Introduction

Remarkable progress has been made in the study of gastrointestinal (GI) motility, particularly gastric motility, in the last century. This progress in GI motility has proceeded from contributions of a wide range of disciplines with advances in smooth-muscle physiology, electrophysiology, neurohormonal regulation of the GI tract, anatomic/mechanical factors, flow dynamics, as well as basic molecular and cellular biology. Increasingly sophisticated instrumentation, biomedical engineering, and pharmaceutical research have also added to this rich harvest over the past 50 years. A central theme to the progress is the greater understanding of the enteric nervous system, where more than 10 ⁶ neurons intercommunicate and integrate messages from the gut and brain to organize and coordinate control of GI motility.

The measurement and quantitation of gut motility has been a constant goal during this era, particularly the study of peristaltic contractions. The measurement of intraluminal pressures started with the use of balloons inflated in the stomach and intestine. In the 1950s, open-tipped catheters began to be used to study the esophagus. Subsequent improvements included the continuous-perfusion catheters with the low-compliance Arndorfer pump, and the development of the Dent sleeve which have facilitated the study of sphincters. At the turn of the century (1900s), gastric flow could be imaged by means of contrast radiograph. By the 1980s, scintigraphy enabled flow studies throughout the GI tract to be performed routinely in clinical practice. Scientific investigation of gut wall movement began with the use of miniature force transducers sewn to the luminal wall. Electromyography has also been used to enhance our understanding of wall movement. Magnetic resonance imaging (MRI) can be used to correlate gut wall motion with intraluminal pressures and other physiologic parameters.

Basic research has focused on neurohormonal regulation and myogenic components of GI motility. In the 1930s, gut motor activity was believed to occur as a result of opposition between excitatory parasympathetic (cholinergic) and inhibitory sympathetic (adrenergic) nerves. Electrical field stimulation of gut muscle preparations led to the discovery of nonadrenergic non-cholinergic (NANC) nerves as the predominant intrinsic inhibitory nerves of the GI tract. The identity of the NANC neurotransmitters, including vasoactive intestinal polypeptide (VIP) and nitric oxide then evolved. Electrical slow waves were appreciated to govern the rhythmicity of contractions, and slow waves of the stomach and small bowel began to be studied extensively by muscle electrophysiologists in the 1950s and 1960s.

W.B. Cannon and F.T. Murphy in 1906-7 reported that gastric emptying and intestinal motility may be inhibited by both central and peripheral mechanisms. In 1943, Wolf and Wolff suggested that certain emotional states can alter gastric motility, secretion and blood flow. Ongoing research defined the influence of GI peptides and hormones on the migrating motor complex (MMC). In a review 10 years after the demonstration of the migrating complex, Wingate noted that neural and hormonal factors are involved in regulation, but ‘specific details remain blurred’ – an observation which is slowly being unraveled.

This chapter is focused on more than a century of historical perspective to help us understand where we are today in the study of gastric motility.

Observation of flow through the gastrointestinal tract

Aside from Beaumont’s famous opportunity in the 1830s in his patient with a gastric fistula , no one had any way to examine directly the flow of the gut until more than 50 years later. Beaumont could only make a crude evaluation of gastric flow because his patient’s fistula extended into the fundus, and so Beaumont’s experiments on flow depended on the measurements of residual volumes collected by aspiration. However, he was more interested in gastric juice and digestion than gastric emptying.

The great impetus to the study of flow came with the development of the x-ray tube at the end of the 19th century. Roentgen’s development of the concepts and methods for x-ray soon found application in the study of gastrointestinal flow. The pioneers Bowditch and Cannon examined the stomach and intestine by contrast radiography before the turn of the century . Cannon and others were mainly interested in gastric motility and adopted contrast radiography as a new means to visualize peristalsis and flow from the stomach. Physicians soon recognized the ability of contrast radiography to demonstrate morphologic lesions in the stomach. Hurst led this advance in the clinical use of radiography . The use of contrast films to observe flow extended to the other organs, including the colon. The biggest problem in the study of flow in the stomach and intestine was the need for rapid changes of film, a need that was resolved only when rapid film-chargers and cineradiography were developed.

By 1933, radiographic techniques had revealed so much that an authoritative textbook could be written on the digestive tract from the point of view of the radiologist . It contained extensive descriptions of flows in all the organs as well as descriptions of peristaltic wall movements and morphologic abnormalities. The descriptions still appear quite modern to the contemporary reader.

Observations by contrast radiography are hard to quantify, cannot easily be repeated for verification, are usually performed with the subject fasting, and use a remarkably unphysiologic material. These problems of radiography to demonstrate motility were overcome with the development of scintigraphy in the 1980s . Scintigraphy made it feasible to do flow studies in routine clinical practice and made flow study more sensitive.

Before the advance of scintigraphy, Hunt had developed a beautifully simple and direct method to advance understanding of gastric emptying, especially of its regulation . He used test meals – liquid volumes of variable composition – passed through a nasogastric tube in various volumes and aspirated at variable times afterward to discover the residual volume. He used anaesthetized human subjects, studying the same subjects repeatedly because habituation eliminates the inhibition produced by anxiety. Thus, he was able to develop data for the rate of gastric emptying as it is regulated by meal composition .

Most discussions of flow in the gut have dealt with bulk flows, the mass translocations of fluid. Interest in microflows came about from theoretic considerations of intestinal absorption, in which the presence of an unstirred layer at the luminal surface of the intestine came to be recognized as a limitation to the rate of absorption. Little can be done to study microflows directly, because it requires the use of the principles of fluid mechanics, a discipline that is largely as foreign to gastrointestinal physiologists as gastrointestinal physiology is foreign to fluid-mechanists. The fluid mechanist, Mecagno, who had extensive experience on flow in rivers and seas, was curious about flow in a system that seemed unique to him. A fluid-mechanical approach to flow in the small intestine by Christensen and Macagno yielded a foundation for rigorous rheologic study of gastrointestinal microflow and a host of new methods and ideas in the 1970s , an area that remains to be explored more fully.

Observation of pressures in the gastrointestinal tract

The idea that one could study wall motions by the measurement of pressures in the gut lumen, by kymography (or manometry, as it came to be called later), arose quite early, even before the development of radiographic methods to study flow. It began largely with the use of balloons inflated in the stomach and intestine, a method used notably by Bayliss and Starling , Carlson , and Thomas , among others. Investigators could record pressure changes in such balloons easily enough, but they had much trouble interpreting the records. They slowly came to confront the problems of balloon recording, which seem so obvious to us today. The size of the balloon, degree to which it stretches the viscus wall, the compressibility of the recording fluid, and the compliance of the system all restrict the reliability of conclusions about the external forces that alter the pressure in such a closed recording system.

The idea of using open-tip catheters rather than balloons to record pressures was explored in the 1920s, but it was most aggressively developed in the 1950s mainly to examine the esophagus. The principal players in this development, which included Code and Ingelfinger , probably sought, at the outset, simply to measure pressures rather than to fully map peristaltic movements. At first, they used air-filled catheters, later changing to water-filled tubes. They adopted catheters with distal openings placed laterally rather than at the tip of the catheters and observed that, in the esophagus, they could measure the characteristics of peristalsis – velocity and force of contraction – with apparent reproducibility and accuracy. The method was soon improved by Dodds and Hogan , and others with the introduction of the continuous perfusion of the catheters with a low-compliance pump (the Arndorfer pump, developed by a colleague of Dodds) and other changes, and the technique soon passed into standard clinical use to describe esophageal motor functions. The technique subsequently has found use in the small intestine, but is used much less in the stomach and colon. Subsequent experimentation with methods led to developments of much more complex devices in which pressures are measured from miniature pressure transducers mounted on flexible catheters. These devices, combined with computer-aided analysis of pressure patterns, now provide objective long-term monitoring of motility in the stomach as well as more distally in the small intestine. A pressure transducer mounted on a radio signal generator, the “wireless motility capsule,” has also found use. Such devices hold the prospect for more careful characterization of gastrointestinal motor disorders.

Perfusion manometry for pressure measurement brought a new importance to the concept of sphincters. Physiologists had long debated the existence of sphincters because, aside from the external anal sphincter, the structures could not be directly observed and radiography was scarcely able to show them satisfactorily. Manometry, however, made it possible to define them, to describe their dimensions, the timing of their opening and closure, and the force with which they occluded the lumen. Thus, both the upper esophageal sphincter and the esophagogastric sphincter were not clearly described until the mid-1950s. The application of a small balloon, the “Dent sleeve,” named after its inventor – John Dent from Adelaide, Australia – greatly facilitated the study of sphincters in vivo, and it remains the major clinical and investigative technique to study sphincters, finding use especially in the esophagus, pylorus and the anal canal.

Observation of gastrointestinal wall movements

Magendie knew what little he did know about the movements of the gut wall from the direct observation of the gut in the open abdomen, and this remained a major method until after the end of the century, even receiving extensive discussion by Alvarez as late as 1928 . After that, the methods to examine flows, and hence to infer wall movements, (radiography and manometry) captured most of the attention.

The ability to observe wall movements more directly without the artifacts associated with the opening of the abdomen arose in the 1950s with the development of miniature force transducers that could be sewn to the gut wall. Wires from these transducers leading to chronically-implanted cutaneous plugs in experimental animals permitted investigators to record movements (mainly from the stomach and the intestine) over long periods under varying conditions . Investigators further developed the use of electrodes implanted in the gut wall to record the electrical events in muscle associated with contractions. Electrodes had been used much earlier by Alvarez and Mahoney in the 1920s, for example, but they were neglected for four decades, only to be salvaged for use – especially by Bass when it was realized that electromyography tracings greatly supplemented the tracings of wall movements made with chronically-implanted transducers. Now both implanted transducers and implanted electrodes find widespread use in chronic preparations in experimental animals. The obvious problem of providing high resolution is overcome by the use of multiple closely-spaced sensors.

The electric slow waves of the gut

Electrophysiology was a fully developed technical discipline in 1939, yet Wiggers could say virtually nothing of the electrical activity of the gut in his textbook of that year; “Numerous attempts have been made to record action potentials from isolated and intact viscera. Unfortunately, the arrangement of muscular tissue in these organs is so complex and the electrical variations derived are so complicated that they are for the present difficult to interpret in terms of functional activity.” But electrophysiology was the great biologic technology of the time (just as molecular biology is the great technology of ours), and therefore it was not long before ideas and methods were more fully transferred from the heart (where electrophysiology began) to the gut.

As early as 1932, investigators could detect the characteristic electromyogram of the small intestine , but it remained a seemingly fresh subject when Daniel’s thorough review appeared in 1963 . The subject advanced rapidly in the 1960s, especially under the guidance of Code and Prosser in America and of Daniel in Canada. The idea of electrical slow waves developed rather slowly, given the ease with which they are detectable and their obvious importance. Thus, it was three decades after the work of Alvarez and Puestow that Code, Daniel, and Prosser took up the subject with their characteristic energy. Investigators focused on the small intestine for a long time, only later extending the method and the concept to the stomach and colon.

From the beginning, investigators recognized that electrical slow waves govern the rhythmicity of contractions. That is, like clocks, the slow waves orchestrate contractions in time and space, not signaling contractions like the cardiac action potentials, but acting purely as pacemaking signals to which the muscle may or may not respond. Indeed, this phenomenon of having strictly a pacemaker or clock function led investigators to give them a variety of names, seemingly because they felt that existing terminology was somehow inadequate. For some years, “electrical slow waves,” “basic electrical rhythm,” “pacesetter potentials,” and “electrical control activity” competed for usage, to the great confusion of outsiders, and they still do to some extent.

The discovery of the electrical slow waves in the gut satisfactorily unified some old observations. For example, Russian physicians had long toyed with the technology of the electrogastrogram, a device to record the electrical signals of the stomach in analogy with the electrocardiogram. This fascination of the Russians with electrical events in the stomach at a time when they were scarcely thought of in other parts of the world or in other organs reflects the legacy of Pavlov which accounts for the fact that so many of the earliest autonomic neuroanatomists were Russians, or from the Eastern part of Europe. Code, Kelly, Szurszewski , and others who later did so much to advance our understanding of slow waves in the stomach validated the electrogastrogram, heretofore largely unknown in the West. It has gained renewed currency if not actual vitality. Similarly, the finding of a declining gradient in slow-wave frequency along the small intestine tied well with the theory of a metabolic gradient along the intestine, which had brought Alvarez to the forefront . The fact that the theory excited some controversy then was partly attributable to the personality of Alvarez and his appeals to the press and to the public. His intestinal gradient theory arose again from the ashes on a firm foundation with the discovery of the intestinal slow-wave frequency gradient.

Although the electrical slow waves generated by the stomach and intestine were known long before, they did not attract detailed scrutiny by muscle electrophysiologists until the 1950s and 1960s . This was true partly because the early investigators were not, for the most part, themselves highly trained in the electrophysiology of smooth muscle, and partly because the electrophysiology of smooth muscle as studied in vitro did not fully develop as a subject until the 1950s. Bozler in the United States and Bulbring in England especially deserve credit for advancing gut smooth muscle electrophysiology forward as a subject worthy of detailed study in vitro by dedicated electrophysiologists. Bozler studied the stomach and intestine, and Bulbring chose the taenia coli of the guinea pig as her model. It was some time, until the mid-1960s, before students of gastrointestinal motility fully realized the significance of the observations of Bozler and Bulbring in their basic electrophysiologic studies.

The interstitial cells of Cajal: the pacemaking system

Experts agree now that the source of the electrical slow waves are the interstitial cells of Cajal rather than the smooth muscle, as previously thought. Cajal did not “discover” the interstitial cells that bear his name, but he raised them from obscurity at the turn of the century. He viewed these tiny cells as secondary nerve cells forming intermediates in the communication between the axons of enteric nerves and the cells of effector tissues, like smooth muscles and gland cells . He thought of them as forming a terminal syncytium or network of nerve fibers that allowed for integration of communication within the substance of the smooth muscle.

For a long time, neuroanatomists argued about these cells, their function, their distribution, and indeed, their very existence. Cajal’s ideas as to their nature and function were neither disproved nor fully accepted, and they remained cells without a clear function for almost a century. As early as 1925, some investigators proposed that the cells might be responsible for “myogenic” rhythmic contractions on little evidence. Thuneberg revived the idea in 1982 , on better evidence, and stimulated the immigration of others who, in fact, have gathered good evidence in its support .

It is ironic that the best evidence for the idea that interstitial cells generate the electrical slow waves comes from the colon (of the cat and dog), one of the latest places where they were described and the organ where motility is less well understood than in any other structure. The interstitial cells of the mammalian colon were only discovered in 1971, by Stach , who found them as a neuroanatomist working on the neglected topic of the innervations of the mammalian colon. The electrical slow waves of the mammalian colon first described in detail only about the same time, not by design but by accident, the discoverer simply choosing an unexplored tissue in which to demonstrate the use of a new kind of electrode he had devised . The small intestine and stomach remain the organs where electrophysiology has been concentrated.

Fasting and postprandial rhythmic activity of the gut

The idea that the pattern or quantities of rhythmic contractions in the gut vary as the animal is fed or fasted goes back a long time. Beaumont, with his limited capacity to see gastric motions in his patient with a fistula to the gastric fundus, concluded that gastric contractions occur only in the fed state and the stomach becomes quiet after it has emptied itself into the duodenum. This idea persisted for a long time, but it was not universally held. Carlson cites the writings of an 18th century physiologist, Haller, who believed that hunger represented contractions of the empty stomach, and referred to others who agreed, especially Boldyreff, who had published his observations in 1905 . Recording from balloons inflated in the stomach of conscious dogs, Boldyreff saw alternate periods of powerful rhythmic contractions and absolute or relative quiescence over a period of 3–4 days of starvation. The period of contractions lasted 20–30 minutes, the periods of relative quiescence, 1 ¼ hours or more. Boldyreff noticed that periodic contractions of the intestine accompanied those of the stomach. Hurst later proposed that these periodic contractions gave rise to the sensation of hunger, an idea that Boldyreff had rejected because he saw the contractions become weaker as starvation was prolonged.

Carlson and his colleagues, after further experiments, concluded that hunger is indeed caused by these periodic powerful contractions of the stomach. He described his studies (which involved yet another patient with a gastric fistula) in 1916 , and the idea of “hunger contractions” of a particular force and regularity, remained part of standard teaching in gastrointestinal physiology until about the 1940s, when it appeared to have died out. Boldyreff’s original work and Carlson’s observations both have been fully reviewed by Dr. David Wingate .

Although periodicity in gastrointestinal contractions in the fasting animal was established by these studies, the matter soon fell into neglect and was forgotten. The picture of vastly different motility in feeding and fasting did not re-emerge until the work of Ruckebusch in France and of Szurszewski in America. Szurszewski and his colleagues confined themselves to man and the dog, Ruckebusch ranged widely across the animal kingdom. Ruckebusch was able to show that periodicity is consistent in many herbivores that eat constantly, and that eating interrupts the periodic cycle mostly in carnivores that normally eat meals at wide intervals in time. Ruckebusch’s broad interests in comparative animal functions are indicated in his textbook .

Thus, the idea of periodicity of gastrointestinal contractions in fasting arose, apparently from causal observation, very long ago, but it found little use then, except by Carlson to explain hunger. It was finally and firmly re-discovered and the periodic activity of the gut in fasting (newly christened the “migrating motor complex” or the “Housekeeper of the Gut”), has become deeply entrenched in the body of knowledge .

Receptive relaxation

Magendie recognized that the stomach contracts to shift its contents, and by 1886, Hofmeister and Schütz described gastric peristalsis. Only after the advent of radiography could Cannon really visualize it in vivo. Beaumont had proposed that food entering the stomach follows a pathway along the greater curvature to reach the pylorus. Cannon was able to disprove the idea. He could see different motor functions of the antrum and fundus and visualized retropulsion of contents with antral contractions. Cannon’s views on gastric contractions prevailed for a long time. The full complexity of gastric flows, including sieving which is the separation of solids from liquids by the antrum, became clear only after 1960 with Meyer’s review and full account of this development .

Cannon recognized the reservoir function of the proximal stomach, and realized that it expanded with swallowing by the process now called receptive relaxation. But it was not until 50 years later that vagal inhibition of the stomach received careful study, when Harper observed that the electrical stimulation of the central stump of the severed vagus induced gastric relaxation by way of the other intact vagus. In the 1960s, Jansson and Abrahamsson extended the concept of vagally mediated gastric relaxation by demonstrating several reflexes. The excitation of non-cholinergic, non-adrenergic inhibitory nerves mediates these reflexes, for the most part, but Miolan and Roman showed that receptive relaxation also involves the suppression of activity in tonic excitatory fibers to the gastric fundus.

Conclusions

We have attempted to merely provide a “snapshot” of the history of this field highlighting the advances that have occurred in our knowledge of physiology, recording, technology and diagnostic methodology. This chapter sets the stage for the chapters in this book which are devoted to updating us about the field of gastroparesis and bringing us to the “cutting edge” of therapy options.