Esophageal Peristalsis in Health and Disease: Mechanistic Insights

Abstract

Mechanism of esophageal peristalsis or sequential contractions of the skeletal and smooth muscle esophagus resides at multiple levels, i.e., brain stem (central pattern generator), neurons within the wall of the esophagus (myenteric plexus) and smooth muscle (myogenic). Esophageal peristalsis consists of initial inhibition followed by excitation, for which there may be parallel pathways from the central program generator, travelling via the vagus nerve to communicate with the inhibitory and excitatory neurons of the myenteric plexus. Primary and secondary esophageal peristalsis are associated with concurrent contraction and relaxation of the circular and longitudinal muscle layers. The longitudinal muscle contraction in the contracted segment exerts mechanical stretch on the segment ahead of it, which likely activate the mechanosensitive inhibitory motor neurons in the myenteric plexus to induce descending relaxation, a peripheral mechanism of the peristaltic reflex.

In the achalasia esophagus, there is inflammation and fibrosis in the muscularis propria and myenteric plexus, resulting in loss of inhibitory nerves in the myenteric plexus. The above also results in replacement of muscle with fibrous tissue in the muscularis propria of the lower esophageal sphincter (LES), impaired LES relaxation and low distensibility of the esophagogastric junction in achalasia esophagus. The esophageal hiatus contains a pad of fat which is replaced with fibrosis in patients with achalasia esophagus. Whether hiatal fibrosis leads to impaired LES relaxation/low distensibility of the esophagogastric junction, and changes in esophageal peristalsis are secondary to obstruction requires further study. Esophageal hypersensitivity is currently the favored mechanism of “angina like” esophageal pain and refractory heartburn. Spastic or long-duration contractions of the longitudinal muscle of esophagus may also play a role in the genesis of non-cardiac esophageal pain and heartburn sensation.

Graphical Abstract

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Introduction

To be able to eat/swallow is one of those pleasures of life that each one of us would want to cherish till the “last supper”. The Swallow is a primitive reflex; fetus begins swallowing amniotic fluid by 14–16 weeks of gestation^{1, 2}. Fetal breathing movements contribute to the efflux of fetal lung fluid (5ml/breath) into amniotic fluid, half of the effluent is swallowed by fetus. Given that fetal breathing occurs 20–30 times per hour, the contribution of fetal breathing to overall amniotic fluid is significant. Increase in amniotic fluid volume, out of proportion to the degree of gestation, signifies fetal swallowing and gastrointestinal motility deficits. At the time of birth, the sucking, swallowing and airway protection mechanisms are fully matured for the newborn to sustain adequate intake without aspiration into lungs to thrive in this world. Generally, one swallows once a minute in the awake state³; no swallowing occurs during deep sleep⁴. The act of swallowing begins as a voluntary process, but it turns into an involuntary one quickly, once the bolus hits the back of the mouth and pharynx. Each swallow results in a monotonous sequence of events in the pharynx and esophagus, with the head end of bolus ahead and the tail end behind, followed by a sequential contraction from the oropharynx to the top of the stomach.

Historical Perspective

The last review on esophageal peristalsis in the “physiological reviews” was published in 1956 by Ingelfinger⁵. As one reads that article, it is clear that earlier investigators (Cannon⁶ and others) had already made critical observations, relaxation and contraction, deglutitive inhibition, mechanisms of peristalsis and bolus transport through the esophagus. Advancements in our understanding of the swallowing mechanism and esophageal peristalsis during last 100 years may be divided into ~ 3 periods, prior to year 1970s, between 1970’s to 2000, and from the 2000’s to the present day. The focus was mostly on the central and brain stem control of swallow reflex prior to 1970’s^{7, 8}. Sequential firing of neurons in the medullary swallowing center was believed to be a mechanism of sequential (peristaltic) contraction of esophagus, an observation true to this day. The majority of the above experiments were conducted in the animals with a skeletal muscle esophagus. Christensen observed that the opossum esophagus resembles the one in humans, i.e., skeletal muscles in the proximal and smooth muscle in the distal esophagus, and made critical observation on the peripheral mechanisms involved in esophageal peristalsis⁹. Weisbrodt discovered the peripheral mechanism of peristalsis, i.e., the one that resides within the esophageal wall (myenteric plexus and smooth muscle) ¹⁰. For the next 30 years, there was an explosion of information on the peripheral control of esophageal peristalsis, neurotransmitters involved in the contraction and relaxation of the smooth muscles of the esophagus and the lower esophageal sphincter. This period led to the major discovery that nitric oxide (NO) is the non-cholinergic non-adrenergic neurotransmitter of the inhibitory motor neurons, and it plays a key role in the latency gradient, which is fundamental to the sequential contractions along the length of the esophagus, observed during peristalsis¹¹. Improvements in the esophageal pressure recording techniques, especially infusion manometry^{12, 13}, played a significant role in the advances of those 30 years. The focus of this time period was mostly on the circular muscle layer of the esophagus. The last 25 years have yielded information on the coordination and discoordination of circular & longitudinal muscle layers during peristalsis and the possibility that longitudinal muscle may be responsible for the descending relaxation phase of peristalsis¹⁴. Besides active muscle contraction, biomechanical properties of the esophageal wall and surround tissues influence the bolus transport through the esophagus in health and disease ¹⁵. Advances in recording techniques during last 25 years (intraluminal high-frequency ultrasound imaging¹⁶, high resolution manometry¹⁷ (HRM), and functional luminal imaging probe^18–20) has played a critical role in our current understanding with regards to the role of longitudinal muscle and biomechanical factors involved in esophageal peristalsis, in health and disease. The major focus of this review is the peripheral control of peristalsis, which is the most common site of pathology in the motor disorders of esophagus.

Pharynx and Upper Esophageal Sphincter

The detailed anatomy, neural control and motion of oropharyngeal bolus transit are beyond the scope of this review and can be found in other excellent reviews ^25–27. Briefly, upon deglutition the pharynx transforms from a breathing structure to a swallow structure that requires closures of the nasopharynx and laryngeal inlet, which is made possible by the intrinsic and extrinsic muscles of the pharynx. It is important to understand that the motions of the pharynx, larynx and adjacent structure during deglutition have an important influence on esophageal peristalsis and bolus flow through the esophagus because the two are connected at its upper end (cricoid cartilage). The cranial and anterior motion of the pharynx is critical for the laryngeal closure (airway protective mechanism) which results in passive or biomechanical changes in the esophagus, i.e., an increase in the circumferential and longitudinal stress on the cervical and thoracic esophagus. The pharynx expands in the circumferential dimension which facilitates the bolus to enter into oropharynx and laryngopharynx. Furthermore, the thrust on the swallowed bolus generated by the oropharyngeal muscles (also known as pharyngeal pump) propels the swallowed bolus into the mid/distal esophagus without any aid from esophageal peristalsis.

The intrinsic muscles of the pharynx are the superior, middle, and inferior pharyngeal constrictors, thyropharyngeus and cricopharyngeus. The extrinsic muscles are the elevators (geniohyoid, mylohyoid, stylohyoid, thyrohyoid, digastric, stylopharyngeus and palatopharyngeus) and tensors of the palate (levator veli palatine, tensor veli palatine, and palatoglossus). The aryepiglottic, thyroarytenoid, and oblique arytenoid muscles are the laryngeal muscles for the closure of the laryngeal inlet (Figure 1A & C). These muscles are supplied by branches of the cranial nerves, V (trigeminal), VII (facial), IX (glossopharyngeal), X (vagus), ansa cervicalis, and XII (hypoglossal), and some of them contract sequentially during the oropharyngeal phase of peristalsis (Figure 1B). The contraction of elevator muscles during deglutition results in cranial and anterior displacement of the larynx with deglutition (Figure 1D). A three-tier system exists to protect the airway from the swallowed contents. From the distal to the proximal end of the larynx, these 3 tiers are: 1) adduction of true vocal cords and arytenoids, 2) vertical approximation of closed arytenoids to the base of epiglottis, and 3) descent of epiglottis to cover the closed glottis (Figure 1E). The larynx is elevated 2.5 to 3 cm with each swallow; it sits under the base of the tongue at the height of its excursion (Figure 1D). Reflex closure of the laryngeal inlet is of critical importance to prevent aspiration of contents from the pharynx and esophagus into the airway during swallowing and esophageal distension. For example, distension of the cervical esophagus results in the closure of 3-tier laryngeal inlet system. Along the same line, the presence of even tiny amounts of liquid in the pharynx results in closure of the laryngeal inlet. Prescott et al. found that the vagal P2RY1 neurons in the brain stem (~100 in number) evoke a coordinated airway defense program in mice²⁴. These neurons form corpuscular endings (primary airway sentinels) in the laryngeal epithelium (Figure 1F), which communicate with the brainstem P2RY1 neurons through ATP. Ablation of these neurons eliminates the airway protective reflexes ²⁴.

Figure 1: Oropharyngeal Phase of Swallowing.

A&C: Relevant Anatomy of the Oropharyngeal Muscles Involved in Primary Peristalsis. B: Sequential activation of the muscles of the oropharynx during primary peristalsis: MH = mylohyoid, GH = Geniohyoid, TH = Thyrohyoid, TP = Thyropharyngeus, CP = Cricopharyngeus, Eso = Cervical esophagus. D: Movement of the hyoid bone during (a) belching and (b) swallowing: the hyoid bone moves in the anterior direction only during belching. On the other hand, during a swallow, the hyoid bone moves cranially and anteriorly. E: Relationship between swallow-related pharyngeal peristalsis, cranial movement of the hyoid bone, vocal cord adduction and vestibular closure. These events are of critical importance for the swallowed contents to not enter the airway, (vocal cord adduction, vestibular closure and epiglottis closing laryngeal inlet. (3 tier airway protection mechanism). TB-O = onset of tongue base movement, SH-O = onset of superior hyoid movement; SM-O = onset of submental myoelectrical activity; UESO = Upper esophageal sphincter opening; OT-O, onset of bolus movement from the mouth; PT-O, arrival of bolus into pharynx. F: Laryngeal taste buds involved in the airway protection: immunohistochemistry for KRT8 (green) and tdTomato (magenta) in cryosections of larynx from P2ry1-ires-Cre mice injected with AAV-flex tdTomato in NJP ganglia. (Scale bar, 50 mm). (A&C) Netter Medical Illustration, used with permission. (B) Lang et al. 2006 (21), used with permission. (D) Shaker et al. 1992 (22), used with permission. (E) Shaker et al. 1990 (23), used with permission, (F) Prescott et al. (24), used with permission.

Anatomically, the upper esophageal sphincter (UES) is located mostly behind the cricoid cartilage; it extends slightly above and below it. The cricopharyngeus is a major contributor to the UES high-pressure zone, but thyropharyngeus (part of the inferior pharyngeal constrictor) and cervical esophagus also contribute to the UES high-pressure zone in its proximal and distal extent, respectively^{28, 29}. The vagus nerve, through its pharyngeal, superior laryngeal, and recurrent laryngeal nerve branches, is the major motor nerve of the UES. Acetylcholine, acting through the nicotinic receptors located on the motor nerve endplate, is the major neurotransmitter of the UES muscles. However, other neuropeptides, calcitonin gene-related peptide (CGRP), neuropeptide Y, substance P, vasoactive intestinal polypeptide (VIP), and galanin are present in the region^{30, 31}, likely for the control of blood flow. Swallow-induced relaxation of the UES lasts for 0.32– 0.5 seconds, and the duration of relaxation increases with the increase in bolus volume³². Two distinct events are responsible for swallow-induced relaxation of the UES: 1) cessation of the tonic discharges of motor neurons of the nucleus ambiguous and, 2), anterior and superior lift of the hyoid bone, cricoid cartilage, and UES³³, which is related to the contraction of the suprahyoid muscles that ablates the residual UES pressure by a forceful superior (2.5 cm) and anterior (0.75 cm) stretch exerted on the UES (Figure 1D). The UES has been called as a grabber³⁴ because it ascends to grab the bolus and then descends with the bolus with each swallow³⁵. With belching, the UES moves mostly in the anterior direction (not in the cranial direction) due to the contraction of the infrahyoid muscles.

Motor Patterns of the Esophagus

Figure 2 shows the relevant anatomy and neural innervation of the esophagus, smooth muscle lower esophageal sphincter, and the crus of the diaphragm (external lower esophageal sphincter). The esophagus is a relatively straight tube guarded at its two ends by the upper (UES) and lower esophageal sphincter (LES). The major function of the esophagus is to transfer ingested contents from the pharynx into the stomach, which is achieved by primary peristalsis (Figure 3A & B). Swallowing begins as a voluntary process (oral phase), but once bolus hits the tonsillar region and pharynx, it becomes autonomous or involuntary (pharyngeal and esophageal phases). A pharyngeal swallow is the one with pharyngeal and esophageal phase but without the oral phase³⁶. Flow in the orad direction, i.e., from the stomach into esophagus and mouth is achieved by a motor pattern that requires relaxation of the lower esophageal sphincter and crural diaphragm (transient LES relaxation), contraction of the longitudinal muscles of distal esophagus and relaxation of the upper esophageal sphincter (for the esophageal contents to reach mouth during belching, regurgitation, vomiting and rumination)^{37, 38}. Repetitive swallows at short intervals (< 5–6 seconds apart), important for drinking of fluids at a fast speed, elicit deglutitive inhibition during which the UES relaxes with each swallow, the esophagus and LES remain relaxed, and the esophagus contracts in a peristaltic fashion only after the last swallow³⁹ (Figure 3A). During repetitive swallows; how far does a swallow-induced contraction traverses the esophagus depends upon the time interval between successive swallows⁴⁰. With a swallow interval of < 2 seconds, each successive swallow induces inhibition of the skeletal as well as the smooth muscle esophageal contraction related to the preceding swallow⁴¹. On the other hand, an inter-swallow interval between 2–10 seconds result in complete inhibition of the preceding swallow-induced contraction in more distal parts of the esophagus (smooth muscle esophagus). A swallow interval of 10 –15 seconds results in the esophageal contraction amplitude of the second swallow being smaller than the first if the swallow interval is > 30 seconds⁴⁰. Above is the basis of using inter-swallow intervals of 30 seconds during the esophageal motility testing performed in the clinical setting⁴². Contraction amplitude of the esophageal peristaltic contraction following repetitive swallows is significantly greater than that of single swallows, spaced 30 seconds apart (so-called peristaltic reserve), the clinical significance of which is that patients with preserved contractile reserve have less chance of developing dysphagia following fundoplication surgery^{43, 44}. Injection of small amount of fluid in the pharynx also elicits LES relaxation⁴⁵ and inhibition⁴⁶ of ongoing contraction in the esophagus. A peristaltic contraction in response to the distension of the esophagus by a balloon or gastroesophageal reflux, or swallowed contents that are not cleared by primary peristalsis induces secondary peristalsis. The latter consists of contraction above (ascending contraction) and relaxation below (descending relaxation) the site of distension⁴⁷. If the distended balloon is held in place in the esophagus (by a string), a sustained esophageal propulsive force above the site of distension is recorded, which lasts for the duration of distension⁴⁸. More recently, repetitive antegrade esophageal peristaltic contractions (6 times/minute) are described during the sustained distension of the esophagus by a functional luminal imaging probe (FLIP) ⁴⁹ (Figure 3C). Primary peristalsis is coordinated through several cranial nerves (5^th, 7^th, 9^th, 10^th, and 12^th), the swallow center in the brain stem, and the cerebral cortex^{9 25}. On the other hand, secondary peristalsis in the smooth muscle esophagus, along with LES relaxation, can be entirely organized at the peripheral level, i.e., myenteric plexus and smooth muscles⁵⁰. Transient LES relaxation, the key motor event for retrograde transport through the esophagus is mediated through the vagus nerve and the brain stem⁵¹.

Figure 2: Relevant anatomy and neural circuitry of the esophagus, lower esophageal sphincter and crus of diaphragm.

A: Upper 1/3^rd of the esophagus is skeletal and lower 2/3^rd smooth muscle. The latter contains myenteric plexus between the circular and longitudinal muscle layers, with excitatory (cholinergic and substance P) and inhibitory nerves (nitric oxide and VIP). There is a loss of inhibitory neurons in achalasia esophagus. B: Myo-architecture of the lower esophageal sphincter – the circular muscle of the distal esophagus crosses at the angle of HIS and continues into stomach as the innermost layer of the stomach also known as sling fibers of the LES or the oblique muscle layer of stomach. The longitudinal muscle fibers of the esophagus terminate in the sling fibers. C: The esophageal hiatus formed by the right crus of diaphragm is the external lower esophageal sphincter; it has unique myo-architecture with crossing muscle fibers at the posterior and anterior locations (marked by arrows).

Figure 3: A: High-resolution manometry recording of primary peristalsis and deglutitive inhibition.

Primary peristalsis: Prior to swallowing, the upper and lower esophageal sphincters are seen as bands of high-pressure zones. Each swallow results in relaxation of the upper and lower esophageal sphincters and sequential contraction along the length of esophagus. Deglutitive Inhibition: one sequence of 5 swallows, spaced 2 seconds apart is shown in this manometry recording. Note that only the last swallow is followed by a contraction wave that traverses the whole length of the esophagus. B: Distension contraction plots of esophageal peristalsis: each swallow is followed by distension of the esophagus first (shown as white waveform), followed by contraction (shown as color pressure topography). Both distension and contraction move sequentially along the length of esophagus. C: Distension of the esophagus with the functional luminal imaging probe: A sustained distension of the esophagus induces repetitive antegrade contractions (RAC) or secondary peristalsis, in the esophagus. Changes in the bag diameter is shown as color heat map and waveform (black) is the pressure recorded by a sensor located at the bottom of the bag.

Inhibitory and Excitatory Phases of Esophageal Peristalsis

Landmark studies of Bayless and Starling, who studied isolated segments of the small and large intestine in an organ bath, revealed that peristalsis consists of two phases: initial inhibition/relaxation followed by excitation/contraction, also known as descending relaxation and ascending contraction, respectively^{52, 53}. The contraction is located behind, while the relaxation is in front and around the bolus during peristalsis. Contraction is the driving force for the bolus propulsion, and relaxation allows the bolus to be propelled with minimal resistance to the bolus flow. In the case of the esophagus, since the original recording of esophageal peristalsis by Kronecker and Meltzer in the 19^th century ⁵⁴ and to this day in the 21^st century, the focus of studies on the esophageal peristalsis has always been on the contraction/excitation, and not the relaxation/inhibition phase of peristalsis. The major reasons for the above are that: 1) there are good techniques available to record the contraction phase of peristalsis, and it is felt to be the driver of bolus propulsion, and 2) there are no good methods to record the inhibitory/relaxation phase of peristalsis, especially in the in-vivo settings, especially in humans. In spite of the major advances in recording techniques, e.g., HRM, color pressure topography, and advanced computer software, the esophageal motor disorders are still classified based on the contraction phase of peristalsis⁴². Recent studies show that the problem in many patients with dysphagia is in the relaxation phase of peristalsis⁵⁵ (discussed later). Another important consideration is that the manometry techniques record primarily the circular muscle contraction, which has been the major focus of research on esophageal peristalsis in the basic and clinical literature. However, the circular muscle is only approximately 50% of the mass of the muscularis propria; the remaining is the longitudinal muscle. Furthermore, manometry only records the active muscle contraction and not the passive or biomechanical properties of esophageal wall at rest or during peristalsis. As discussed later in this review, the two functions, i.e., relaxation function and longitudinal muscle contraction during peristalsis are functionally related. Furthermore, the bolus flow through the esophagus is also determined by the passive properties of the esophageal wall, which is not recorded by manometry.

Circular and Longitudinal Muscle Contraction During Peristalsis

The circular muscles of the esophagus are arranged in a spiral fashion along the long axis of the esophagus ⁵⁶, and the angle between the circular muscle fibers and the long axis of the esophagus increases from the proximal to distal esophagus ⁵⁷. The longitudinal muscles are arranged perpendicular to the circular muscles. Even though the circular and longitudinal muscles of the esophagus in normal healthy subjects are relatively thin (0.75mm each in humans) ⁵⁸, each layer can generate considerable force/pressure during peristalsis. In animal studies, one can record an isometric force of up to 150gm at the lower end of esophagus during peristalsis related to the axial shortening of the esophagus due to longitudinal muscle contraction ^{59, 60}. Manometry studies record pressure (circular muscle contraction) of approximately150mmHg in normal healthy subjects and considerably more ^{61, 62} in some patients (up to 500mmHg or more in nutcracker/jackhammer esophagus). There are no comprehensive studies on the concurrent recordings of circular and longitudinal muscle contraction in the skeletal muscle esophagus, neither in animals nor in humans. On the other hand, several investigators have recorded circular and longitudinal muscle contraction simultaneously during peristalsis in the smooth muscle esophagus in animals. The circular muscle contraction in these studies was recorded using either manometry or stain gauze transducers, and longitudinal muscle contraction by tracking the motion of radio-opaque markers tethered to the esophageal wall using X-ray fluoroscopy ^{63 64, 65} or strain gauze transducer^{66, 67}. While manometry can measure circular muscle contraction at a point location in the esophagus, the techniques used in most of the studies recorded longitudinal muscle contraction over a segment of the esophagus, rather than at a point location. Furthermore, passive changes in the circular and longitudinal dimensions occur in the contracted and non-contracted segments of the esophagus, secondary to muscle contractions, which can confuse the issue at hand. These passive changes cause axial lengthening/shortening and changes in the luminal diameter (passive effect, law of mass conservation) above and below the contracted segment, which can be misinterpreted as muscle relaxation/contraction. In spite of these limitations, it was found that similar to the circular muscle, the longitudinal muscle also contracts sequentially along the length of the esophagus during peristalsis ⁶³. Using ultrasound imaging of the esophagus with high-frequency ultrasound catheter probes and applying the law of mass conservation, Nicosia proved that it is possible to record the longitudinal muscle contraction at a point location in the esophagus¹⁶. It was found that there is an excellent relationship between the increase in muscle cross-sectional area or thickness observed on ultrasound images, as a marker of longitudinal muscle contraction and axial shortening of the esophagus recorded by fluoroscopy ⁶⁸. Nicosia found that at each location in the esophagus, the longitudinal muscle contraction starts before (approximately, 1 second) and outlast circular muscle contraction during peristalsis. Later, it was found that the manometry recordings miss a part of the circular muscle contraction, both at the beginning and at the end of circular muscle contraction⁶⁹, and if one takes into account the above, the circular and longitudinal muscle contractions during peristalsis are perfectly synchronized, at their onset, peak and the end of contraction. The two muscle layers contract in perfect synchrony during balloon distension-induced secondary peristalsis as well⁷⁰. Another important aspect of the peristaltic contraction is that at any given moment in time, a segment of the esophagus, 8–10 cm in length is contracted, and this length increases from the oral to aboral end⁷¹ during peristalsis. The amplitude of circular and longitudinal muscle contractions along the long axis of the esophagus are bell shape curves⁷². The peak circular muscle contraction (peak pressure), and peak longitudinal muscle contraction (peak muscle thickness) are perfectly aligned and the two move together from the oral to aboral direction⁷² during peristalsis (Figure 4 A & C).

Figure 4: Patterns of circular and longitudinal muscle contraction during antegrade (aboral) (peristalsis) and retrograde (orad) transport in the esophagus (Reflux & Regurgitation).

A: Concurrent recording of the ultrasound images of esophagus (for longitudinal muscle contraction) and manometry (circular muscle contraction) at 5 cm above the lower esophageal sphincter) during primary peristalsis. The timing of manometric contraction (MC) onset and end, longitudinal muscle contraction (LMC) onset and offset, and lumen collapse (LC) onset are indicated. Changes in muscle thickness (or muscle cross-sectional area) is a marker of longitudinal muscle contraction. Following a swallow, the esophageal lumen expands, followed by its collapse and an increase in the muscle thickness. LM: longitudinal muscle, CM: circular muscle, MCSA: muscle cross-sectional area. B: M-mode ultrasound image of the esophagus during transient lower esophageal sphincter; note an increase in the muscle thickness (yellow line) without a significant increase in esophageal pressure (pink line), i.e., selective longitudinal muscle contraction, which occurs during a transient LES relaxation. C: Schematic of circular and longitudinal muscle contraction during aboral and oral transport through the esophagus. The 2 motor patterns, i.e., simultaneous contraction of circular and longitudinal muscles during peristalsis (for aboral transport), and selective contraction of longitudinal muscle during transient LES relaxation (for oral transport) are shown in the schematic.

Transient LES relaxation (TLESR) is a distinct motor pattern that was first described in connection with gastroesophageal reflux (GER)^{4, 37}, belching and vomiting. It is designed for the retrograde transport of gastric contents through the esophagus on its route to mouth; it is the major mechanism of GER in normal subjects and patients with GER disease. During TLESR there is selective contraction of the longitudinal muscle of the distal esophagus. The longitudinal muscle contraction begins in the distal esophagus before the onset of TLESR, and it spreads proximally, like reverse peristalsis^{73, 74}. The longitudinal muscle contraction during TLESR is significantly stronger than the one associated with primary or secondary peristalsis. The Longitudinal muscle contraction lasts for the entire duration of TLESR (20–30 seconds) while the circular muscle remains relaxed (Figure 4B & C). Study also shows a relative sliding between the circular and longitudinal muscle contraction during peristalsis as well as during TLESR⁷⁵. Since the circular muscles of the distal esophagus are arranged in a spiral fashion, their contraction can also lead to axial shortening of the esophagus ⁵⁶. The axial shortening of the circular muscle layer is greater than that of the longitudinal muscle during peristalsis, and the reverse is the case during TLESR⁷⁵. Differences in the axial shortening of two muscle layers imply that they are not completely tethered together and slide relative to each other like the two tubes of a telescope (Figure 5). The above would result in the deformation of myenteric neurons located between the two layers, as shown by Gabella⁷⁶ which can lead to activation of mechanosensitive motor neurons in the myenteric plexus (discussed later). At the end of transient LES relaxation, there is a sudden shift of the contraction pattern of the two muscle layers to a peristaltic pattern, i.e., synchronous contraction of the two layers⁷³. A subthreshold pharyngeal stimulus induces isolated LES relaxation in the absence of esophageal peristalsis, related to axial shortening in the proximal esophagus (distal to the upper esophageal sphincter)⁷⁷. It is interesting to note that the pattern of circular and longitudinal muscle contraction during peristalsis, i.e., synchronous contraction and relaxation in the two layers of the esophagus, is similar to the one described by Bayliss and Starling in the small intestine and colon using kymographs. Many years later, Smith and Spencer used sophisticated tools, calcium transients in the two muscle layers^{78, 79} and intracellular electrical recordings^{80, 81} to prove that the two layers indeed contract and relax synchronously during peristalsis in the colon. Intracellular electrical recordings reveal hyperpolarization (inhibition phase) and depolarization (excitation phase) of the resting membrane potential, in the circular as well as longitudinal muscle layers during peristalsis in the large intestine. In the case of esophagus, hyperpolarization and depolarization occur in the circular muscle layer only⁸²; the longitudinal muscle layer shows depolarization only. It is interesting though, that similar to the circular muscle, the longitudinal muscle also relax during repetitive swallows(deglutitive inhibition)⁸³. The sliding between the two muscle layers, resulting in deformation and activation of mechanosensitive inhibitory motor neurons is a possible mechanism of the descending relaxation of peristaltic reflex (Figure 5B). Transverse stretch on the other hand, may activate mechanosensitive excitatory motor neurons located in the myenteric plexus (Figure 5C)

Figure 5.

A: Schematic of the organization of circular and longitudinal muscle layers, myenteric plexus, vagus nerve and polarity of inhibitory and excitatory neurons in the myenteric plexus. The two layers of esophagus slide, relative to each other like 2 tubes of a telescope. The axons of inhibitory neurons and excitatory neurons in the myenteric plexus are located in aboral and orad direction, respectively. Relative motion between the two muscle layers, depending upon the direction of sliding may activate mechanosensitive inhibitory (B) and excitatory (C) neurons, resulting in relaxation and contraction of the circular muscle layers, respectively. Figure created with AI and a licensed version of Biorender.com

Central & Peripheral Control of Esophageal Peristalsis

In general, the entire gastrointestinal (GI) tract has dual neural control through extrinsic (vagus (parasympathetic) and sympathetic nerves) and intrinsic nerves (myenteric plexus). Nowhere else in the GI tract, the role of extrinsic, i.e., cortical, brain stem, and vagus nerve (extrinsic) is as evident as in the case of esophagus. The likely reason is that swallowing, a voluntary act (oral phase), requires integration with an involuntary act, i.e., the pharyngeal and esophageal peristalsis, and LES relaxation. Central control is required for the control of muscles of the oropharynx, UES, and skeletal muscle esophagus. In addition, central control is of crucial importance for the aero-protective reflexes to prevent aspiration of swallowed content into the trachea-bronchial tree. Sequential contractions in the skeletal muscle of the pharynx and esophagus are the result of sequential activation of neurons in the central pattern generator (CPG) located in the brain stem. On the other hand, peristalsis in the smooth muscle esophagus can be due to sequential activation of the neurons in the CPG and the neuromuscular elements located in the esophageal wall (peripheral control).

Central Pattern Generator of Primary Esophageal Peristalsis

A swallow can be induced by mechanical stimulation of the pharynx in the anesthetized animals or electrical stimulation of the superior laryngeal nerve (SLN) in decerebrate animals^{7, 84}. The SLN is an afferent nerve with the relay station in the nucleus solitarius (NTS). Prolonged electrical stimulation of the SLN induces rhythmical contractions of muscles involved in the oropharyngeal and esophageal phases of swallowing (primary peristalsis). These contractions are sequential, similar to primary peristalsis. The oropharyngeal phase of swallowing requires activation of approximately 25 pairs of muscles that are innervated by multiple cranial nerves, i.e., trigeminal (5^th), facial (7^th), glossopharyngeal (9^th), vagus (10^th), and hypoglossal (12^th)⁷. The latter implies that there is a pre-programmed set of connections between the NTS, several cranial nerves, premotor neurons of the nucleus ambiguous and dorsomotor nucleus of vagus nerve (DMV). The brainstem neurons in the medulla, responsible for generating the swallow reflex, are referred to as the CPG or swallow program generator (SPG) (Figure 6 & 7A). A detailed discussion of the CPG can be found in the review by Andre Jean ²⁵. Briefly though, anatomically, the CPG is a poorly demarcated collection of neurons; the critical elements of which are the NTS, adjacent reticular formation, nucleus ambiguous, and DMV. These have been studied in detail in mice, rats, cats, and sheep. CPG neurons are also involved in the respiratory and cardiovascular reflexes. There is topographical representation of the sensory input into the NTS such that the dense labeling of pharyngeal and laryngeal fibers is found in the intermediate and interstitial subnuclei, and esophageal afferent labeling is primarily located in the central subnucleus of the NTS⁸⁵. Local medullary connections, directly or through the reticular formation, project to the premotor nucleus of the vagus nerve. In addition, the NTS receives descending projections from the supra-medullary and cortical centers. The NTS is not a simple relay station; sequential activity in the NTS neurons can be recorded following stimulation of the SLN. Microinjection of excitatory amino acid (EAA) agonist into the NTS induce rhythmical peristaltic motor events in the oro-pharynx and esophagus, which can be blocked by EAA antagonists. N-methyl-D-aspartate (NMDA) receptor agonist also induce rhythmic “primary peristalsis” in the pharynx and esophagus. Microinjection of GABA-A agonist and antagonist inhibit and facilitate motor events associated with swallow and peristalsis, respectively, suggesting that the NTS must also exert tonic inhibitory control over the motor neurons of the DMV^{86, 87}. Lesions in certain areas of the CPG result in disassociation between the oropharyngeal and esophageal phase of peristalsis (in response to SLN stimulation), which suggest that there are set of CPG neurons that control the esophageal phase of swallowing ²⁵. It is likely that the swallow reflex is a polysynaptic reflex at the level of the brainstem; several neurotransmitters are involved at these synaptic sites, i.e., acetylcholine (through nicotinic and muscarinic receptors⁸⁶), epinephrine (alpha receptors), monoamines, serotonin, vasopressin, oxytocin, somatostatin, thyrotropin, NO, and serotonin⁸⁸. Studies show that the activation of neurons in the DMV, rostral and caudal to the Obex of the brain stem, induces contraction and relaxation of the LES, respectively⁸⁹. The LES relaxation response is blocked by the GABA-B agonist baclofen⁹⁰. Above implies that the inhibitory and excitatory components of the esophageal peristaltic reflex can be selectively activated at the central level. Transient LES relaxation, which selectively activates the inhibitory events in the esophagus and LES, is blocked by the cooling of vagus nerve in neck⁵¹. It suggests that certain areas of the brain stem (CPG) indeed control the inhibitory phase of peristalsis and the other areas the excitatory phase of esophageal peristalsis; thus one can be activated without the other.

Figure 6: Brain stem control of peristalsis.

The central pattern generator (CPG) includes two main groups of neurons located within the medulla oblongata: a dorsal group (DSG), located within the nucleus tractus solitarius (NTS) and the adjacent reticular formation, and a ventral group (VSG), located in the ventrolateral medulla (VLM) adjacent to the nucleus ambiguous (nA). The DSG contains the generator neurons involved in triggering, shaping, and timing the sequential swallowing pattern. The VSG contains the switching neurons, which distribute the swallowing drive to various pools of motor neurons involved in swallowing. It should be noted that the pathway including the peripheral afferent fiber neurons in the DSG and VSG and motor neurons forms an oligosynaptic loop involved in swallowing. Adapted from Jean 2001(25), figure created with a licensed version of biorender.com

Figure 7: Central and Peripheral Mechanisms of Peristalsis: Central mechanism of peristalsis.

A: Sequential firing of dorso-medullary neurons during oropharyngeal (early) neurons (a) and esophageal (late) (b) neurons. MHm: mylohyoid muscle, SwN: Swallowing neuron. B: Effect of vagus efferent stimulation on the smooth muscle segment of the esophagus. Stimulation with (a) 3mA, 4 sec train, 5Hz and 1 ms pulse duration evoked an anti-peristaltic response, (b) 5mA, 0.5 ms pulse, 10Hz and 2 sec train produced a peristaltic response, VS–vagal stimulation, E – electrical activity, M – mechanical activity. C: Myenteric Mechanism of Peristalsis: isolated strips of circular smooth muscle (CMS) from different levels of the esophagus. Distance is in centimeters from the gastroesophageal junction. Following stimulation, contraction occurred following a latency period, which was longer in the distal as compared to the proximal esophagus. D: Myogenic mechanism of peristalsis: opossum esophagus in vitro in an organ bath. A contraction initiated in the mid esophagus by tetramethylammonium (2mM) propagated in both antegrade and retrograde direction (dashed line) in the presence of nerve blocker tetrodotoxin. These experiments prove that the control of esophageal peristalsis is possible at the level of the brain stem (A & B), myenteric neurons of the esophagus (C), or the smooth muscle (D). (A) Jean 2001(25), used with permission, (B) Gidda et al. 1981 (91) used with permission, (C) Weisbrodt et al. 1972 (10), used with permission, (D) Helm 1992 (92), used with permission

Vagal Efferent Discharge During Peristalsis

Bilateral cervical vagotomy or cooling of the vagus nerves abolishes primary peristalsis in both the skeletal and smooth muscle esophagus^{93, 94}, thus proving the crucial role of the CPG in esophageal peristalsis. Unilateral vagotomy does not prevent peristalsis completely⁹³ because of the crossing over of nerve fibers from the NTS to the motor nuclei. Secondary peristalsis in the skeletal muscle, elicited by balloon distension, is also mediated through the brainstem and vagus nerve. The ingenious nerve suture studies of Roman and Tieffenbach^95–97 support sequential excitation of esophageal muscles during the contraction phase of peristalsis. These studies prove that the CPG fires in a sequential manner in both the skeletal muscle esophagus (in the sheep with a skeletal muscle esophagus), and the smooth muscle esophagus (baboon esophagus). Swallow-evoked discharges in the preganglionic efferent of the vagus nerve have short (<1 sec) and long (1–5 sec) latency fibers. Short-latency fiber discharges have a lower threshold of activation, and their latency can be modulated by the frequency of electrical current used to stimulate the superior laryngeal nerve. These short latency fibers likely correspond to and mediate the inhibitory phase of peristalsis. On the other hand, long latency fibers have a higher threshold of activation, and their discharge pattern is not modulated by the stimulation frequency; they coincide with the excitatory phase of esophageal peristalsis⁹⁸. Abrahams found that activation of the rostral and caudal areas of the DMV elicit contraction and relaxation of the LES, respectively, suggesting the presence of neurons in the CPG that can mediate relaxation and contraction in the esophagus^{89, 99}. Transient LES relaxation, which is a major inhibitory pathway for the esophagus and LES, is also abolished by cooling the vagus nerve in the neck, which blocks all efferent discharge⁵¹. All of the above arguments prove that the vagus nerve indeed contains efferent fibers that mediate inhibitory and excitatory neurons of the myenteric plexus to cause relaxation and contraction, respectively (parallel pathways).

Peripheral Mechanism of Sequential Inhibition and Excitation During Peristalsis

From the 1970’s to the mid 1990’s, several investigators contributed to our understanding of the peripheral control of esophageal peristalsis. The focus of most of these studies was the circular muscle, even though it is clear now that the peripheral mechanism of peristalsis must exist in both layers because balloon distension induced peristalsis in the isolated in-vitro esophagus is associated with the simultaneous contraction of circular and longitudinal muscle layers⁷⁰. In this regard, it is important to emphasize that during primary and secondary peristalsis the circular and longitudinal muscle contract in a synchronous fashion but with electrical stimulation of the peripheral end of a transected vagus nerve, used extensively in literature to study peripheral mechanism of peristalsis in-vivo (animal studies), results in the contraction of the longitudinal muscle and relaxation of the circular muscle during the stimulation period^{59, 60}. Even electrical stimulation of the isolated circular muscle strip produces opposite responses in the two muscle layers ¹⁰. Christenson & Lund found that esophageal peristalsis can be elicited in an ex-vivo preparation of the esophagus by pinching the wall of the esophagus, luminal distension by a balloon and electrical field stimulation, similar to what was seen previously in the ex-vivo preparations of the colon and small intestine⁹. They described “ON” contraction (soon after the stimulus) and “OFF” contractions (following a latency period at the end of the stimulus) of the circular muscle layer. Weisbrodt prepared circular muscle strips (2cm apart) from the distal 12cm of the opossum esophagus. Electrical stimulation of these muscle strips at the same time elicited circular muscle contraction following a certain latency period at the end of the stimulus⁹. The latency was longer for the muscle strips of the distal as compared to the proximal esophagus (Figure 7C). Mukhopadhyay found that electrical stimulation of the peripheral end of a transected cervical vagus nerve (which stimulates all vagal efferent fibers at the same time) elicits sequential or peristaltic contraction in the opossum esophagus, proving beyond doubt that a mechanism of peristalsis (sequential contraction of the circular muscle) resides within the wall of the smooth muscle esophagus¹⁰⁰ (Figure 7B). Dodds et al found that electrical stimulation of the peripheral end of a transected vagus nerve in the cat esophagus also induces contraction following the onset of electrical stimulus, which was called the “A” wave and another contraction following the end of stimulus, the “B” wave, both of which were peristaltic¹⁰¹. The speed/velocity of peristalsis differed for the “A” and “B” waves. Whether the “A” or the “B” wave represents the true swallow-induced peristalsis under physiological conditions was contested for a long time¹⁰². The neurotransmitters responsible for the “ON” and “OFF” contractions are different; the “ON” contraction can be antagonized by atropine and hence mediated by cholinergic nerves. On the other hand, the “OFF” contraction is mediated through non-cholinergic non-adrenergic nerves that we now know is NO¹¹.

Gidda found that “ON” and “OFF” contractions induced by electrical stimulation of the vagus nerve can be explained on the basis of the strength and the duration of the electrical stimulus¹⁰³. A strong electrical current and longer duration stimulus result in only “OFF” contraction. On the other hand, a weak and long-duration stimulus elicits only “ON” contraction. A short-duration stimulus elicits only one response. On the other hand, long-duration stimulus elicits either “ON” or “OFF” response depending upon the strength of the stimulus. The above observations are somewhat similar to what one sees with the repetitive swallows in humans (explained on the basis of deglutitive inhibition and refractory period⁴⁰). Crist studied rings of muscle from different regions along the length of the esophagus to demonstrate an intramural mechanism of peristalsis¹⁰⁴. An increase in stimulus frequency causes an increase in the latency of contraction in the rings from the distal esophageal sites, and a decrease in the latency in the rings from the proximal sites. Increasing stimulus frequency also caused an increase in the duration and amplitude of contractions at the proximal sites that was reversed by atropine. In the presence of atropine, increasing the stimulus frequency caused an increase in the latencies of contraction at all sites. The above proves that the influence of cholinergic innervation is most prominent in the proximal esophagus, and non-cholinergic (nitric oxide) in the distal esophagus. Keep in mind that the focus of the above studies was solely on the contraction phase of the circular muscle during peristalsis, and the latency period represented the inhibitory phase of the circular muscle.

The fact that the inhibition occurs prior to contraction during esophageal peristalsis can be seen in the human recordings using repetitive swallows (deglutitive inhibition). In the skeletal muscle esophagus, esophageal inhibition is explained by the inhibition of neurons in the CPG (ones responsible for skeletal muscle contraction)¹⁰⁵. On the other hand, in the smooth muscle esophagus, the mechanism of inhibition can be either central or peripheral. The latency to contraction in the ex vivo preparation of the esophagus and muscle strip is related to the inhibition phase of peristalsis. A longer latency implies a longer inhibitory phase of the esophagus. The inhibitory neurons release NO, which is responsible for the latency period¹¹. The NO antagonists reduce the latency period in the distal esophagus, and esophageal peristalsis become simultaneous instead of sequential. These studies have been carried out in healthy humans¹⁰⁶ as well as in animals¹¹. The reason for a longer latency period in the distal esophagus may be related to the properties of the smooth muscle themselves along the length of the esophagus; 1) resting membrane potential along the esophagus is more negative distally, which may be related to the gradient of potassium content along the smooth muscle esophagus¹⁰⁷ 2) a more depolarized resting membrane potential due to the sodium permeability and an increase in the density of voltage-dependent potassium channels proximally¹⁰⁸, 3) regional differences in the soluble N-ethylenemaleimide sensitive factors attachment receptor (SNARE) protein, SNAP-25, which regulates potassium channels¹⁰⁹, 4) response to stretch and cholinergic stimulation with strips from more proximal regions being more responsive¹¹⁰ and 5) increased expression and current density of L-type calcium channels in the proximal versus distal smooth muscle esophagus^{111, 112}.

Rattan demonstrated that with each swallow, there is hyperpolarization of the resting membrane potential that corresponds to the inhibitory phase of peristalsis⁸². Following a swallow, inhibition spreads rapidly in the entire esophagus, followed by depolarization/spike burst that corresponds with the excitation/contraction phase of peristalsis. Whether hyperpolarization also spreads sequentially through the esophagus is not known. By distending small balloons in the esophagus, Sifrim created artificial high-pressure zones in the esophagus and demonstrated relaxation of the esophagus prior to contraction^{113, 114}. Esophageal tone in the esophagus can be demonstrated by using a barostat and it is reduced with amyl nitrite¹¹⁵. Abrahao found that during primary peristalsis, the esophagus distends sequentially prior to the contraction, along the whole length of the esophagus⁷². Furthermore, there is a close temporal correlation between contraction and luminal distension during peristalsis. A segment of the esophagus, not the entire esophagus distal to the contraction, distends in the shape of an “American Football” (Figure 8). Since the pressure in the entire distended segment is identical, greater distension implies higher compliance or greater inhibition at the location of peak distension. Sequential increase in the compliance during peristalsis implies sequential relaxation/inhibition during peristalsis. The peak distension is anatomically located at the onset of contraction in the esophagus. The above observation is important because it implies that, similar to contraction, the inhibition also moves sequentially through the esophagus.

Figure 8: Temporal Relationship between Luminal Distension and Circular and Longitudinal Muscle Contraction.

A: Concurrent contraction of circular (by manometry-pressure) and longitudinal muscle (by ultrasound imaging-increase in muscle thickness) recorded at 2cm and 12 cm above the lower esophageal sphincter. Two ultrasound probes were used to record ultrasound images. Luminal distension and changes in muscle thickness (marker of longitudinal muscle contraction) were measured from the ultrasound images. The line drawing at the bottom of each ultrasound image shows changes in luminal cross-sectional area (CSA-esophageal distension) and pressure at the corresponding location in the esophagus. Note the sequential increase in the luminal CSA and luminal pressure waves. B: Schematic of the temporal relationship between luminal distension in relationship to the circular and longitudinal muscle contraction. Circular muscle contraction is shown in pink, longitudinal muscle contraction in black and distension in yellow waveforms on the right of the schematic. The esophagus distends in the shape of an “American Football” (shown in yellow color) during peristalsis.

Myenteric Plexus & Peristalsis

Esophagus, similar to small and large intestines, has myenteric plexus located between the circular and longitudinal muscle layers, both in the skeletal and smooth muscle esophagus^116–118. The role of myenteric plexus in the skeletal muscle esophagus is not clear because these muscles are activated by efferent vagus nerves through the neuromuscular junction located on the skeletal muscle fibers. One argument is that the myenteric plexus in skeletal muscle esophagus is a remnant of the early developmental days, at the time when the entire esophagus was made up of smooth muscle^{119, 120}. The smooth muscle trans-differentiates into skeletal muscle at some time points in the proximal part of the esophagus. Another possibility is that the myenteric plexus in the skeletal muscle has a modulatory role on the contraction and relaxation of the skeletal muscle³¹. The myenteric plexus in the smooth muscle esophagus is less dense compared to the small and large intestine. The above may be in line with the simplicity of its function, i.e., mostly transport (no significant secretion, absorption and other complex functions). The density of neurons and ganglia in the myenteric plexus declines along the length of the esophagus, higher in the proximal than the distal esophagus, and least in the lower esophageal sphincter¹¹⁶. The neural circuitry of small and large intestines has been studied using advanced techniques, i.e., neurochemistry, single cell impalement, advanced imaging and genetics approaches; such studies are not available in the case of esophagus. The myenteric plexus plays a major role in the smooth muscle peristalsis; tetrodotoxin, a blocker of neuronal activity, abolishes the contraction as well as the relaxation phase of peristalsis. There are two predominant types of motor neurons: excitatory and inhibitory. The acetylcholine and substance P are the neurotransmitters of the excitatory motor neurons, and NO, along with VIP and possibly ATP, of the inhibitory motor neurons.

In general, the neurons within the myenteric plexus can be functionally assigned as sensory neurons, motor neurons, and interneurons. Schemann found that 60% of the neurons in the myenteric plexus of the small and large intestine have mechanosensory properties¹²¹, and many of these are motor neurons. Above observation is in agreement with the studies of Spencer and Smith that the stretch-activated neurons in the peristaltic reflex are S or motor neurons^{80, 122}. Studies show that motor neurons of the esophagus also have mechano-sensory properties, i.e., they can be activated by mechanical deformation^{123, 124}. The location of myenteric plexus, i.e., in between the circular and longitudinal muscle layer is ideally suited to take advantage of the mechanical deformation that they would undergo during the contraction of circular and longitudinal muscle layers. For example, during TLESR, only the longitudinal muscle (not the circular muscle) contracts in the distal esophagus^{73, 74}. On the other hand, during swallow-induced peristalsis, the two layers contract in perfect harmony⁶⁹. Above implies different types of deformation of myenteric neurons during different motor patterns. Inhibitory and excitatory motor neurons have projections (axons) directed anally and orally^{125, 126}, respectively, which implies that the direction of spatial deformation may determine the activation of excitatory and inhibitory neurons (Figure 5).

Mechanical Stretch and Peristaltic Reflex

Motion of the radio-opaque markers observed on the X-ray fluoroscopy, first described by Dodd’s et all¹²⁷ reveal interesting information on the possible role of mechanosensitive motor neurons, especially in the inhibitory phase of peristalsis. It shows that during esophageal peristalsis, each segment of the esophagus is first pulled in oral direction, then it elongates in its long axis, and finally it shortens in the long axis of esophagus ^{63, 128} (Figure 9). The marker movement follow a “P” loop pattern in most of the esophagus except for the most distal esophagus where it follows a “D” loop pattern. These specific patterns of motion has relevance to the lengthening and shortening of each adjacent segments, which is temporally aligned with the inhibitory and excitatory phases of esophageal peristalsis, respectively. Interestingly, these lengthening and shortening patterns in the adjacent segments are similar to the findings in the isolated segments of colon studied in vitro for peristaltic reflex (described later). Furthermore, studies show that the longitudinal and circular muscle slide in different directions relative to each other during the contraction and relaxation phase of peristalsis and during TLESR⁷⁵. The axial shortening of the circular muscle is greater than that of the longitudinal muscle during peristalsis, and the reverse is the case during TLESR. Axial stretch and relative sliding between the two layers would cause distortion of the myenteric neurons (described by Gabella many years ago⁷⁶), and it can result in their activation through the mechanosensitive mechanism. Preiksaitis observed hyperpolarization of the circular muscle of the esophagus during spontaneous longitudinal muscle contraction in an ex vivo preparation of the cat esophagus, (figure 2 of their paper)¹²⁹, which is similar to what happens during the electrical stimulation of the vagus nerve in the opossum esophagus, i.e., longitudinal muscle excitation and circular muscle inhibition. Whether longitudinal muscle contraction activates the inhibitory motor neurons through a mechanosensitive mechanism to induce relaxation in the circular muscle of esophagus is a likely possibility and need to be further studied. Esophageal distension in the smooth muscle esophagus in bilateral vagotomized animals and in an ex vivo preparation of the esophagus induces peristalsis in the circular muscle layer and LES relaxation. Using a 3-partition chamber preparation, Paterson et al found that distension of the proximal esophagus evokes nerve-mediated inhibitory and excitatory responses in the circular muscle of the distal esophagus that were blocked by a NO antagonist, but not by a synaptic blocker¹³⁰. They concluded that muscle stretch in the proximal esophagus activates inhibitory motor neurons in the distal esophagus to cause NANC (non-cholinergic non-adrenergic) mediated inhibition, and withdrawal of NANC inhibition induces esophageal contraction. Paterson used a balloon to distend the esophagus and could not distinguish the effects of longitudinal versus circumferential stretch on the peristaltic reflex. Using an in vivo study in opossum, Dogan et al observed that a mechanical pull of esophagus in the longitudinal and transverse direction causes nerve-mediated LES relaxation and LES contraction, respectively¹³¹ (Figure 10A & B). Axial (longitudinal) stretch-induced LES relaxation was confirmed in 3 animal species^131–133: opossum, rat, and mice. There is a direct correlation between the force exerted by axial stretch and the magnitude of LES relaxation¹³³. It was found that there is no synapse involved in the axial stretch-activated LES relaxation, suggesting that mechanical stretch can activate inhibitory and excitatory motor neurons. In further studies, Dong et al developed primary culture of esophageal myenteric neurons¹³⁴ from the rat and human esophagus and, using intracellular calcium imaging technique (to record activation), observed that the inhibitory motor neurons are indeed mechanosensitive; when activated (increase in intracellular Ca⁺), they release NO in response to mechanical stretch¹²³ (Figure 10C). In other words, the esophageal motor neurons possess mechanosensitive properties.

Figure 9: Peristalsis in the longitudinal muscles of the esophagus.

A: Peristalsis in the longitudinal muscle was recorded using X-ray fluoroscopic images (in coronal and sagittal planes) of the radio-opaque markers implanted along the length of the cat esophagus. The esophagus was divided into 1 cm-long imaging regions. B: Marker movement in the coronal plane during esophageal transport (primary peristalsis) of a liquid bolus: (a) with a manometric tube, (b) without a manometric tube. These markers made a “P” loop in the proximal esophagus and “D” loops in the most distal esophagus. C: The distance between markers (a measure of longitudinal muscle contraction between the markers) revealed sequential contraction along the length of the esophagus. At the moment of the peak shortening, as compared to the baseline length, the distal esophagus shortened by 40% (A-C) Dodds et al. 1973 (63), used with permission.

Figure 10: Mechanosensitive Activation of the Inhibitory Neurons.

A: Schematic of the experimental design to induce oro-axial and transverse stretch of the esophagus. A solid-state transducer is located in LES. Two silk sutures were tied, (a) to exert oro-axial stretch; and (b) to exert transverse stretch. B: Shows the LES pressure recording of the oro-axial and transverse stretch. Oro-axial stretch induced dose-dependent relaxation of the lower esophageal sphincter and transverse stretch induced LES contraction. C: Inhibitory motor neurons of the myenteric plexus are mechanosensitive (a) Shows the esophagus myenteric neurons grown in culture on a silicon membrane. Cells were loaded with calcium imaging dye (Fura) to study activation (yellow color) and quiescence (blue color). (b) Activation of the neurons in response to mechanical stretch and deactivation (c) following mechanical stretch. D: shows the schematic of the current and proposed hypotheses on the vagus nerve-induced relaxation of the LES. (a) The vagus nerve synapses with myenteric neurons, which release nitric oxide to induce LES relaxation. (b) The other possibility is that the vagus nerve induces contraction of the longitudinal muscle, which, through a stretch-sensitive mechanism, deforms and activates the inhibitory neurons in the myenteric plexus. (D) Figure created with AI and a licensed version of Biorender.com

Brookes and Costa found that the axons of inhibitory and excitatory neurons project in the aboral and oral direction, respectively. Dendrites, on the other hand, project in the direction opposite to axons ^{125, 126} (Figure 5 and 11). It may be that the polarity of stretch-activated reflexes in the esophagus and colon is related to the polarity of projection of inhibitory and excitatory neurons. Mechanical deformation of the dendrites of inhibitory neurons in axial direction may lead to the activation of inhibitory neurons with axons projected in the aboral direction result in descending relaxation of the peristaltic reflex. On the other hand, in response to circumferential stretch, mechanical deformation of excitatory neurons with projections directed orally and circumferentially leads to the ascending contraction of the peristaltic reflex (Figure 5). Such a mechanism can explain tight coupling between the ascending contractions and descending relaxation of the peristaltic reflex at a local level. It can also explain why contraction of longitudinal muscle in the distal esophagus induces relaxation of the circular muscles of esophagus and LES during TLESR.

Figure 11: Stretch-activated Peristaltic Reflex in an Ex-Vivo Preparation of Guinea Pig Colon.

A: Simultaneous intracellular microelectrode recordings from an isolated sheet preparation of guinea-pig distal colon. Two independent recordings were made from the circular muscle (CM) layer (proximal and distal) in response to maintained circumferential stretch. Stretch evoked a maintained discharge of coordinated excitatory junction potentials (EJPs) at the proximal electrode, that were closely time-locked with inhibitory junction potentials (IJPs) at the distal electrode. B: shows what is known about the intrinsic neural circuit that underlies this stretch-activated reflex. The basic pathway involves convergence of ascending and descending interneurons, which generates time-locked proximal EJPs and distal IJPs. C: When longitudinal stretch is imposed on the preparation, it leads to inhibition of coordinated EJPs and IJPs. D: Evidence suggests that a population of descending nitrergic interneurons are principally sensitive to longitudinal stretch, that release nitric oxide (see neuron in yellow), leading to inhibition of cholinergic interneurons and suppression of proximal EJPs and distal IJPs in the CM layer. This pathway has been thought to be involved in storage or facilitation of fecal content in the colon.

The LES relaxation during TLESR occurs faster and is more complete than the swallow-related LES relaxation¹³⁵. The longitudinal muscle contraction of the distal esophagus during TLESR is significantly stronger than the one during peristalsis. A stronger longitudinal muscle contraction would result in greater distortion of the inhibitory motor neurons and hence trigger stronger inhibitory stimulus and explain more complete LES relaxation during TLESR. Manometry recordings reveal that the LES relaxation starts at the onset of swallow, as recorded by the mylohyoid muscle electromyographic (EMG) activity (the first muscle to be activated with swallow)¹³⁶. The cranial movement of the hyoid and cricoid during the pharyngeal phase of peristalsis results in a mechanical pull on the esophagus, almost at the onset of swallow (mylohyoid muscle contraction), which raises the possibility that the mechanical pull in the oral direction is the stimulus for the onset of swallow-induced LES relaxation. As peristalsis progress towards the distal esophagus, the mechanical pull on the LES gets stronger and so does the amplitude of swallow-induced LES relaxation.

It is interesting that there are number of similarities, with regards to the patterns of circular and longitudinal muscle contraction during peristalsis and stretch activated peristaltic reflexes in the esophagus and colon. The neural circuitry in the wall of large intestine has been studied using advanced techniques, i.e., optogenetics, chemogenetics and in-vivo imaging; such studies have not been performed in the esophagus. Hence, a brief review of the current state of knowledge of the mechanism of peristalsis in the large intestine is presented here; it is critically important in view of the current literature on the mechanosensitivity of enteric neurons in reference to peristaltic reflex.

The first documented evidence that the gastrointestinal tract could respond to local stimuli was published in the mid 1700’s by Albrecht Von Haller ¹³⁷, who found that the peristaltic reflex could be readily elicited in the isolated segments of intestine ¹³⁷. Carl Lüderitz^{138, 139} demonstrated polarized neural reflex responses in the intestine in the late 1800’s. However, it wasn’t until the 1990’s that unequivocal evidence was presented that a population of neurons in the myenteric plexus were directly responsive to mechanical and chemical stimuli ¹⁴⁰. This unique class of neuron was identified as having Dogiel Type II morphology; it sent projections into the mucosa and multiple arborizing projections within the myenteric plexus. This particular neurochemical class of neuron expressed calbindin as an immunohistochemical marker ¹⁴¹. The Furness laboratory coined the term intrinsic primary afferent neurons (IPANs) to formally classify Dogiel Type II as intrinsic sensory neurons¹⁴⁰. A hypothesis was promulgated by several investigators that IPANs initiate peristalsis in the gut. According to this hypothesis, in response to mechanical deformation of the mucosa, the enterochromaffin (EC) cells release 5-HT, which activates the IPANs in a paracrine fashion ¹⁴². However, later on it was found that peristalsis still occurred when the mucosa was surgically removed from the colon ^{143, 144}. Furthermore, when the mucosa and submucosal plexus were removed from the colon, neither did it prevent nor it reduced the threshold of stretch-activated motor reflexes ^{143, 144}. More recently, the ablation of the gene to synthesize 5-HT in the mucosa revealed no change in the GI transit times and major neurogenic motor patterns, including peristalsis ¹⁴⁵. Taken together, all evidence suggests that it does not require paracrine mediators to elicit peristalsis in the GI tract.

Besides IPANs, many other functional classes of myenteric neurons exhibit mechanosensitivity ^{146, 147}. Imaging the ENS using voltage-sensitive dyes has provided important clues of the mechanosensitivity of the ENS. It revealed that a substantial proportion of the myenteric neurons that have morphological appearance of interneurons and motor neurons exhibit mechanosensitivity and they could realistically participate in the distension-evoked reflexes, like peristalsis ^{121, 148}. Work from the Schemann’s laboratory revealed that about 60% of the neurons in the myenteric plexus of the small and large intestine have mechanosensory properties¹²¹ and many of these are motor neurons. Also, intracellular recordings from the morphologically confirmed interneurons showed robust mechanosensitivity in response to circumferential stretch of the distal colon. These interneurons in the myenteric plexus have Dogiel Type I morphology. The activity of these neurons was demonstrated in stretched segments of distal colon, where proximal process potentials occurred in these neurons when all synaptic transmission had been blocked ¹²². The notion that an interneuron could also behave as a sensory neuron changed the way enteric neuroscience viewed the circuitry of the ENS. Whether mechanosensory interneurons exist in the myenteric plexus of the esophagus and contribute to esophageal peristalsis has not been demonstrated to date.

There are marked similarities in the stretch-related responses in the isolated colonic segment of the guinea pig colon studied in an organ bath with the human esophagus recordings in vivo. A sustained circumferential stretch of the colon activates repetitive discharge of coordinated excitatory junction potentials in the circular and longitudinal muscle layers orally that are time-locked with the inhibitory junction potential in the smooth muscle aborally (Figure 11 A & B). When recordings were made from myenteric neurons, it was found that the myenteric S neurons were mechanosensitive and IPANs defined with Dogiel Type II morphology were electrically quiescent ¹²². Above showed that the S-neurons can generate complex neural circuits independent of IPANs that project into the mucosa. A longitudinal stretch induces inhibition in the ENS of the large intestine, and inhibition of polarized motor reflexes in the neighboring smooth muscle ¹⁴⁹ (Figure 11C & D). It was speculated that descending interneurons are mechanically sensitive, they are immunoreactive for nitric oxide synthase (NOS) and release NO onto the other classes of myenteric interneurons to suppress the reflex circuitry underlying peristalsis. It is possible that NO-synthesizing inhibitory motor neurons are also mechanosensitive, and as the gut is distended, these neurons inhibit the gut directly. In the esophagus, studies show that motor neurons of the esophagus also have mechanosensory properties, i.e., they can be activated by mechanical deformation^{123, 124}.

Intestinofugal neurons (IFNs) have remained somewhat of an enigma for many years ^150–153. They respond directly to the mechanical stimuli ¹⁵³ and can participate in the coordinated firing with other enteric neurons during complex neurogenic motor patterns ¹⁴⁷. IFNs are myenteric neurons, but unlike other classes of enteric neurons, they send single axonal projections out of the gut that synapse onto sympathetic prevertebral ganglia. They do not directly reach the spinal cord or brain. Distension has been clearly shown to activate IFNs, which can then elicit extrinsic reflex responses to neighboring segments of intestine ¹⁵⁴. Much of the activation of IFNs is indirect, since they are substantially reduced in activity when exposed to hexamethonium. Interestingly, colonic mechanosensory afferent nerves projecting to the superior mesenteric ganglion function as length or stretch detectors in parallel to the circular muscle layer ^{151, 152}. Longitudinal stretch does not activate IFNs. This is very different from spinal afferent nerve endings in the colon (with cell bodies outside the gut in the dorsal root ganglion). These sensory endings are activated equally by circumferential or longitudinal stretch and potentially activated by contraction of the muscle ¹⁵⁵. There is no evidence to suggest that IFNs exist in the esophagus.

Axial Stretch and Skeletal Muscle Inhibition

Relaxation of crural diaphragm, a skeletal muscle, is an integral component of TLESR^{135, 156}. Crural diaphragm contraction, similar to the rest of diaphragm is mediated through inspiratory neurons in the brain stem via phrenic nerves. Studies show that the contraction of longitudinal muscle of esophagus is tightly linked to crural diaphragm inhibition during distension of the esophagus by a balloon as well as during TLESR^{157, 158}. One possibility is that the crural diaphragm inhibition is located at the level of brain stem (inspiratory neurons). Esophageal distension-mediated crural diaphragm inhibition is blocked by bilateral vagotomy in cats suggesting a central mechanism^{159, 160}. However, the mechanism of crural diaphragm inhibition may also reside in the periphery¹⁶¹, as evidenced by the following observation: electrical stimulation of the crural diaphragm by electrodes placed in the muscle result in an increase in the esophagogastric junction pressure that is inhibited by distension of a balloon in the esophagus. The crural diaphragm inhibition is tightly linked to the axial stretch exerted by the longitudinal muscle contraction on the crural diaphragm muscle (transmitted through the phrenoesophageal ligament). Interestingly, crural diaphragm is innervated by vagus nerve¹⁶²; however, it does not have any myenteric neurons. The cellular mechanism of axial stretch-induced crural diaphragm inhibition at the peripheral level requires further investigation. It is possible that the deglutitive inhibition in the skeletal muscle esophagus and crural diaphragm during repetitive swallows at short intervals is also related to the stretch exerted on the esophagus during the oropharyngeal phase of peristalsis (cricoid cartilage lifts 2.5–3 cm with each swallow).

Myogenic Mechanism of Peristalsis:

Sarna found that electrical stimulation of the esophageal muscle in the presence of tetrodotoxin elicits esophageal contraction that can traverse in the proximal and distal directions with the same velocity as the swallow-induced peristalsis, suggesting a myogenic spread of excitability¹⁶³. Helm et al. stimulated circular muscle strip along the length of the esophagus using agents that cause direct membrane depolarization and excitation (tetraethylammonium, K⁺ and bethanechol)^{92, 164}. These agents elicited phasic contractions of the esophageal circular muscle, which were not blocked by atropine and tetrodotoxin (Figure 7D). The frequency of phasic contraction was higher in the distal as compared to proximal esophageal sites. In an ex vivo preparation of the esophagus, these contractions were found to travel in both antegrade and retrograde fashion (unlike normal peristalsis that travels only in the antegrade direction). The velocity of peristalsis, amplitude and duration of contractions were similar to the swallow-induced primary peristalsis. Preiksaitis recorded electrical and mechanical activity in an ex vivo preparation of the cat esophagus and found no spontaneous electrical activity in the circular muscle¹²⁹. Direct electrical stimulation in the presence of bethanechol or tetraethylammonium chloride (TEA) produced slow-wave oscillations and spike potentials accompanying smooth muscle contraction that progressed antegrade and retrograde along the esophagus. An increase in the concentrations of either drug in the presence of tetrodotoxin produced slow waves and spike discharges, accompanied by sequential contractions in some, but not all preparations. Depolarization of the muscle by increasing K⁺ concentration produced slow waves but no peristalsis. The myogenic contractions are not preceded by the hyperpolarization of resting membrane potential (inhibition) of circular muscle during esophageal peristalsis, and therefore it seems that the myogenic mechanism of peristalsis alone is not sufficient; intramural nerves are indeed required for the orderly progression during esophageal peristalsis.

Modulation of Primary and Secondary Peristalsis

It is clear that input from the CPG can modify the amplitude of contractions, speed of peristalsis, and even the polarity of esophageal contraction (peristalsis or reverse peristalsis). Inputs to the CPG may come from the supra-medullary regions of the brain or from the periphery. Wet swallows, as compared to dry swallows, elicit greater amplitude of contractions and lower speed of peristalsis¹⁶⁵. Viscosity of the bolus reduces the speed of peristalsis (Figure 3B). Temperature of swallowed bolus has significant effects; a warm bolus increases, and a cold bolus decreases the contraction amplitude and occurrence of esophageal peristalsis^{166, 167}. Outflow obstruction in an experimental animal model results in pronounced effects on esophageal peristalsis and contraction amplitude¹⁶⁸. In the human studies, laparoscopic gastric band surgery (an effective strategy to treat obesity) was used to study the effect of outflow obstruction of the esophagus on esophageal peristalsis. It resulted in shortening of the esophagus, an increase in the distal esophageal contraction amplitude, and an increase in the intraluminal bolus pressure¹⁶⁹. An aborally progressing contraction does not traverse over the obstructed bolus; instead, it dissipates when it can no longer propel the bolus, resulting in an escape of bolus towards the mouth¹⁶⁸ that may be misinterpreted as gastroesophageal reflux. In the skeletal muscle esophagus, these effects are mediated through the vago-vagal pathway. On the other hand, in the smooth muscle esophagus, control mechanisms exist both in the esophageal wall and through a central mechanism in the CPG. The mechanism of repetitive antegrade contractions induced by FLIP, so-called secondary peristalsis, requires further study.

Role of Vagal and Spinal Afferents in Peristalsis

The details of the vagal and spinal afferent nerves in the esophagus and their role in the physiological reflexes and pain can be found in an excellent review¹⁷⁰. There are no IPANs in the esophageal wall. The processes, in the form of intra-ganglionic laminar endings (IGLES) that surround the myenteric ganglia, and intramuscular arrays (IMA) are found in the mucosa, submucosa and muscle layers^171–173. The IGLES have a unique shape (like a chandelier) and they are found in the skeletal muscle of the esophagus. The IMA’s are present in between the muscle bundles of the smooth muscle layers of the esophagus. The neurons of sensory processes that travel in the vagus nerves are located in the nodose and jugular ganglia. On the other hand in the case of spinal nerves these neurons are in the dorsal root ganglion of the spinal cord. The sensory fibers are multimodal, i.e., they respond to mechanical, chemical and thermal stimuli. The Vagal afferents carry mostly low-threshold fibers, important for the physiologic reflexes, e.g., modulation of esophageal contraction during peristalsis¹⁷⁴. On the other hand, spinal nerves carry high threshold fibers, responsible for the noxious or pain sensation in the esophagus¹⁷⁵. A recent study found subtypes of vagal sensory neurons in the nodose and jugular ganglia that express Prox2 and Runx3 transcription factors that play an important role in the reflex control of esophageal peristalsis in mice that have a skeletal muscle esophagus. Their ablation leads to disordered peristalsis in the skeletal muscle esophagus¹⁷⁶.

Bolus Flow & Esophageal Peristalsis

The ultimate purpose of peristalsis (primary or secondary) is to transport the swallowed or refluxed contents into the stomach. The characteristics of bolus flow, i.e., velocity and volume of flow, along with bolus pressure can reveal important information on the nature of active (muscle contractions) and passive (biomechanical) properties ^{15, 177} of the esophageal wall during peristalsis. Kronecker and Meltzer (1883) noted that a swallowed bolus enters the distal esophagus, much ahead of the esophageal contraction. They used litmus paper positioned in the distal esophagus to demonstrate the above phenomenon. Cannon observed the above phenomenon using X- ray Fluoroscopic examination⁶. Using concurrent X-ray barium swallow and esophageal manometry¹⁷⁸, it became clear that contraction of the oropharyngeal muscle (also known as pharyngeal pump) can propel the swallowed bolus forcefully into the mid or even distal esophagus (even in the supine position when there is no gravity involved). The peristaltic contraction arrives several seconds later in the distal esophagus to propel the bolus further; it forces open the relaxed LES. Simultaneous manometry and intra-luminal impedance recordings show the relationship between bolus flow and esophageal contractions exquistely(Figure 3B). With a 5ml or 10ml bolus of saline swallow, the intraluminal impedance values fall sequentially from cranial to caudal direction in the esophagus¹⁷⁹. The admittance (inverse of impedance) value, as per principles of Ohms law of electricity, is directly related to the luminal cross-sectional area of the esophagus. Concurrent recording using the catheter-based high-frequency intraluminal ultrasound images, intraluminal impedance and manometry revealed a significant correlation between the luminal CSA and nadir impedance values in the esophagus during peristalsis¹⁸⁰. Therefore, it is now possible to visualize the distension contraction plots of peristalsis along the entire length of the esophagus, at closely spaced intervals (Figure 3B). These recordings show that the esophagus distends ahead of contraction in the shape of an “American Football” (not as a cylinder as suggested before). The peak of contraction as well as the peak of distension move sequentially through the esophagus (Figure 8). Furthermore, at any given moment during esophageal peristalsis, a segment of the esophagus is contracted with peak contraction located at a point location in that segment. This pattern of luminal distension is consistent with the concept that the maximal inhibition in the esophagus during peristalsis occurs at one point location, similar to the point location of the peak contraction⁷². Furthermore, the peak inhibition traverses sequentially through the esophagus, similar to the peak contraction. In other words, there is tight coupling between the relaxation and contraction phase of peristalsis. At each location in the esophagus, the esophagus first starts to distend, reaches peak distension, then starts to collapse and finally collapses fully, at which time point the manometry records the contraction (onset of contraction). The peak of contraction occurs later in the course of events, (Figure 10). Alterations in the bolus flow patterns through the esophagus, and the relationship between luminal distension and esophageal contractions, have revealed unique aspects of esophageal motor dysfunction in patients with dysphagia in the setting of normal contraction phase of peristalsis¹⁸¹ (discussed later).

Radiologists have observed for a long time that the most distal part of the esophagus, also known as the phrenic ampulla has a saccular appearance on the barium swallow study,. Esophageal vestibule (likely the relaxed and stretched LES), and a small herniated stomach¹⁸² form the phrenic ampulla. On HRM recordings, the phrenic ampulla is ~ 3 cm long (seen only during peristalsis). It extends from the contraction deceleration point (CDP)¹⁸³ to the crural diaphragm impression (seen rhythmically with each inspiration). The mechanism of phrenic ampullary emptying is different from that of the esophagus; it is related to the descent of an ascended and hypercontracted LES in the chest, back into the diaphragmatic hiatus and abdomen. The LES is hypercontracted following the swallow-induced relaxation in normal subjects. The phrenic ampulla empties only during the expiratory phase of the respiratory cycle¹⁸⁴ because the crural diaphragm contraction with each inspiration is obstructive to the bolus flow from the phrenic ampulla into the stomach. In some patients with dysphagia, impaired LES hypercontraction and high phrenic ampullary pressure lead to impaired phrenic ampulla emptying¹⁸⁵. Instead of emptying into the stomach, phrenic ampulla empties into esophagus, which gives impression of gastroesophageal reflux on the HRM impedance studies and likely on the barium swallow study¹⁸⁵.

Esophageal Motility Disorders

Disorders of esophageal peristalsis are common in general population; they manifest with symptoms of dysphagia, chest pain, heartburn and regurgitation. Management of these patients is a huge burden on the healthcare resources worldwide. For example, in 2015, annual health care expenditure of all GI diseases in the United States totaled $136 billion of which $18.1 billion was spent on the esophageal disorders, most of which was for benign disorders, i.e., reflux disease, its complications and dysphagia. High-resolution manometry (HRM) is the gold standard for recording esophageal peristalsis in the year 2026. The HRM catheters are generally equipped with 36 solid-state pressure transducers (spaced 1 cm apart) and 19 electrodes (2cm apart) to record pressure and intraluminal impedance at closely spaced intervals. Recordings are displayed as topographical plots or heat maps (Figure 3). The computer software programs interpolate values between pressure sensors to display relaxation of the upper and lower esophageal sphincter, sequential esophageal contraction. Along the same line, impedance values record the bolus transit in the esophagus, luminal distension and the spatiotemporal correlation between luminal distension and contraction. The consensus-driven scheme of classifying esophageal motor disorders (EMD) (CC-4.0) is based on the 3 parameters of esophageal and LES contraction parameters: 1) integrated LES relaxation pressure (IRP), 2) latency of contraction in the distal esophagus (distal latency), and 3) the strength of contraction in the distal 10 cm of esophagus (distal contractile integral)⁴². These parameters can be analyzed using various artificial intelligence algorithms and can accurately predict/diagnose various esophageal motility disorders. More recent studies study show that several parameters derived from the spatiotemporal relationship between distension and contraction improve diagnosis of esophageal motility disorders, especially in the setting of normal contraction derived parameters.

There are no animal models of esophageal motor disorders; the precise pathogenesis of EMDs remains unclear. Abnormalities in the parameters recorded by HRM are only the indirect markers of the suspected pathogenesis of EMDs. Achalasia esophagus is the major primary EMD. The HRM recording shows impaired LES relaxation and panesophageal pressurization of the esophagus (instead of peristalsis) in response to swallows in achalasia esophagus. Panesophageal pressurization implies simultaneous increase in pressure, generally of same magnitude throughout the esophagus. The circular muscle contraction is either absent in achalasia esophagus or it is not lumen obliterating contraction. Panesophageal pressurization is likely due to the contraction of the longitudinal muscle of esophagus that results in a decrease in the luminal cross-sectional area^{186, 187}, which in the presence of a closed upper and lower esophageal sphincter results in simultaneous increase in pressure throughout the esophagus; it appears as iso-color columns on the HRM recordings. Depending upon the amplitude of swallow-induced esophageal pressurization, achalasia esophagus is categorized into 3 types: type 1(low or absent pan esophageal pressurization, <20mmHg), type 2 (pressurization of esophagus >20–30mmHg), and type 3 (vigorous esophageal contractions) (Figure 12A)¹⁸⁸. The pattern of esophageal emptying and bolus flow through the esophagus in 3 achalasia subtypes are different, as shown in figure 11B. In achalasia 2 the bolus flows intermittently from the esophagus into the stomach at times when esophageal pressure exceeds LES pressure (Figure 12B). The longitudinal muscle contraction in 3 achalasia subtypes is also different; it is mostly absent in type 1 achalasia, is not in synchrony with the circular muscle in type 2, and relatively normal in type 3 achalasia esophagus (Figure 12C).

Figure 12: Achalasia esophagus 3 types, achalasia 1, 2 and 3 based on the high-resolution manometry and bolus flow.

A: High-resolution manometry (HRM) patterns in 3 types of achalasia. B: Simultaneous HRM and impedance (pink) recording in 3 achalasia types. In type 1, the bolus (pink) stays in the esophagus above the non-relaxing lower esophageal sphincter. In type 2, the bolus flows intermittently through the LES, at the instance when the increase in esophageal pressure exceeds LES pressure. The increase in esophageal pressure in type 2 achalasia is due to longitudinal muscle contraction. In type 3 achalasia, the bolus may clear completely or result in ineffective bolus clearance. C: HRM, impedance (white lines superimposed on HRM) and M-mode ultrasound (US) image at 5cm above the LES in achalasia type 2 (a) and type 3 (b). In type 2, the lumen becomes smaller and muscle thickness increases during swallow-induced esophageal pressurization, also known as pan-pressurization. The increase in the muscle thickness during pressurization is due to the contraction of the longitudinal muscle of esophagus (yellow line on ultrasound image). In type 3 achalasia esophagus, the muscle is markedly thicker compared to normal subject at rest and during contraction it gets thicker further. The luminal distension during pressurization is significantly smaller in patient compared to normal subject.

The histology of the esophageal wall shows loss of inhibitory neurons (NO synthase positive) from the myenteric plexus of the esophagus ^{189, 190}. The degree/extent of neuronal degeneration differs between the 3 types of achalasia, greater in type 1 and type 2, as compared to type 3 achalasia¹⁹¹. In addition, there is a loss of interstitial cells of Cajal (ICC) in the LES of achalasia patients¹⁹². Administration of NO antagonist (recombinant hemoglobin that mops up nitric oxide) in healthy humans results in esophageal motor patterns that resembles achalasia esophagus thus confirming that that loss of inhibitory innervation can indeed produce an achalasia like motor pattern in the esophagus ¹⁰⁶. The histochemistry of muscularis propria from patients with achalasia esophagus shows inflammatory cells, loss of NOS neurons, and replacement of myenteric plexus with fibrosis (Figure 13A). The inflammation is predominantly T cell-mediated with some B cells. One can observe degranulating mast cells in the vicinity of the myenteric plexus^193–196 (Figure 13C); these likely release number of cytokines, which are toxic to myenteric neurons. There is an increase in the antineuronal antibody in the blood of achalasia patients; however, these antibodies are not specific¹⁹⁷ and have been found in patients with reflux esophagitis. Herpes virus, which has affinity for the squamous epithelium with secondary immune inflammation of the myenteric plexus, has been suggested¹⁹⁸ as the cause of myenteric inflammation, but not confirmed by other studies¹⁹⁹. A genetic predisposition with high prevalence of HLA-DQB1 is found in achalasia patients²⁰⁰. In patients with distal esophageal spasm, an infrequent motor disorder, the latency of contraction in the distal esophagus is reduced^{201, 202}. In patients with high amplitude contractions (nutcracker and jackhammer esophagus), an imbalance between excitatory (cholinergic) and inhibitory (NO) innervation is suspected but not proven definitely because of the lack of the availability of esophageal tissue from these patients for histopathologic examination¹⁹¹.

Figure 13: Pathogenesis of Achalasia Esophagus.

A: Histology of esophageal wall reveals inflammation around the myenteric plexus (ganglionitis) with predominantly T cell type immune inflammation, fibrosis and scarred nerves. B: Ultrasound images reveal hypertrophy of circular and longitudinal muscle layers of the esophagus in increasing degrees in patients with high amplitude esophageal contractions, distal esophageal spasm and achalasia esophagus compared to normal. C: Mast cells in the muscle layers (brown color), normal (a), achalasia patient (b) and (c). Unlike normal subjects, the achalasia patients show degranulating mast cells. D: Inhibitory junction potentials recorded from the muscle layers of a control opossum (a) and from an animal with esophageal obstruction (b) Note presence of hyperpolarization/fall in resting membrane potential in control but not in hypertrophic muscle of the obstructed esophagus. (A) Golblum et al. 1996 (189), used with permission. (C) Nelson et al. 2021 (204), used with permission. (D) Conkin et al. 1991 (205), used with permission.

The muscularis propria of patients with achalasia esophagus, distal esophageal spasm, high-amplitude esophageal contraction, and in many patients with dysphagia symptoms yet normal HRM study show evidence of hypertrophy of the circular and longitudinal muscles of esophagus⁵⁸ (Figure 13B). It might be that changes in the esophageal musculature are secondary to esophageal obstruction caused by impaired relaxation/opening of the LES. In a partially obstructed model of opossum esophagus, Tung et al observed changes in the esophagus that resemble findings in patients with achalasia esophagus, i.e., esophageal dilation, muscle hypertrophy, (Figure 13D), infiltration of the esophageal wall with degranulating mast cells^{193, 194, 203, 204} and loss of inhibitory innervation of the circular muscles of the esophagus ²⁰⁵. Nelson et al observed degranulating mast cells in the lower esophageal sphincter of patients with the achalasia esophagus^{203, 204}. One of the complications of laparoscopic gastric band surgery in humans is achalasia esophagus (secondary achalasia) ^{206, 207}. In some of the gastric lap band-induced secondary achalasia patients, esophageal peristalsis returns to normal after removal of the gastric band. On the other hand, in other patients, the loss of peristalsis is permanent, similar to what is described in patients with idiopathic achalasia. The latter might be due to the degeneration of the myenteric neurons. Above observations suggest that impaired LES relaxation/opening might be the root cause of achalasia esophagus (idiopathic variety), which leads to the loss of myenteric neurons in the body of the esophagus and aperistalsis. Goyal & Rattan speculate that a mechano-transduction pathway in the smooth muscle esophagus drives immune-mediated inflammation; it stimulates muscle hypertrophy and degeneration of myenteric neurons²⁰⁸. Smooth muscle cells, in response to mechanical stretch, release several cytokines that attract mast cells in the vicinity of muscle cells, which then release mediators of muscle hypertrophy and neuronal degeneration. A similar or mechano-transduction mechanism is operative in patients with bronchial asthma, where eosinophils and mast cells induce hyperplasia and hypertrophy of the bronchial smooth muscle cell. It might be that the hypertrophic muscle results in spasticity initially, i.e., high amplitude contraction, and in later stages it leads to the loss of contractility and degeneration of myenteric neurons.

Recent studies found that the fat pad (phrenoesophageal pad fat) present in the esophageal hiatus of normal subjects is replaced by the fibrous tissue in patients with achalasia esophagus^{209, 210} (Figure 14A–D). With axial shortening of the esophagus during peristalsis, the LES located in the esophageal hiatus and abdomen, slides into the chest. It results in the formation of a phrenic ampulla or transient (physiological) hiatus hernia (Figure 14C). Phrenoesophageal fat pad under normal physiological conditions likely functions as a lubricant to allow the LES to slide from the hiatus into the chest during peristalsis. A sliding hiatus hernia is rare in patients with achalasia esophagus²¹¹, which can be explained on the basis of fibrosis in the esophageal hiatus. The latter anchors the LES to crural diaphragm and prevents formation of a sliding hiatus hernia. It might be that fibrosis in the hiatus of esophagus, by restricting axial shortening of the esophagus, impairs LES relaxation and reduces compliance of the esophagogastric junction, both of which then become obstructive to the esophagus. Fibrosis in the hiatus of the esophagus is also present in patients with less severe forms of esophageal motility disorders, such as high-amplitude esophageal contractions²¹², esophagogastric junction outflow obstruction (EGJOO)²¹³, and even in patients with dysphagia symptoms with normal esophageal motility (functional dysphagia)²¹⁴, albeit to a lesser degree than in achalasia esophagus. Studies also show that there is an increase in fibrous tissue in the muscularis propria of the LES in patients with achalasia esophagus^{215, 216}.

Figure 14: Hiatal Fat and Hiatal Fibrosis.

A: Normal subjects contain a pad of fat between the two leaves of the phrenoesophageal ligament (phrenoesophageal pad fat), which allows the lower esophageal sphincter to slide out of the hiatus into chest during peristalsis, when there is axial shortening of the esophagus. B: In patients with achalasia esophagus, swallow-associated pan pressurization is not accompanied by axial shortening and separation between the crus of the diaphragm and LES, the two are glued together due to replacement of the phrenoesophageal fat pad with fibrosis. CT image of the esophageal hiatus from a normal subject (C) and a patient with achalasia esophagus (D). Note the ground glass appearance of the esophageal hiatus in the patient with achalasia esophagus.

Relaxation and opening of the LES are two distinct functions. The former is related to the inhibition of active LES muscle tone, and is a neurogenic event (induced by the release of NO from the inhibitory motor neurons). On the other hand, the LES opening depends upon the passive/viscoelastic elements of the LES and surrounding structures (phrenoesophageal fat pad, hiatal fibrosis, right crus of the diaphragm). While LES relaxation can be measured with manometry techniques, the LES/esophagogastric junction opening is best measured by the FLIP. It records the relationship between the intraluminal luminal cross-sectional area and pressure, also known as esophagogastric junction distensibility. Studies show that low distensibility of the EGJ is sensitive but not specific marker of patients with achalasia esophagus^{217, 218}. A low EGJ distensibility implies low compliance and impaired opening of the EGJ (relative outflow obstruction), which can be due to the active (muscle contraction) and/or passive (viscoelastic) properties of the EGJ^{219, 220}. Lack of LES relaxation due to impaired inhibitory innervation, along with changes in the viscoelastic elements (fibrosis) of the LES and surrounding structure, are likely causes of low distensibility of the EGJ. Studies show that some patients with achalasia esophagus have normal LES relaxation²²¹ yet reduced distensibility, suggesting that the passive properties of the LES and surrounding structures are important players in the pathogenesis of achalasia esophagus. Some achalasia patients who continue to have symptoms after adequate surgical myotomy have reduced distensibility of LES ²²². The latter is also found in patients with distal esophageal spasm, high-amplitude esophageal contractions, and in many patients with dysphagia who have normal esophageal manometry studies (functional dysphagia)²²³. In other words, obstruction at the level EGJ (impaired relaxation and or opening) seems to be a common theme in all primary esophageal motility disorders. Esophageal obstruction can lead to secondary changes in peristalsis¹⁶⁸ and neuromuscular abnormalities^{193, 194 205} seen in patients with primary or idiopathic EMD. It might be that all esophageal motor disorders are forms of obstructive esophago-myopathies, the primary dysfunction is at the level of lower esophageal sphincter (impaired LES relaxation and or impaired opening). The changes in the body of the esophagus, i.e., dilation of the esophagus, esophageal muscle hypertrophy, loss of myenteric plexus and inhibitory motor neurons are secondary to the EGJ obstruction.

Treatment of obstructive LES is the mainstay of treatment of achalasia esophagus; it can be accomplished in several ways, injection of botox, endoscopically into the LES, which provides temporary (3–6 months) relief of symptoms. Definitive and long-term symptom relief requires either surgical (Heller myotomy) or per oral endoscopic myotomy (POEM). Pneumatic or forceful dilation of the LES using balloons (30mm, 35mm or 40mm) is also an effective treatment, but the symptom relief does not last as long as myotomy²²⁴. Gastroesophageal reflux following POEM is common and requires careful patient follow-up²²⁵. Esophageal peristalsis may return following treatment of obstructive LES in a minority of patients with achalasia esophagus^{226, 227}. However, it is possible that peristalsis was present even before myotomy, but the manometry technique could not record it accurately because it can’t distinguish between the bolus pressure and contraction pressure. A high bolus pressure is usually present in the setting of an obstructed esophagus. Patients with type 3 achalasia and distal esophageal spasm require long myotomy, extending up to the aortic arch, the reason of which is that these patients have significant hypertrophy of muscularis propria that reduces opening function of the esophagus during the inhibitory phase of peristalsis. Patients with symptomatic high amplitude contractions (angina like pain) can be managed with smooth muscle relaxants (calcium channel blockers), donors of NO (nitroglycerine or long-acting nitrates) or botox injection into the distal esophagus.

Hypotensive Esophageal Peristalsis

Low amplitude but sequential or peristaltic esophageal contractions are seen in the setting of 1) gastroesophageal reflux disease²²⁸ (damage from acid), 2) systemic sclerosis or scleroderma esophagus (loss of muscle)^{229, 230}, and 3) lung disease such as chronic obstructive or restrictive lung disease²³¹. Acid-induced esophagitis is not a simple burn to the lining of the esophagus, instead it is mediated by the release of number of cytokines (immune response) and ultimately an inflammatory response that leads to mucosal ulceration²³². Animal studies show that perfusion of acid into the cat esophagus for half an hour for 4 days results in significant reduction in the LES pressure²³³, by impairing a signal transduction mechanism that mediates the release of intracellular CA² stores in response to acetylcholine²³⁴. On the other hand, there was no such effect observed in the circular muscle of the esophagus, that utilize extracellular CA². Acid-induced esophagitis impairs acetylcholine release from the nerve terminal²³⁵. The effect of acid on the circular muscle contraction is mediated by platelet-activating factor (PAF) that is secreted by the squamous epithelium of the esophagus. It initiates a cascade of events, ultimately leading to the activation of NADPH oxidase in the circular muscle to produce H2O2, which is ultimately responsible for the reduction of circular muscle contraction. Catalase, a scavenger of H2O2 restored LES hypotension in a human organ donor sample that had reflux esophagitis²³⁶. The molecular/cytokinin cascade in the human sample was found to be similar to the acid-induced esophagitis in the cat²³⁷. The damage caused by chronic acid reflux is not reversible; healing esophagitis with proton pump inhibitor does not restore low-amplitude contraction²³⁸.

Hypotensive esophageal peristalsis is common in patients with systemic sclerosis/scleroderma esophagus and other connective tissue disorders. Its pathogenesis is related to several factors^{239, 240}, i.e., fibroproliferative vascular lesions of small arteries and arterioles, fibrosis in the muscular propria of the esophagus²³⁰, and increase in the production of pro-fibrotic growth factors such as transforming growth factor-β (TGF-β), connective tissue growth factor, and insulin-like growth factor. Multiple alterations in innate, humoral and cellular immunity result in the accumulation of Th2 lymphocytes and the production of numerous autoantibodies. The serum from patients with systemic sclerosis contains antibodies that bind to muscarinic receptors on the smooth muscle cells and myenteric neurons, which prevent the actions of acetylcholine²⁴¹. It is suggested that the genesis of antimuscarinic antibodies occurs early in the disease and may be amenable to treatment with intravenous immunoglobulin and immunosuppressive therapy²⁴¹. The pathogenesis of hypotensive esophageal peristalsis in patients with chronic lung disease may be related to acid reflux disease which is common in these patients²⁴².

Hypotensive peristalsis is more common in the setting of restrictive as compared to obstructive lung disease. It is also associated with a higher rate of rejection following lung transplantation, as compared to patients with normal peristalsis. It may be related to aspiration of reflux material. Studies also show reversal of hypotensive peristalsis following lung transplant^{243, 244}, which might be due to alteration in the length of esophagus related to the position of diaphragm (smaller in restrictive lung disease and greater in obstructive disease) that can affect the length-tension relationship of esophageal muscles.

Motor Disorders and Bolus Flow in Esophagus

Each swallow can be separated into two phases or two domains on the manometry recordings. Soon after the onset of swallow bolus traverses through the esophagus (bolus domain) followed by esophageal contraction (contraction domain). There is no bolus present in the esophagus during the contraction domain under normal circumstances. The current scheme of classification of esophageal motor disorders, Chicago 4.0, is based on the contraction domain of peristalsis⁴². Significant number of patients with dysphagia yet normal HRM studies by Chicago Classification have alterations in the bolus domain of peristalsis that suggests alteration in the bolus flow patterns through the esophagus that is suggestive of esophageal motor dysfunction⁵⁵. The spatiotemporal relationship between bolus flow and contraction phase of peristalsis can provide important information in assessing esophageal motor dysfunction in these patients, who otherwise appear to have a normal contraction phase of peristalsis. Omari and colleagues were the first one to observe that in the distal esophagus of patients with non-obstructive dysphagia, a 5ml bolus swallow resulted in intraluminal nadir impedance value that were higher (lower admittance, or smaller luminal distension) than those of normal subjects²⁴⁵. Furthermore, they found that nadir impedance occurred closer to the esophageal contraction (in time) as compared to normal subjects. Several parameters, derived from the impedance and pressure values (automated impedance manometry or AIM analysis) distinguished non-obstructive esophageal motility disorders patients from controls^{245, 246}, which set the stage for the distension contraction plots of esophageal peristalsis. Esophageal distension during peristalsis depends upon the active relaxation and passive (biomechanical) properties of the esophagus. The spatiotemporal relationship between distension contraction plots reveals two major abnormalities in dysphagia patients with a normal contraction phase of peristalsis: 1) the luminal distension/ luminal cross sectional area during peristalsis is smaller in patients compared to controls and, 2) distension during peristalsis occurs either earlier or later in reference to the onset of swallow or the contraction phase of peristalsis in patients, as compared to controls¹⁸¹ (Figure 15). Based on the principles of bolus flow, a faster velocity of bolus flow through the esophagus is expected if the pharyngeal pump were to propel a bolus through a narrow lumen esophagus as opposed to a wide lumen one. Luminal distension wave travelling closer to the contraction wave implies luminal closure distal to esophageal distension. Furthermore, the intraluminal pressure in the distal esophagus, during the bolus flow is greater in patients, which along with a smaller luminal CSA implies a stiffer esophageal wall (low compliance) as compared to controls²⁴⁷. In some patients, the two waves, luminal distension and pressure, overlap with each other, suggestive of greater abnormality in the relaxation phase of peristalsis²⁴⁸. The reason for alteration in bolus flow pattern can be best explained on the basis of biomechanical factor during peristalsis described in the next paragraph.

Figure 15: Distension Contraction Plots from a control subject and a patient who had significant dysphagia but normal esophageal manometry study.

Contraction, shown as color heat map that follows behind the distension. In patient with dysphagia but normal manometry, the luminal distension is smaller and there is an alteration in the temporal relationship between distension and contraction.

Biomechanical Factor in Esophageal Peristalsis & Bolus Flow

Lengthening of a tube in the axial direction leads to a reduction in its circular dimension (law of mass conservation), and it renders the esophageal wall less compliant^{15, 177}. Both of these factors affect the luminal cross-sectional area and bolus flow through the tube, which can be considered as the biomechanical factors of peristalsis. Biomechanical factors are often not considered in terms of their effect on bolus transit through the GI tract/esophagus because they can’t be observed using routine intraluminal pressure recordings or manometry. Circular and longitudinal muscle contraction during peristalsis affect the non-contracted segments (above and below the site of contraction) (Figure 16A & B). For example, the lift of hyoid and cricoid cartilages during oropharyngeal phase of primary peristalsis increases circumferential wall tension in the cervical esophagus which decreases the luminal cross-sectional area ¹⁵. The longitudinal muscles of the esophagus originate from the cricoid cartilage and are inserted into the sling fibers of the LES at the esophagogastric junction²⁴⁹. The LES is attached to the crus of the diaphragm by the phreno-esophageal ligament²⁵⁰. The esophageal segments above and below the contracted segment during peristalsis are stretched (elongated) due to the axial shortening of the esophagus in the contracted segment⁶⁵. The LES slides out of its normal location in the diaphragmatic hiatus/abdomen; it moves into the chest during peristalsis in normal subjects, which prevents excessive stretching/lengthening of the segment distal to the contracted segment. On the other hand, if the LES were to be tethered firmly to the diaphragmatic hiatus because of the replacement of phreno-esophageal fat pad by fibrosis, it results in a narrow lumen esophagus and even the closure of esophagus distal to the site of contraction (Figure 16 C). The luminal closure distal to the contraction wave results in the intraluminal pressure that is obstructive to the bolus flow. Recent studies show mismatch between the presence of bolus and “bolus pressure” in the bolus domain of peristalsis, which is explained based on the dynamic obstruction during peristalsis related to biomechanical effects of peristalsis in patients with esophagogastric junction outflow obstruction and “functional dysphagia”^{251, 252}. Indeed, many patients with dysphagia who have normal contraction phase of peristalsis have a narrow lumen esophagus ahead of the contracted segment during bolus transport, as revealed by the distension-contraction plots of esophageal peristalsis^{181, 253, 254}. Besides tethering of the LES to hiatus, there are many other reasons for a narrow lumen esophagus ahead of the contracted segment, such as discoordination between circular and longitudinal muscle during peristalsis⁵⁸ (Figure 17 A–C), hypertrophy of esophageal muscles (seen in patients with primary esophageal motility disorders)²⁵⁵, increase in connective tissue (scleroderma esophagus) and inflammation induced fibrosis (eosinophilic esophagitis and reflux esophagitis). Patients with abnormalities in the passive properties are likely the ones, currently labelled as “functional dysphagia²⁵⁶. In this regard, FLIP is a powerful tool to assess the biomechanical properties of the esophageal wall and esophagogastric junction (LES) and has provided important insights. Studies show that the esophageal distensibility is low in patients with eosinophilic esophagitis²⁵⁷. The FLIP recordings have also revealed low distensibility of the esophagogastric junction in patients with the achalasia esophagus²²² and, to a lesser degree, in patients with other primary esophageal motility disorders^{223, 258}. While loss of inhibitory innervation is the hallmark of primary esophageal motility disorders, low distensibility of the LES, which is a passive property of the LES implies structural changes (fibrosis) in the LES and surrounding tissues²⁰⁹. The hiatal fibrosis is like an anchor between the crus of the diaphragm and the LES; it prevents sliding between the two structures. Impaired axial shortening of the esophagus can lead to impaired LES relaxation, which can result in secondary changes in the body of the esophagus. Tung et al found that obstruction to the esophagus results in secondary changes in the body of the esophagus^{194, 259} that resemble findings seen in achalasia esophagus, i.e., esophageal dilation, muscle hypertrophy, including loss of inhibitory innervation of the circular muscles of the esophagus and LES ²⁰⁵.

Figure 16: Biomechanical Effects of Contracted Segment on Non-Contracted Segment of Esophagus During Peristalsis.

A: Stretching the esophagus in the longitudinal direction results in an increase in circumferential stress on the esophageal wall in an ex vivo preparation of the esophagus. B: Effect of physical elongation of the esophagus on basal circumferential tension and reflex-activated contraction of the esophagus. The figure shows that applying a force of 50 gm to pull the cervical esophagus distally increased the basal circumferential tension of the esophagus (E2 SG, about 5 gm) and increased the maximal response of the esophago-esophageal contractile reflex (EECR) at each distension volume. Physical esophageal elongation increases basal and active esophageal circumferential tension without a change in EMG. CP = crico-pharyngeus; E#, esophagus number of centimeters from the CP; Eso Long, esophageal longitudinal; EMG, electromyography; g, gram; SG, strain gauge; Stim, EECR stimulation volume distension. C: Segmental shortening of the esophagus during peristalsis (related to longitudinal muscle contraction) in the contracted segment results in pulling of the LES from the hiatus into the chest in normals (b). Fibrosis in the esophageal hiatus results in tight anchoring between the LES and crus of diaphragm. As a result, segmental shortening in the contracted segment results in passive elongation and a narrow lumen esophagus distal to the contraction (smaller luminal distension) during distension phase of peristalsis. (A&B) Lang et al. 2023 (15), used with permission.

Figure 17: Discoordination between the Circular & Longitudinal Muscles of the Esophagus.

A: Concurrent circular and longitudinal muscle recording from a normal healthy subject: changes in pressure (gray line) and muscle thickness (white line), over time, are superimposed on the M-mode ultrasound image of the esophagus at 5 cm above the LES. Note, that the peaks of circular and longitudinal muscle contractions are aligned indicating synchrony between the two muscle layers. B: Concurrent circular and longitudinal muscle recording from a patient with high amplitude esophageal contraction: changes in pressure (gray line) and muscle thickness (white line) over time are superimposed on the M-mode ultrasound image of the esophagus at 5 cm above the LES. Note, that the peaks of circular and longitudinal muscle contractions are separated by 3.5 seconds indicated discoordination between the two muscle layers. C: Concurrent circular and longitudinal muscle recording from a normal subject and 2 patients with eosinophilic esophagitis (EO-1) and (EO-2): Esophageal manometry (the bottom panel) which records only the circular muscle contraction is normal in all 3 subjects. Changes in muscle thickness (yellow line) and pressure (purple line) shows synchronous contraction of the two muscle layers in normal subject and discoordination in patients with eosinophilic esophagitis.

Heartburn and Esophageal Pain

Heartburn and “angina-like” non-cardia esophageal pain symptoms are extremely common in the USA and worldwide. 15–35% of the world’s population²⁶⁰ suffer from heartburn symptoms and 15–30% of the coronary angiograms performed for chest pain thought to be cardiac in origin are actually normal. The esophagus is likely to be the source of chest pain in majority if not all of these patients. Acid reflux and esophageal dysmotility (high-amplitude esophageal contractions⁶¹, distal or diffuse esophageal spasm and achalasia esophagus) are important causes of heartburn and esophageal pain symptoms. Proton pump inhibitors, the revolutionary medication to treat acid reflux-related symptoms, have been around for more than 40 years. The annual sale of these medications (billions of dollars) is a testament to their effectiveness in relieving symptoms in a significant number of patients. However, it is also clear that they are more effective in healing esophagitis than treating heartburn and chest pain, raising questions on the genesis of these symptoms²⁶¹. Prolonged pH monitoring or concurrent pH and manometry recordings in patients with heartburn and chest pain reveal poor correlation between acid reflux and abnormal motility with heartburn^262–264 and chest pain symptoms^265–267. Bear in mind that manometry records only the circular muscle contraction (not longitudinal muscle) of the esophagus. Ultrasound imaging, along with the manometry recordings, reveals a strong temporal correlation between the long-duration longitudinal muscle contractions (detected by ultrasound imaging) and heartburn²⁶⁸ and chest pain events²⁶⁹. Blood flows in the esophageal wall only in between the esophageal contractions. The longitudinal and or circular muscle contraction restricts the blood flow entry into to the esophageal wall^{270, 271}, similar to myocardial blood flow that enters myocardium during diastole, and not during systole. Patients with chest pain have lower blood perfusion of the esophageal mucosa as compared to normal subjects²⁷². Therefore, low perfusion or relative ischemia of the esophageal wall can be the source of pain in many patients with esophageal motility disorders, which explains why some patient’s chest pain responds to vasodilator medications such as nitroglycerine and calcium channel blockers.

Heartburn and chest pain are examples of visceral pain, they are neither site nor stimulus specific²⁶¹. Besides acid, distension of the esophagus²⁷³ and esophageal muscle spasm can cause heartburn²⁶⁸ and chest pain²⁶⁹. Furthermore, the same stimulus, i.e., acid or distension or muscle spasm may induce heartburn and chest pain, depending upon the intensity of the stimulus²⁷⁴. In experimental studies, esophageal distension is perceived as heartburn at low levels of distension and chest pain (pressure squeeze) at the high levels of distension^{273, 275}. The esophageal distension-induced sensation is not affected by atropine that blocks muscle contractions, which suggests that the stretch (strain) of the esophageal wall is an important stimulus for painful sensation²⁷⁵. Patients with esophageal pain have a lower threshold of distension-induced pain^{276, 277}, and hypercontractile esophagus²⁷⁸. Repeated infusion of the esophagus with acid²⁷⁴ and distension increases pain perception, hyperalgesia, and allodynia. Hyperalgesia implies hyperresponsiveness to painful stimuli (acid or distension) and allodynia means non-painful stimulus perceived as painful. Elegant studies by Aziz et al reveal that esophageal hypersensitivity can be located on the nerve terminals in the mucosa/submucosa (peripheral)²⁷⁹, or at the level of the spinal cord and cerebral cortex (central)^280–282. Recent studies show that esophageal mucosal sensory nerve endings are located closer to the lumen in the proximal esophagus as compared to the distal esophagus in normal subjects²⁸³. Furthermore, in patients with hypersensitive esophagus, these nerve endings are more superficial compared to controls, which may provide easy access for the luminal contents^{284, 285}. Acid sensitive ion channels (ASIC) and capsaicin sensitive vanilloid receptors (sensitive to heat, pH and capsaicin) are potential candidates for the acid and distension-induced esophageal sensation^286–288.

Summary

Mechanism of esophageal peristalsis or sequential contractions of the skeletal and smooth muscle esophagus resides at multiple levels, i.e., brain stem (central pattern generator), neurons within the wall of the esophagus (myenteric plexus) and smooth muscle (myogenic). Esophageal peristalsis, similar to the other areas of the GI tract (colon), consists of initial inhibition followed by excitation. Experimental studies show number of similarities between the peripheral control of peristalsis in the esophagus and colon, especially with regards to the relationship between longitudinal and circular muscle contraction. There may be parallel pathways, inhibitory and excitatory, from the central program generator (CPG), that travel via vagus nerve and communicate with the inhibitory and excitatory neurons of the myenteric plexus in the esophageal wall, respectively. However, another possibility is that the inhibitory phase of peristalsis in the smooth muscle esophagus is due to the mechanosensitive inhibitory neurons of the myenteric plexus, activated by the longitudinal muscle related axial stretch. The biomechanical effects of the contracted segment on the non-contracted segment of esophagus during peristalsis have not received consideration; they likely play a critical role, both in physiology and pathophysiology. Under physiological conditions, stretch on the esophagus in the cranial direction due to the lift of the cricoid and hyoid bone during the oropharyngeal phase of primary peristalsis may cause deglutitive inhibition in the smooth muscle esophagus. Along the same line, longitudinal muscle contraction in the contracted segment of the esophagus during primary/secondary peristalsis exerts mechanical stretch on the segment distal to the contracted segment, which may result in the activation of mechanosensitive inhibitory motor neurons. The role of the longitudinal muscle in esophageal peristalsis has not been fully appreciated. It is likely that it plays a critical role in the descending relaxation of the peristaltic reflex. Primary and secondary peristalsis are associated with concurrent contraction and relaxation of the circular and longitudinal muscle layers in the contracted and relaxed segments of the esophagus. On the other hand, stimulation of the peripheral end of the vagus nerve induces opposite responses in the two layers, i.e., contraction of longitudinal and relaxation of the circular muscle layers of the esophagus. Whether the excitatory phase of peristalsis is due to the excitatory cholinergic nerves of the myenteric plexus or entirely due to post-inhibitory rebound excitation of the smooth muscles remains to be fully resolved. The stretch induced, i.e., balloon distension or mechanical pull-related responses in the circular and longitudinal muscle layers of the colon have significant relevance to our understanding of the peristaltic reflex have relevance to esophageal peristalsis.

There is general consensus that in achalasia esophagus, there is loss of inhibitory motor neurons in the myenteric plexus of esophagus. The cause of inflammation and fibrosis in the myenteric plexus and loss of inhibitory nerves in the myenteric plexus remains obscure. It might be that fibrosis in the hiatus of esophagus leads to impaired LES relaxation and changes seen in the esophagus in esophageal motility disorders are secondary to obstruction caused by impaired LES relaxation. The esophageal hiatus, formed by the right crus of the diaphragm, is located in close proximity to the thoraco-lumbar spine. A recent epidemiological study found a high prevalence of thoracolumbar spine symptoms in patients with esophageal symptoms¹⁸⁵. Degenerative changes in the lumbar spine lead to degenerative changes in the muscles attached to the spine^{289, 290}. Whether the right crus of the diaphragm and esophageal hiatus fibrosis is due to the pathology in thoracolumbar spine requires further exploration.

Unanswered Questions and Future Research

The focus of work on esophageal peristalsis has been mainly on the circular muscle layer for a very long time; clinical esophageal motility studies, even in the year 2026 only assess the circular muscle function of esophagus. There are many unanswered questions with regard to the role of longitudinal muscle in esophageal peristalsis under normal and pathological conditions; 1) Does vagus nerve innervate the circular and longitudinal muscles differently? 2) Does vagus nerve contain only the excitatory efferent fibers; the inhibitory phase of peristalsis is related to the longitudinal muscle contraction related deformation and activation of the inhibitory motor neurons in the myenteric plexus through a mechanosensitive pathway? 3) In achalasia esophagus there is degeneration and loss of only the inhibitory neurons, what happens to the excitatory neurons? 4) The longitudinal muscle contraction of the esophagus is still present in achalasia esophagus. Does it mean that there is loss of excitatory nerves of the circular and not the longitudinal muscle layer? Maybe the circular muscle contraction in the distal esophagus under normal conditions is entirely a rebound excitation following nitrergic inhibition. Maybe degeneration of inhibitory neurons in myenteric plexus causes impairment of LES relaxation and impaired circular muscle contraction? What is the mechanism of discoordination between the two muscle layers, and how important is it in causing dysphagia and chest pain? 5) From a clinical perspective, what is the root cause of esophageal motility disorders? Is fibrosis in the hiatus of esophagus ²³¹ the root cause of all primary esophageal motility disorders, and if so, what is the cause of hiatal fibrosis? The treatment of dysphagia, heartburn, and chest pain is a massive burden on the health care budget. A better understanding of the pain receptors and treatment strategies is desperately needed.

Clinical Highlights.

• Esophageal peristalsis (primary & secondary) consists of initial inhibition followed by excitation, both of which travel sequentially from oral to aboral direction. Mechanisms of esophageal peristalsis reside at the level of brainstem, myenteric plexus and smooth muscles.

• Muscularis propria of the esophagus consists of two layers, circular and longitudinal, both of which contract and relax together during peristalsis and antegrade transport through the esophagus. On the other hand, there is selective contraction of the longitudinal muscle during retrograde transport through the esophagus, i.e., during reflux and vomiting.

• Impaired peristalsis that results in symptoms such as dysphagia, chest pain and possibly heartburn is due to dysfunctional smooth muscle of distal esophagus and loss of inhibitory motor neurons of the myenteric plexus. Chest pain and heartburn, not related to acid reflux are likely related to the longitudinal muscle contraction that is not recorded by manometry; it requires tools that are not user friendly at the present time.

• Abnormal bolus flow patterns through the esophagus result in altered spatiotemporal patterns of luminal distension and contraction during peristalsis that explains dysphagia in many patients who appear to have normal peristalsis.

• Obstruction related to impaired relaxation/opening of the lower esophageal sphincter affects esophageal peristalsis, smooth muscles and myenteric plexus that resemble changes observed in primary/idiopathic esophageal motor disorders. Phrenoesophageal fat pad located in the hiatus of esophagus in healthy subjects is replaced with fibrosis and may be the primary cause of dysfunctional LES in primary esophageal motility disorders.