activation of the esophageal phase, there is an immediate inhibition of the esophageal phase. This causes any ongoing esophageal motor activity, including esophageal peristalsis, to be inhibited. Deglutitive inhibition is an important protective function as explained in the manuscript. The second inhibitory response is the pharyngo-esophageal inhibitory reflex (PEIR) which is activated through muscular slowly-adapting tension receptors (MsST) and the glossopharyngeal nerve (GPN). The PEIR probably has a similar function as deglutitive inhibition, but under different circumstances as they are mediated by different neural pathways. NTSa, one portion of the nucleus; NTSb, another portion of the nucleus tractus solitarius; SLN, super laryngeal nerve; 1°P, primary peristalsis; CPGp, pharyngeal phase central pattern generator; CPGe, esophageal phase central pattern generator; McST, mucosal slowly-adapting tension receptors.

The excitatory and inhibitory relationships between the pharyngeal and esophageal phases of swallowing are illustrated in Figure 7. While the pharyngeal phase has both excitatory and inhibitory effects on the esophageal phase during primary peristalsis, these effects are not simultaneous. The inhibitory response, ie, deglutitive inhibition, occurs first and a few seconds later is followed by the excitatory effect. This timing is controlled by the brainstem swallowing nuclei.

Figure 7.

The neural pathway controlling the inhibitory and excitatory relationship between pharyngeal and esophageal phases of swallowing. This figure is a combination of Figures 3 and 6 in which the excitatory and inhibitory effects can be observed in one figure. While the normal swallow process activates an excitatory as well as inhibitory process, the brainstem nuclei control the timing such that the inhibitory process occurs at the very beginning of primary peristalsis and the excitatory process is delayed by a few seconds. NTSa, one portion of the nucleus; NTSb, another portion of the nucleus tractus solitarius; SLN, super laryngeal nerve; 1°P, primary peristalsis; CPGp, pharyngeal phase central pattern generator; CPGe, esophageal phase central pattern generator; GPN, glossopharyngeal nerve; PEIR, pharyngo-esophageal inhibitory reflex; RNL, recurrent laryngeal nerve; EPSR, esophago-pharyngeal swallow reflex; 2°P, secondary peristalsis; McST, mucosal slowly-adapting tension receptors.