The Migrating Motor Complex

Symposium on Gastrointestinal Motility Disorders

The Migrating Motor Complex C. Vantrappen, M.D., Agg.H.o.,* j. janssens, M.D., Agg.H.O.,t and T. L. Peeters, Ph.D.t GENERAL DESCRIPTION Until recently the motility of the stomach and the small intestine was described in terms of numbers and types of contraction waves occurring in an apparently incoordinated manner. The electrical basis for the occurrence of these contractions has been elucidated for a long time. Slow waves are present all the time at any location of the stomach or small intestine at a rhythm that is fixed for a given segment of the bowel. If spike potentials are superimposed on the slow waves, the bowel wall contracts. The factors that regulate the occurrence of spikes, however, have been poorly understood, and no clear patterns of motility were recognized until recently. In 1969 Szurszewski identified in the small intestine of fasted dogs an electric complex characterized by a front of intense spiking activity that migrates down the entire small bowel; as the activity front reaches the terminal ileum another front develops in the stomach and duodenum and again progresses down the intestine. 76 In dogs this recycling goes on as long as the dog is fasting. The phenomenon has been called the interdigestive migrating myoelectric complex or the migrating motor complex. As shown by Code and Marlettll feeding interrupts the cycle and changes the "interdigestive, fasted pattern" into a pattern of irregular spiking activity, which has been called the "fed pattern." These authors also divided the complex into four phases. During phase 1, there is almost no spiking activity; the intestine is completely quiescent. During phase 2, spike activity begins and gradually becomes more and more intense; the spikes, however, occur quite irregularly. Phase 3 is characterized by the sudden onset of a burst of intense spiking activity on every slow wave; during this phase the intestine is contracting at its maximal frequency, which is equal to its basal electrical rhythm. Phase 3 is the most characteristic part of the complex and has been called the activity front. Phase 3 is usually followed by a short phase 4, characterized by a period of rapidly decreasing spiking activity. Thereupon begins a new phase 1. Each phase of the cycle moves sequentially along the gastroin·Professor of Medicine, University of Leuven; Head, Department of Medicine and Division of Gastroenterology, University Hospitals of Leuven; Head, Laboratory of Gastrointestinal Pathophysiology, University of Leuven, Belgium tDivision of Gastroenterology, Departments of Medicine and Medical Research, University Hospital, St. Farael, Leuven, Belgium :j:Lecturer, University of Leuven Medical School, Leuven, Belgium

Medical Clinics of North America-Vo!' 65, No. 6, November 1981

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VANTRAPPEN, J. JANSSENS, AND

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PEETERS

testinal tract; therefore, each phase is present at some point along the gastrointestinal tract at anyone time. The duration of the entire cycle (i.e. the time interval between the onset of two consecutive activity fronts at any level of the intestine) varies in dogs from 1.5 to 2 hours.

The Migrating Motor Complex in Man The migrating motor complex also occurs in man,84 and resembles closely that of dogs. It also consists of four different phases. The duration of the cycle in man is about 130 minutes. In the upper small intestine the activity front (phase 3) lasts for about 5 minutes and has a progression velocity of about 7 cm/min; the calculated length of the front is about 30 cm. During phase 2, the spiking activity in the jejunum of man may occur quite irregularly, or may be arranged in bursts appearing with minute intervals (the minute rhythm)24 (Fig. 1). As in dogs, feeding interrupts the complex. A continental breakfast of 450 Kcal causes the complex to disappear for 213 ± 48 minutes and changes the fasted pattern into a fed pattern. Our data in man have been confirmed by several investigators.lO, 23, 25, 44, 47,63 The migrating motor complex pattern is not limited to the stomach and the small intestine, but involves the lower esophageal sphincter as wel1. 30 Not every complex starts in the lower esophageal sphincter or stomach. Some originate in the duodenum or even beyond the ligament of Treitz. 84 Moreover, not every complex migrates down the entire small bowel to the distal ileum; as shown in dogs, about 25 percent stop somewhere in the proximal ileum,ll

Differences Among Species The migrating motor complex has been observed in several animal species including calves,65 horses,64 pigs,3 rabbits,26 rats,68 and sheep.8 In some species a fasted pattern may persist in the nonfasted state. This seems to depend on the feeding habits of the animal. When pigs, rabbits and sheep are fed ad libitum, the migrating motor complex recycles continuously throughout the day without disruption by feeding. However, when the animals take food only once or twice daily, the migrating motor complex occurs only during the fasting state and is disrupted by feeding.

Relation to Propulsion To study the nature of the motor action of each phase of the migrating motor complex, Code and Schlegel 12 performed simultaneous radiocinematographic and electromyographic studies in fasted dogs. Almost no motor activity was present during phase 1. Phase 2 consisted of segmental nonpropulsive contractions which became more propulsive near the end of phase 2. The activity front was composed of a series of consecutive peristaltic contractions; each contraction passed rapidly along the length of bowel displaying the front and the progression velocity was equal to that of the slow waves (which is much faster than the progression velocity of the front itself). These contractions swept the bowel clean and "acted as a housekeeper." Phase 4 was a mixture of segmental and peristaltic contractions. Analogous results have been obtained in man by simultaneous manometric and radiocinematographic studies. In the human small intestine, also, the consecutive peristaltic contractions of the activity front of the migrating

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Figure 1. Schematic representation of 5 consecutive migrating motor complexes in a normal subject, displaying the number of contraction waves per minute throughout a 400 min recording period at 3 different levels of the upper small intestine. D, duodenum; JI: jejunum I (± 15 cm below the angle of Treitz); and JII: jejunum 11 (± 40 cm below the angle of Treitz).

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motor complex appeared to be highly propulsive and efficiently cleared the bowel of all injected contrast material. 84 The different phases of the complex greatly influence intestinal transit and absorption. Sarr and Kelly showed in dogs that the transit of liquids was most rapid during phase 3, slowest in phase 1 and intermediate during phase 2. During phase 2 the transit resembled that after feeding,12 Jejunal absorption during fasting was related to transit. Absorption was greatest during phase 1 and least during phase 3. However, after feeding absorption was greater than that seen during any phase of fasting although transit time was similar to phase 2,13

The Secretory Component of the Migrating Motor Complex Recently we have shown in man that the migrating motor complex is accompanied by secretory phenomena.85. 87 Phase 3 of the migrating motor complex in the duodenum is preceded by an increase in gastric acid and pepsin output and followed by a peak of bicarbonate and amylase secretion. In addition, the activity fronts in the duodenum are preceded by an increase in bile acid secretion in patients who have had cholecystectomy as well as in normal subjects58 (Fig. 2). We have called these secretory phenomena "the secretory component of the migrating motor complex." Our studies have been confirmed by several groups of investigators in dogs l7, 38 and in man. 46 There is some evidence that small intestinal secretion also might be modulated by the migrating motor complex. 61

THE MIGRATING MOTOR COMPLEX IN DISEASE STATES Up to now only few disease states have been associated with a disordered migrating motor complex pattern. Because of the "house-keeper" function of the activity front of the migrating motor complex, we speculated that a deficient clearing mechanism (absence of phase 3) would result in accumulat:'ion of remnants of food, desquamated cells, and secretions, and would, therefore, create a medium favorable to bacterial overgrowth in the small intestine. Of the more than 250 patients with various gastrointestinal diseases we have studied thus far, only 9 were found to lack the activity front. All 9 had bacterial overgrowth in the small intestine. Two patients had systemic sclerosis, one total gastrectomy, one Crohn's disease, three with pseudoobstruction, and two without apparent gastrointestinal disease in spite of intensive investigation. Therefore, absence of the activity front of the migrating motor complex may be added to the list of diseases and abnormalities which can cause small intestinal bacterial overgrowth. 83, 84 Malagelada and co-workers47 studied the migrating motor complex in patients with diabetic and postvagotomy gastroparesis. They found a normal migrating motor complex in duodenum and small intestine whereas the migrating motor complex in the stomach was absent. Studies by Atchinson and co-workers 4, 5 indicate that castor oil and ricinoleic acid produce in the canine small intestine a complete disruption of the migrating motor complex within 40 to 60 minutes and induce a characteristic pattern of electrical activity consisting of repetitive bursts of spike potentials. This laxative-induced pattern continues for 48 to 72 hours. It is

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THE MIGRATING MOTOR COMPLEX

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Figure 2. Secretory component of the migrating motor complex. Acid, pepsin, and bile acid output and bicarbonate and amylase concentrations during the 30 minute period before (B) and after (A) the occurrence of an activity front in the duodenum (mean and SEM, seven normal subjects).

similar in various respects to the migrating action potential complex that occurs in the small intestine of the rabbit under the influence of Vibrio cholerae or its enterotoxin. 49 We administered castor oil to volunteers in doses sufficient to produce urgent bowel movements within 5 hours. 83 Castor oil reduced significantly the incidence of organized motility patterns (phase 3, minute rhythm during phase 2) without affecting the number of phase 1 and 2 contractions (Table 1). In contrast to the observations in dogs, castor oil did not disrupt the migrating motor complex in the human upper small intestine and did not induce a novel motility pattern.

Table 1.

Effect of Castor Oil on the Migrating Motor Complex of the Human Jejunum

No. of subjects No. of activity frontslh No. of burstslh' No. of sequential burstslh* Minute rhythm as percent of time' No. of contractions/min'

CONTROLS

CASTOR OIL

PVALUE

15 0.59 8.40 3.83 23.45 1.07

12 0.34 4.79 2.15 11.83 0.88

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*during phase 1 + 2 Note: A burst was defined as one or a few pressure peaks, preceded and followed by a quiescent period of at least 30 seconds and developing simultaneously or sequentially over a distance of at least 25 cm. Bursts which occurred at regular intervals of ± 1 min for a period of at least 5 minutes were classified as minute rhythm.

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REGULATING MECHANISMS Many investigators have tried during the past 10 years to elucidate the mechanisms that regulate the migrating motor complex pattern. Hormonal and nervous factors have been studied, and the existence of an extraintestinal "clock" has been proposed. 92 However, the nature of the control system remains unclear. It seems probable that the initiation and distal progression of the migrating motor complex and its disruption by food are produced by different mechanisms.

Initiation and Progression of the Migrating Motor Complex Until recently, the available evidence suggested that motilin was the most important factor for the initiation of the migrating motor complex, and that the orderly progression of the complex was under nervous control. Three recent studies have markedly influenced our insights regarding the control system of the complex. There is circumstantial evidence for a clock mechanism located in the bowel wall itself. An autotransplanted segment of dog jejunum, deprived of all extrinsic nerve supply, still displays a migrating motor complex pattern. 71 The complexes in the loop, however, are no longer coordinated with the migrating motor complex pattern of the bowel outside the loop, and occur at a faster rhythm. These studies seem to be in agreement with earlier studies of Ruckebusch and Bueno66 who found in sheep an increase in the rhythm of the migrating motor complex after combined vagotomy and splanchnicectomy. The coexistence of two different rhythms in the same dog makes it very unlikely that a periodic increase in hormone level is the main factor that controls the recycling of the migrating motor complex in all regions of the gastrointestinal tract. The final proof of an intestinal clock mechanism would be the demonstration that a segment of small bowel in an organ bath still exhibits migrating motor complex activity. The observations of Sarna et aJ.7° indicate that the intrinsic nervous plexus is necessary for the orderly progression of the migrating motor complex. Via intra-arterial perfusions, they administered drugs to a short segment of intestine and showed that atropine (anticholinergic agent), hexamethonium (ganglionic blocking agent) and tetrodotoxin (blocking nerve conduction), given prior to the arrival of the activity front of the migrating motor complex, block the front in the perfused segment and prevent its distal progression. A third important observation was the demonstration that the migrating motor complex of an auto-transplanted pouch of canine gastric fundus is perfectly coordinated in time with the migrating motor complex of the remainder of the stomach. 78• 79 Exogenous infusion of motilin elicited an activity front in the pouch as well as in the rest of the stomach and the duodenum in situ. In these conditions a hormonal mechanism must be involved. Indeed, even if the pouch and the remainder of the stomach had an intrinsic clock with the same frequency, the two rhythms would become out of phase after some time; that this is not the case can only be explained by a hormonal factor coordinating the two rhythms. These results are in agreement with earlier studies 33 showing that the interdigestive contractions in a Heidenhain pouch of dog are nicely correlated with those of the main stomach.

THE MIGRATING MOTOR COMPLEX

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Hormonal Control Mechanisms. It has already been pointed out that each phase of the migrating motor complex is always present somewhere in the bowel. If circulating hormones take part in the control of the migrating motor complex they must be involved in its initiation rather than in the regulation of its distal progression. Which of the gastrointestinal hormones is the best candidate? For a circulating hormone to be a candidate for this function, its serum level should change cyclically in accordance with the different phases of the migrating motor complex. The serum concentrations of gastrin, secretin, CCK, insulin, GIP and glucagon are all low during the fasting state, and cyclic changes of these hormones in accordance with different phases of the complex have never been reported. 62 Lux et al. 43 and Peeters and co-workers 57 studied plasma somatostatin levels in man during the. interdigestive state and were unable to show any fluctuation. The only gastrointestinal hormones which are known to change cyclically during fasting in accordance with the migrating motor complex are motilin 32. 35, 4Cl-42, 43, 59, 60,62,63,79,86,99 and pancreatic polypeptide. 38,43 Another prerequisite for a candidate for the initiation of the Migrating Motor Complex is that the circulating hormone should be capable of inducing a migrating motor complex when it is exogenously administered or endogenously released. This has been shown for motilin in dogs 28, 31, 34, 79, 95-97 and in man,l8, 45, 86 Infusion of pancreatic polypeptide neither induces a migrating motor complex nor prevents its occurrence,36 There is circumstantial evidence that motilin is involved in the initiation of the migrating motor complex. The plasma level of endogenous motilin changes cyclically in accordance with the migrating motor complex and is highest at the time the activity front develops in the gastroduodenal area. This has been shown in animals 32, 35, 4Cl-42, 60, 79 as well as in man 43, 59, 62, 63, 86, 99 (Fig. 3). Exogenous infusion of motilin is able to induce a complex l8 , 28, 31, 34, 45,79,86,96,97 at doses which produce an increase in plasma motilin levels of the order of magnitude of the naturally occurring motilin peaks,42,86 Moreover, experiments in dogs with an autotransplanted fundic pouch indicate that exogenous infusion of motilin increases the rhythm of the migrating motor complex in the pouch and in the remainder' of the stomach to an equal degree. 79 However, several observations on the relation between motilin and the migrating motor complex remain unexplained. The rise in plasma motilin during the latter stages of phase 2 and during phase 3 is statistically significant, but in man not every migrating motor complex is accompanied by a motilin peak and a peak of plasma motilin can occur without a migrating motor complex. 29 ,62 Therefore the possibility that the motilin peak is the consequence and not the cause of the increased motility during the activity front cannot be excluded. 86 This interpretation, however, is very unlikely because infusion of gastrin, CCK or secretin, alone or in combination, eliminates in fasted dogs the activity front but does not affect the cyclic changes in plasma motilin concentrations. 40 Unexplained, also, is the observation that infusion of motilin not only elicits an activity front but also induces a peak in plasma pancreatic polypeptide whereas exogenous pancreatic polypeptide inhibits spontaneous release of motilin without inhibiting the migrating motor complex, 1,43,36 These findings could be interpreted as suggesting that pancreatic polypeptide, and

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Actions of Gastrointestinal Hormones on the Migrating Motor Complex (MMC)

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THE MIGRATING MOTOR COMPLEX

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not motilin, is the hormone involved in the initiation of the activity front of the migrating motor complex. However, in contrast to motilin, infusion of pancreatic polypeptide is unable to induce an activity front. 36 The plasma motilin level, therefore, cannot be the only factor controlling the initiation of the migrating motor complex. The mechanism of the cyclic rise in plasma motilin levels in the fasted state is unknown. Motilin is present in the duodenal mucosa,27 but it has also been found in the central nervous system, particularly in the pineal gland. 98 Motilin can be released by duodenal perfusion of alkali in dogs 6 and of acid in man. 50 However, aspiration of gastric acid or inhibition of acid secretion by cimetidine in man does not inhibit the migrating motor complex and has no effect on the cyclic variations in plasma motilin. 63 In man, motilin is also released by fat that is ingested or instilled intraduodenally.50 Fat seems to exert this effect, at least in part, via bile secretion. 18 It is not known whether the cyclic changes in plasma motilin during fasting are produced via a local gastrointestinal mechanism or as a result of some extraintestinal clock mechanism. Interactions between hormonal and nervous pathways in the regulation of the migrating motor complex further complicate our understanding of the control system. Atropine blocks the cyclic increase in plasma motilin as well as the activity front of the migrating motor complex. 41 .99 It also blocks the effect of exogenous motilin. 54 These data suggest that nervous pathways play an important role in the release of motilin as well as in the production of the migrating motor complex. Motilin has also been shown to increase the effect of the myenteric plexus excitatory neurons on gastric smooth muscle in vitro by increasing the release of acetylcholine from myenteric nerve terminals. 51 Data on the effect of somatostatin on dog small intestinal motility are controversial. Induction80 as well as inhibition39. 56. 60 of the activity front of the migrating motor complex by infusion of somatostatin have been reported. In man, somatostatin clearly induces activity fronts, as shown by Lux et al. 44 and by Peeters et al. 57 (Fig. 4). Our studies indicate that the migrating motor complexes induced by somatostatin differ from spontaneous complexes and from those induced by motilin: during intravenous somatostatin infusion the migrating motor complex comprises only phase 1 and phase 3 activity without phase 2 activity. In unpublished observations we showed that intravenous infusion of motilin in man elicits a peak of plasma somatostatin, suggesting that motilin may induce activity fronts via somatostatin. Therefore, somatostatin may be a good candidate for the hormonal control of the activity front of the migrating motor complex. The fact that, in man, plasma somatostatin levels do not fluctuate in accordance with the different phases of the migrating motor complex43. 57 may be due to the extremely short half-life of somatostatin (± 1.5 minutes), acting more as a paracrine agent than as a circulating hormone. Nervous Control Mechanisms. Several observations indicate that the extrinsic nerves have a regulatory function. The activity front in a Thiry Vella loop is better coordinated with the Migrating Motor Complex in the main intestine9 than it is in an autotransplanted jejunal segment, where the Migrating Motor Complex seems to occur at its own independent rhythm. 71 If jejunal and ileal segments are interchanged with their extrinsic nerve sup-

1322

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VANTRAPPEN, J. JANSSENS, AND

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Figure 4. Autocorrelation of motilin values computed for up to 120 lags. Plasma motilin values of 20 migrating motor complex periods obtained in 10 volunteers were used. During the experiment blood samples for motilin assay were drawn every 10 minutes. Because of the variable duration of the migrating motor complex cycle, each cycle was divided into 10 equal time units and the motilin values at 0.5, 1.5, 2.5 ... 9.5 unit were calculated by linear interpolation of the actually measured levels at the original 10 minute intervals. The motilin values for every volunteer were transformed into normal variates (U = (X - X) IS). The transformed data were then arranged into a continuous string (20 migrating motor complex periods and therefore 200 data points). As shown in the figure autocovariance of transformed motilin values fluctuated sinusoidally, reaching positive and negative peaks every 10 lags (ideal position of positive and negative peaks is indicated by open and close triangles) indicating that the spontaneons fluctuations of endogenous motilin are related to the different phases of the migrating motor complex. (For details see Peeters T.L. et aI., Gastroenterology, 79: 716-719, 1980.)

ply remaining intact, the jejunal activity front precedes the ileal one as if the two segments were still in their normal location. 3 After a delay of 3 to 4 weeks, however, the transplanted segments adapt to their new anatomic·location and become integrated into a normal aborad sequence. The role of the sympathetic nervous system in the orderly progression of the migrating motor complex was studied by Van Deventer et a1. 82 They performed celiac and superior mesenteric ganglionectomy in dogs. No effect on the small intestinal migrating motor complex was observed. Section of the splanchnic nerves in sheep resulted only in a minor increase in the duration of the migrating motor complex cycle. 66 These studies suggest that the effect of the sympathetic nervous system on the migrating motor complex, if any, is minor. Several authors studied the effect of bilateral truncal vagotomy on the migrating motor complex. They all agree that the migrating motor complex pattern persists in both the small intestine 2, 48, 54, 66, 89 and the stomach. 2,48,54 Some reported that the cycle becomes irregular2.48 while others found it to remain normal. 54, 66, 89 Motilin was still able to induce a complex after bilateral truncal vagotomy.54 . Stimulation of the vagus by sight and smell of food lengthened the period of the migrating motor complex in dogs, even if the accompanying se-

THE MIGRATING MOTOR COMPLEX

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cretion was drained via a gastric fistula. 75 Ruckebusch and Buen067 performed combined vagotomy and splanchnicectomy and observed a marked increase in the number of migrating motor complexes per day. According to Diamant and co-workersl6 the lower esophageal sphincter and gastric components, but not the small intestinal component of the migrating motor complex, require vagosympathetic integrity. In their ingenious experiments in dogs they isolated the vagosympathetic nerve trunks in skin loops on each side of the neck. After bilateral nerve blockade by cooling, the migrating motor complex was preserved in the small intestine but not in the lower esophageal sphincter and stomach. These data indicate that the extrinsic nervous system (with the possible exception of the lower esophageal sphincter and stomach) is not required for the initiation and progression of the migrating motor complex. However, it may contribute to normal migration, and influences the rhythm of the migrating motor complex. Disruption of the Migrating Motor Complex by Food In most animal species and in man the migrating motor complex is disrupted whenever a sufficiently large meal is taken. ll ,13,84,91 For any of the three major food components (protein, carbohydrate, fat), the duration of the disruption is related to the amount of calories taken,13,74 Not only the amount of calories but also the nature of the food determines the duration of the disruption. For a given amount of calories the duration of disruption is longer for carbohydrate than for protein; fats produce the longest disruption,13,74 The mechanism responsible for the conversion of the motility pattern from the fasted to the fed state is poorly understood. Regulation by hormones is an attractive hypothesis. Hormones are undboutly involved in the disruption of the migrating motor complex in the stomach because feeding abolishes the complex in an autotransplanted fundic pouch. 78 ,79 Feeding raises the plasma levels of almost all gastrointestinal hormones. Motilin is an exception. After a short initial rise,50 the plasma motilin levels decrease and the cyclic changes no longer OCCUr. 35.40 If hormones are involved in the disruption of the migrating motor complex pattern by food, it is likely that the effect is produced by the integrated effect of various hormones. Infusion of gastrin,80, 88, 93 insulin,1, 8, 69, 80, cholecystokinin,53, 80, 93 glucagon,94 and secretin40 have all been reported to disrupt the migrating motor complex. It is not known whether this disruption of the migrating motor complex represents a physiologic or a pharmacologic action of the hormone. Endogenous release of gastrin only has been reported to disrupt the migrating motor complex. 77 However, in the experiments of Eeckhout et al. 22 there was rio relation between the food-induced disruption and the plasma level of gastrin or insulin. Moreover, in patients with high plasma gastrin levels, caused by Zollinger-Ellison's syndrome or pernicious anemia, the migrating motor complex pattern is preserved. 37 Recently Thor and co-workers reported that intravenous infusion of neurotensin in man inhibited the occurrence of the activity front of the migrating motor complex and changed the fasted motility pattern into a fed type. This inhibition occurred at plasma neurotensin levels below those obtained after a meal. 81 Are the extrinsic nerves involved in the disruption of the migrating motor complex by food? After transthoracic bilateral vagotomy a larger amount

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PEETERS

of food is required to interrupt the complex,48 and the disruption is frequently incomplete. 89 The time interval between feeding and the onset of disruption of the migrating motor complex is increased after vagotomy.67 If the vagosympathetic nerve trunks, brought subcutaneously in the neck of a dog, are blocked by cooling during the fed state, the fed pattern is reversed into a fasted pattern with reappearance of activity fronts in duodenum and jejunum but not in the lower esophageal sphincter and stomach. 15 These studies are in agreement with those of Sarr and Kelly,71 who showed that feeding is unable to disrupt the migrating motor complex in an autotransplanted segment of dog jejunum. These data point to an important role of the extrinsic innervation in the disruption of the Migrating Motor Complex after feeding. Since parenteral alimentation does not interrupt the migrating motor complex of dogs,90 the stimulus for the interruption seems to originate from the gastrointestinal tract. The disruption can be triggered not only from the stomach l l but also from the jejunum and the ileum,14 Therefore, no specific trigger zone exists for eliciting the fed pattern. Local factors also are involved in the disruption of the MMC.20, 21 Experiments in dogs, in which a Thiry Vella loop was perfused with various substances of different osmolality, showed that both the nature and the osmolality of the perfusate are important for the disruptive effect on the migrating motor complex. Perfusion of a Thiry Vella loop of about 30 cm disrupted the migrating motor complex only in the loop and not in the main intestine, suggesting that the length of the intestinal segment from which the disruption is triggered and/or the continuity of the bowel are important for determining whether the disruption will be a local or a generalized phenomenon,19-21

CONCLUSIONS The migrating motor complex is controlled by a complex and multifactorial mechanism. The data available at present do not allow us to construct a precise framework for this control system.

Initiation and Progression of the Migrating Motor Complex It seems likely that the regulation of the migrating motor complex is different for the gastroesophageal sphincter and stomach and for the small intestine. In the upper part of the tract, a hormonal mechanism plays .an important role in the initiation of the migrating motor complex. Motilin might well be the hormone involved, but it is not known which mechanism produces the cyclic changes of the hormone. A nervous mechanism, perhaps acting as an additional pathway, also seems to be involved. In the small intestine the nervous control system is probably the more important. An intact intramural plexus may be sufficient, since an autotransplanted segment of small bowel generates a migrating motor complex. Another control mechanism must act via the extrinsic nervous system, since the migrating motor complex in a Thiry Vella loop occurs mainly in sequence with that in the remainder of the tract. It is unknown whether the vagus or the sympathetic system is the more important pathway. A regulat-

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ing nerve pathway via the abdominal sympathetic ganglia and plexuses may also be involved. In normal conditions, the migrating motor complex in the small bowel is perfectly coordinated with that in the lower esophageal sphincter and the stomach. Whether this coordination is hormonal or nervous (or both) remains unknown. However, many of the data available would fit with the concept that the initiation and progression of the migrating motor complex in the small bowel are regulated at different levels of control, so that a lower level of control is able to take over when a higher level fails. Thus, the occurrence of a migrating motor complex in the small intestine but not in the lower esophageal sphincter and the stomach after blocking the vagosympathetic nerve trunk in the neck, and the occurrence of a migrating motor complex in an autotransplanted jejunal segment might well represent an "escape phenomenon."

Disruption of the Migrating Motor Complex After Feeding Disruption of the migrating motor complex after feeding is initiated by a stimulus originating from the gastrointestinal tract. Any segment can function as a trigger zone, provided the stimulus is sufficiently strong and the trigger segment is sufficiently long. The disruption of the complex in the stomach may be mediated by hormones. In the small intestine, however, a nervous pathway is more likely. CONCLUSION

Thus, for the generation of normally progressing migrating motor complexes as well as for their disruption by food, hormonal mechanisms seem to constitute the more important control system in the lower esophageal sphincter and in the stomach, whereas nervous pathways predominate in the small intestine. Much remains to be done before a definite scheme for the regulation of the migrating motor complex can qe proposed.

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