Gastric Neuromuscular Function and Neuromuscular Disorders

Electrophysiologic Basis for Normal Gastric Neuromuscular Function

Extracellular Slow Waves and Plateau and Action Potentials

The stomach is a sophisticated sphere of smooth muscle organized into circular, longitudinal, and oblique muscle layers. Gastric myoelectrical activity (GMA), termed slow waves or pacesetter potentials , regulate, control, and pace gastric smooth muscle contractions. ^, In the normal human stomach the slow waves occur at approximately 3 cycles per minute (cpm) or between 2.5 and 3.7 cpm. ^, From the pacemaker region on the greater curvature of the stomach, between the fundus and the proximal corpus, slow waves propagate distally and circumferentially toward the pylorus every 20 seconds, with highest amplitude and velocity (approximately 7 mm/sec) in the distal 2 to 4 cm of antrum ( Fig. 50.1 ). The gastric slow waves originate from the ICCs. ^,

The depolarization upstroke of the slow wave reduces the electrical threshold for circular smooth muscle contraction, and, in the appropriate situation, the amplitude of the circular smooth muscle contraction increases with the onset of the plateau potentials and action potentials. ^, The aborad propagation of slow waves linked to plateau potentials (with or without action potentials) is the electrophysiologic basis of gastric peristaltic waves ( Fig. 50.2 ). Thus, the slow waves linked with plateau or action potentials propagate through the corpus and antrum and create moving “ring contractions” that resolve in the antrum or at the pylorus in a terminal antral contraction. The pylorus provides an electrical barrier between the 3-cpm slow wave of the distal antrum and the 12- to 13-cpm slow wave of the duodenum.

Intracellular Electrical Recordings From Gastric Smooth Muscle Cells

Intracellular recordings from smooth muscle cells from the different regions of the stomach (fundus to the midcorpus to the terminal antrum) illustrate the electrophysiologic characteristics that distinguish these regions ( Fig. 50.3 ). Key features are (1) regional differences in resting membrane potential, which range from −48 to −75 millivolts (mV), (2) regional differences in threshold for contraction, which range from −52 to −40 mV, and (3) the occurrence of plateau potentials with or without spike potentials. The fundic smooth muscle cells are unique because their resting membrane potential lies at or above the threshold for contraction (−50 mV), a situation that promotes sustained smooth muscle contraction and ongoing fundic tone. Inhibitory vagal input to the fundus increases during swallowing and results in decreasing muscle tone associated with “receptive relaxation” and the accommodation of swallowed foodstuffs. ^, Fundic muscle tone decreases in proportion to the intensity and duration of the inhibitory neural discharge.

In contrast to the fundus, intracellular recordings from the corpus indicate a lower resting membrane potential of −60 mV. The rapid upstroke depolarization in these cells is followed by a plateau potential that slowly returns to the baseline resting electrical potential. The plateau potentials are associated with circular muscle contraction activity in the corpus and antrum. The plateau potential may be accompanied by action potentials in the corpus and antrum. Extrinsic stimuli such as release of acetylcholine or stretch of the stomach wall increases the amplitude and duration of the plateau potential and the occurrence of action potentials, resulting in contractions of varying force, as seen in the muscle of the terminal antrum. Depending on the excitatory neural stimuli and the amplitude of plateau potentials and the number of action potentials, peristaltic contraction waves of the circular muscle layer vary from very-low-amplitude contractions to high-amplitude lumen-occluding contractions. At the pylorus, the plateau potentials have long durations with superimposed action potentials that result in closure of the pyloric sphincter in conjunction with the terminal antral contraction.

The membrane potential and the force of smooth muscle contraction also distinguish the fundus, corpus, and antrum ( Fig. 50.4 ). The resting membrane potential of the fundus is approximately −50 mV and produces the sustained contraction and the resting tone of the fundus. This fundic tone ensures a sensitive response to excitatory or inhibitory stimuli for relaxation or further contraction of the fundus. Receptive relaxation during ingestion of food is accomplished by these electrophysiologic attributes of smooth muscle in the fundus. In contrast, the resting membrane potentials of the corpus and antrum are −60 to −70 mV, respectively. In the presence of plateau potentials or action potentials the membrane potential reaches −45 mV or less and smooth muscle contraction occurs. If the plateau potentials have higher amplitude, then contractions of larger amplitude or force occur. When the plateau potential and action potentials are linked to the propagating slow waves in the antrum ( Fig. 50.5 ), then the moving ring contractions of the gastric peristaltic “waves” are formed.

In conjunction with terminal antral contractions, the pyloric sphincter contraction prevents emptying of gastric content into the duodenum and results in retention of solid foodstuffs in the stomach. Thus, the peristaltic waves associated with terminal antral and pyloric sphincter contraction produce little or no emptying of the gastric contents from the stomach into the duodenum. In contrast, if the pylorus remains open during the gastric peristaltic wave, then an aliquot of nutrient chyme is emptied into the duodenum.

Interstitial Cells of Cajal

ICCs are the “pacemaker cells” for the smooth muscle apparatus of the GI tract. ^{, ,} ICCs originate from c-Kit–positive mesenchymal cell precursors. ICCs in the stomach are located in submuscular, intramuscular, myenteric, and subserosal layers of the gastric wall. Figure 50.6 shows the anatomic relationships between the ICCs in the myenteric plexus (MY-ICCs), the intramuscular ICCs (IM-ICCs), the enteric neurons, and the circular smooth muscle cells. MY-ICCs are located between the circular and longitudinal muscle layers of the stomach and are the ICCs responsible for the generation of the slow waves. These ICCs spontaneously generate slow waves that are conducted into adjacent smooth muscle cells and cause depolarization and contraction of the smooth muscle by activating voltage-dependent, dihydropyridine-sensitive (L-type) calcium channels. ^, Increased amplitude of the plateau potential correlates with increased amplitude of smooth muscle contraction. The slow waves propagate circumferentially and distally through the ICC network via gap junctions and entrain more distal ICCs with slower intrinsic frequencies to the higher slow wave frequency, the normal 3-cpm pacemaker frequency.

ICCs are also located within the layers of the circular smooth muscle (IM-ICCs), where they integrate and coordinate the spread of the slow wave and the smooth muscle contraction initiated by the MY-ICCs. Slow waves are not regenerated in the smooth muscle cells because the ion channels needed to generate and propagate slow waves are not expressed by gastric smooth muscle.

In the corpus and antrum the MY-ICCs and IM-ICCs form a continuous lattice-like network of interconnections that extend from the pacemaker region circumferentially and aborally to the pylorus. The MY-ICCs establish the dominant pacemaker frequency, and IM-ICCs carry the slow wave into the circular smooth muscle bundles to coordinate circumferential and aboral propagation of the contraction wave.

The ICCs have innate rhythmicity that is based on their unique metabolism and fluxes in intracellular and extracellular calcium ions. ^, The most active area of depolarization and repolarization of the ICCs is in the pacemaker area of the stomach located between the fundus and the proximal corpus. The depolarization and repolarization of the ICCs is regenerated and propagated through the network of ICCs in a migrating wave front that moves from the pacemaker region on the greater curve through the corpus and antrum to the pylorus proscribing the pathway of gastric peristaltic contractions. Excitatory input to the MY-ICC (e.g., cholinergic stimuli, stretch) results in opening of calcium channels and depolarization of the smooth muscle cells with IM-ICC activation to coordinate the contractions of the circular muscle cells in time and space. Thus, the ICC networks provide the control of frequency and propagation velocity for the circular muscle contractions that comprise gastric peristalsis waves.

The fundus of the stomach lacks slow waves. The IM-ICCs in the fundus have a role in mechanoreception and act as sensory cells with interconnections to the vagal afferent neurons that innervate the fundus. Fundic IM-ICCs are also innervated by inhibitory vagal neurons that regulate tone in the fundus. Thus, the ICCs also participate in the relaxation of fundic tone that occurs during accommodation.

Normal human corpus and antrum have more than 5 ICCs/high-power field (HPF). ^, Depletion of ICCs in the corpus-antrum and loss of CD206 macrophages are associated with gastroparesis in patients with diabetes mellitus and idiopathic gastroparesis (IGP). Severe depletion of ICCs is also associated with a variety of gastric dysrhythmias ranging from bradygastrias to tachygastrias and conduction defects. ^, Patients with DGP and loss of ICCs have more gastric electrical dysrhythmias (tachygastria), more upper GI symptoms, and poorer response to gastric electrical stimulation (GES) compared with patients with normal numbers of ICCs. Interruption of ICC pathways from nondiabetic mechanisms also results in gastric dysrhythmias and ectopic pacemakers that are similar to gastric dysrhythmias found in patients with diabetes. The loss of ICCs in DGP in mice is related to inflammatory infiltrates of M1 macrophages and increased production of inflammatory mediators such as interleukin-6, whereas M2 macrophages appear to protect ICCs. ^,

Gastric Neuromuscular Activity During Fasting

In the fasting state, electrical and contractile events of the corpus or antrum occur in a highly regular pattern termed the migrating myoelectrical (or “motor”) complex , or MMC. The 3 phases of the MMC, as described by changes in intraluminal contractions, recur approximately every 90 to 120 minutes. Phase 1 is a period of quiescence wherein little or no contractile activity is recorded. In phase 2 random, irregular contractions occur. Phase 3 of the MMC is a burst of regular, high-amplitude phasic contractions that last from 5 to 10 minutes ( Fig. 50.7 A ). Phase 3 contractions are also termed the “activity front.” The activity front migrates from the antrum to the ileum, a journey of 90 to 120 minutes’ duration. The 3 phases of the MMC occur regularly in the small intestine, although approximately 50% of the phase 3 activity fronts originate in the stomach and then migrate through the small intestine. The MMCs that originate either in the stomach or duodenum travel through the small intestine and terminate in the distal ileum. If fasting continues, then another phase 3 activity front reappears in the antrum or duodenum at the 90- to 120-minute interval. The high-amplitude, 3-per-minute contractions of phase 3 that develop in the distal antrum empty nondigestible, fibrous foodstuffs that remain in the stomach.

Cyclic contractile activity associated with the onset of phase 3 also has been identified in the lower esophageal sphincter, the sphincter of Oddi, and the gallbladder. The phase 3 contractions correlate with rapid eye movement sleep and are related to a larger system of biological clocks. ^, MMCs develop after vagotomy, indicating that nonvagal mechanisms initiate and sustain MMC neuromuscular activity. Motilin is released during the intense phase 3 contractions that occur in the proximal duodenum.

Gastric Neuromuscular Activity After a Meal

Three basic gastric neuromuscular activities occur during and after ingestion of solid foods: (1) receptive relaxation to accommodate the ingested food, (2) trituration of the ingested solid food by recurrent corpus-antral peristaltic waves to produce chyme, and (3) antral peristalsis with antropyloroduodenal coordination to empty chyme in small aliquots into the duodenum in a controlled manner for optimal digestion and absorption of the nutrients.

Response to Ingestion of Solid Foods

The neuromuscular work of the stomach in mixing, milling, and emptying food depends upon the physical characteristics, volume, and the fat, protein, and carbohydrate content of the ingested food. For example, 240 minutes of neuromuscular work by the normal stomach is required to empty 90% of a 255-kcal low-fat, egg substitute sandwich. In contrast, only 35 minutes of gastric neuromuscular work is required to empty 70% of a 20-kcal 500-mL soup broth meal that was consumed in 4 minutes. Figure 50.8 illustrates gastric neuromuscular activity required to receive, mix, and empty a solid meal. The spectrum of gastric work extends from fundic relaxation to gastric peristalsis to antropyloroduodenal coordination, the work that is needed to produce chyme and empty it into the duodenum. Ingestion of food abolishes the fasted state as regular 3-per-minute gastric peristalsis begins in the corpus and antrum to mix the food; in the fed state, a pattern of continuous small bowel contractions with short runs of peristalsis over distances of 2 to 4 cm optimize digestion and absorption of nutrients (see Fig. 50.7 B ).

Solid food delivered from the esophagus into the fundus is associated with receptive relaxation of the fundus, the “work” of fundic muscle relaxation. As the fundic smooth muscle relaxes, larger amounts of solid or liquid food are accommodated in the fundus and proximal corpus with little or no increase in intraluminal pressure. Liquids, in contrast, are immediately distributed throughout the antrum and corpus (emptying of liquids is discussed in the next section). Relaxation of the fundus occurs before the work of trituration in the corpus-antrum and is a vagal nerve–mediated event that requires nitric oxide. Figure 50.9 shows an example of the changes in intragastric volume during relaxation of the fundus and proximal corpus in response to a caloric meal. Relaxation of the fundus and the stimulation of mechanoreceptors (stretch), mediated through IM-ICCs in the fundic wall, activate vagal afferent neurons and vagovagal reflexes. These reflexes involve the nucleus of the tractus solitarius and efferent neurons from the dorsal motor nucleus of the vagus. Vagal excitatory neurons are inhibited and the vagal inhibitory neurotransmitters nitric oxide and vasoactive intestinal peptide are released to accomplish receptive relaxation.

Other factors influence the muscle tone of the fundus. Antral distention, duodenal distention, duodenal acidification, intraluminal perfusion of the duodenum with lipid or protein, and colonic distention all decrease fundic tone through various reflexes. The gastric reflex is mediated through an arc initiated by capsaicin-sensitive afferent vagal nerves and is mediated by 5-hydroxytryptamine 3 (5-HT ₃ ), gastrin-releasing peptide, and CCK _A receptors.

Solid foods labeled with technetium are accommodated initially in the fundus and proximal corpus, and by obtaining frequent scintigraphic images, the distribution of the labeled solid meal can be followed over 4 hours using scintigraphic methods. Figure 50.10 shows that immediately after ingestion of this solid meal, the food is accommodated and the majority of the meal is retained in the fundus and proximal corpus. Subsequently, contractions of the fundus press portions of the food into the corpus and antrum for trituration. This early postprandial period of accommodation and trituration that occurs before gastric emptying of the nutrients is termed the lag phase . The lag phase may last from 45 to 60 minutes for solid foods, but the duration of the lag depends on the thoroughness of chewing the food, the time required to ingest the meal, and the components of the meal. For a 255-kcal egg substitute test meal that is ingested in a 10-minute period, the lag phase is 30 to 45 minutes.

Once portions of the meal have been triturated into 1- to 2-mm particles suspended in gastric juice, a linear phase of gastric emptying of the chyme begins. Recurrent gastric peristaltic waves mix saliva, acid, and pepsin with the chewed food and then mill the food to produce chyme. The normal peristaltic waves occur every 20 seconds, generated by 3-cpm slow waves linked to plateau and action potentials. In healthy subjects approximately 60% of the egg substitute meal has emptied in 2 hours, and more than 90% has emptied at 4 hours ( Fig. 50.11 ).

During the linear phase of gastric emptying, each peristaltic wave empties from 3 to 4 mL of chyme through the open pylorus and into the duodenum. Movement of chyme into the duodenum is usually, but not always, pulsatile due to the systole-like effect of antral peristaltic waves. The volume of chyme delivered into the duodenum by each peristaltic wave is modulated by the configuration of the peristaltic wave (e.g., depth of contraction, length of the peristaltic wave), pressure within the stomach, and resistance to flow provided by the pyloric sphincter and duodenal contractions. ^, The gastric peristaltic wave delivers a larger “stroke volume” when the pylorus and the duodenum are relaxed to receive the aliquot of chyme, but the overall rate of calories delivered each minute to the duodenum is consistent at approximately 3 to 4 kcal/min.

As time elapses after ingestion of the meal, the chewed/swallowed food is continually redistributed from the fundus to the antrum for trituration. Some gastric peristaltic waves end at various points in the antrum and others end with a terminal antral contraction associated with closure of the pylorus that prevents the emptying of larger food particles or indigestible solids. These terminal antral and pyloric contractions result in delayed emptying of the solid particles in the corpus and antrum. The terminal antrum, the 3 to 4 cm of antrum immediately proximal to the pylorus, is also where the slow waves have the greatest amplitude and velocity (5). In this manner, solid food particles that require further trituration are retained and subjected further to the milling effects of the recurrent peristaltic waves.

The intragastric pressure and intraluminal pH values recorded after a healthy subject ingested an egg substitute meal are shown in Figure 50.12 . Approximately 3.5 hours after the solid meal was ingested, high-amplitude contractions (>65 mm Hg) occur just before the pH suddenly increases from 1 to 6 as the wireless motility/pH capsule is emptied from the acidic antrum into the more alkaline environment of the duodenum. After the digestible components of the meal are emptied, strong antral contractions (phase 3–like contractions) empty the capsule from the stomach into the duodenum. Thus, fibrous and indigestible materials are emptied by high-amplitude antral contractions, whereas the digestible nutrients in the chyme are emptied earlier by the lower-amplitude peristaltic waves during the linear phase of emptying.

The pylorus modulates the rate of gastric emptying by several mechanisms. Increased pyloric tone and isolated pyloric pressure waves prevent gastric emptying and promote retention of food for further milling. Pyloric contractions associated with terminal antral contractions are common during the lag phase when trituration is occurring. Once the linear phase of emptying of solids begins, the numbers of isolated pyloric contraction waves diminish as chyme is available for emptying via the gastric peristaltic waves. Neuromuscular dysfunction of the pyloric sphincter is associated with gastroparesis, is more common than previously appreciated, and is reviewed later.

Response to Ingestion of Liquids

The gastric neuromuscular activity required to mix and empty liquids from the stomach is distinctly different from the emptying of solid foods. ^{, ,} Figure 50.13 shows 3-dimensional US images of the stomach in a healthy subject during the fasting state and 10 minutes after the subject ingested 500 mL of soup. The intragastric volume was approximately 40 mL during fasting and increased to 350 mL 10 minutes after ingestion of the soup, indicating the remarkable relaxation of the smooth muscle of the antrum and corpus (in addition to the fundic relaxation) that was required to accommodate this liquid volume. (In contrast, solid meals are initially accommodated and retained primarily in the fundus and proximal stomach.) Once accommodated, nutrient liquids are emptied into the duodenum in a controlled but more rapid rate compared with solid foods, which require trituration. Noncaloric liquid meals empty without the lag phase in a curve described as monoexponential emptying ( Fig. 50.14 ). ^, Caloric-dense liquids, on the other hand, are retained for longer periods in the antrum and are emptied slower than noncaloric liquids. Liquids are emptied from the stomach by a combination of (1) pressure gradients between the stomach and the duodenum that produce flow of liquid into the duodenum, (2) antral peristaltic contractions that produce a pulsatile pattern of emptying of liquids from the antrum into the duodenum, and (3) duodenogastric reflux events that modify gastric emptying rates. ^, From a GMA viewpoint, ingestion of water until the point of fullness induces a brief “frequency dip” followed by return of normal 3-cpm activity recorded noninvasively in the electrogastrogram (EGG) ( Fig. 50.15 ). The rate of gastric emptying of liquids is influenced by the volume, nutrient content, viscosity, and osmolarity of the ingested liquid. ^{, , ,} These factors affect the neuromuscular activity of the stomach, which ultimately produces the rate of emptying. These factors are discussed later.

Regulation of Gastric Neuromuscular Activity After A Meal

Gastric emptying rates are regulated to achieve a consistent, regular presentation of calories in the form of chyme to the duodenum in order to optimize secretion of pancreatic enzymes and bile appropriate for digestion of the contents of the chyme. Various gastric emptying rates are achieved by variations in the neuromuscular armamentarium of the stomach: fundic relaxation and contraction, the characteristics of gastric peristaltic contractions, temporary suspension of 3-cpm slow waves and the onset of gastric dysrhythmias; the coordination of antropyloroduodenal contractions and duodenal contractions; pyloric sphincter contraction and relaxation; and duodenal contractions that promote duodenogastric reflux. The attributes of a specific meal stimulate the appropriate gastric neuromuscular responses that affect the rate of gastric emptying. Table 50.1 lists gastric neuromuscular factors, meal-related factors, and other factors that modulate the rate of gastric emptying. The rate of gastric emptying is decreased by the temporary occurrence of gastric dysrhythmias, modulation of the amplitude and the propagation distances of antral contractions, enhanced contractions of the pylorus, and reduced antropyloroduodenal coordination.

Meal-related factors that affect gastric emptying include the digestible components of the solids and liquids, fat content (nutrient density), viscosity, acid content, volume, osmolality, and indigestible foodstuffs. For example, foods with high fat content empty slower than foods with high protein or carbohydrate content. TGs are mixed with gastric lipase during the initial intragastric phases of digestion (see Chapter 102 ) and are broken down to fatty acids and monoglycerides or diglycerides before emptying into the duodenum. The duodenum is exquisitely sensitive to diet-derived fatty acids. Longer chain fatty acids (>C12) exposed to the mucosa of the duodenum result in release of CCK. CCK relaxes fundic tone, decreases antral contraction, and increases pyloric tone, all of which result in delay in gastric emptying. In contrast, short- and medium-chain fatty acids (<C12) do not have these neuromuscular effects on gastric emptying rates. ^, CCK released from the duodenum also activates CCK _A receptors on vagal afferent neurons with synapses in the nucleus tractus solitaries. Neurons from the nucleus tractus solitarius ascend to the periventricular nucleus of the hypothalamus that participate in mechanisms of satiation, and descending vagal efferent neurons from the dorsal motor nucleus of the vagus inhibit gastric emptying and maintain fundic relaxation. The sensitivity of the duodenal mucosa to fat and other nutrients led to the concept of duodenal tasting and duodenal brake, sensorimotor events that modulate gastric emptying of nutrients. ^,

Monosaccharides in the duodenum stimulate the release of incretins such as glucagon-like polypeptide-1, which promotes insulin secretion to match increasing postprandial blood glucose levels and decreases antral contractions. ^, In order to harmonize the relationships between glucose absorption, glycemia, and insulin secretion, the gastric emptying of carbohydrates is highly regulated. ^, Hasler and colleagues showed that hyperglycemia decreases antral contractions and increases gastric dysrhythmias, a “physiologic” gastric dysrhythmia that decreases the rate of gastric emptying ( Fig. 50.16 ). ^, Hyperglycemia increases fundic compliance and decreases sensations related to fundic distention. ^, Blood glucose levels greater than 220 mg/dL result in decreased antral contractions, decreased gastric emptying, and induced gastric dysrhythmias, all of which are gastric neuromuscular activities that reduce gastric emptying and reduce further exposure of the duodenum to nutrients. Hypoglycemia episodes are also associated with delayed emptying in patients with insulin-dependent diabetes.

The interaction between nutrients in the lumen and the regulation of the rate of gastric emptying continues in the later postprandial period as digestion and absorption of nutrients occur throughout the small intestine. For example, if diet-derived fatty acids or carbohydrates reach the lumen of the ileum, the so-called ileal break is activated and gastric emptying is delayed. Infusion of nutrients into the lumen of the ileum delays gastric emptying.

Regulation of stomach emptying also is achieved by vagus nerve and splanchnic nerve activity that modulates the neuromuscular activities of the stomach described earlier. Vagal afferent nerves “monitor” neuromuscular function in the stomach moment by moment, and interactions between afferent vagal nerve activity and the nucleus tractus solitarius and synapses with the efferent vagal nerve output from the dorsal motor nucleus produce an ongoing interaction of CNS excitatory and inhibitory effects on the stomach. Gastric emptying is delayed during stress. Corticotrophin-releasing factor plays a role in the mediation of stress and inhibits gastric emptying through central dopamine ₁ and dopamin ₂ and vasopressin pathways in the periventricular nucleus. Other factors that affect the rate of gastric emptying not already mentioned include rectocolonic distention, nausea and vomiting of pregnancy, and vection-induced motion sickness. Stimulation of various areas in the CNS affects gastric neuromuscular function. Illusory self-motion (vection) induces antral hypomotility, tachygastria, and decreased gastric emptying. ^, A series of studies using the experience of illusory self-motion, a unique CNS sensory stimulation, showed that the onset of nausea was associated with tachygastria and increased levels of plasma vasopressin. ^,

Gender affects the gastric emptying rate of a standard meal. Gastric emptying is significantly slower in healthy women compared with men. Gender differences in gastric emptying rates may be related to fluctuations in sex hormones, but phases of the menstrual cycle (variations in estradiol and progesterone concentrations) have not shown consistent relationships with emptying measurements. The rate of gastric emptying increases as body mass index rises, a relationship that may be relevant to the onset and maintenance of obesity.

Gastric Sensory Activities

Free nerve endings in the stomach act as polymodal sensory receptors that respond to light touch or pressure, acid, and other chemical stimuli. Afferent neurons within the stomach are termed intrinsic primary afferent neurons , or IPANs. Cell bodies of IPANs reside in the submucosal or the myenteric plexus areas of the stomach wall. IPANs may be activated by serotonin release from local enterochromaffin cells. ^, The afferent information in the IPANs is used in local reflexes and provides input to vagal and splanchnic afferent neurons for vagovagal and spinal reflexes, respectively, to subserve transmission of visceral sensory information to CNS centers. Vagal afferent neurons whose cell bodies reside in the nodose ganglia connect with the nucleus of the tractus solitarius and second-order neurons connect with higher center of the hypothalamus, and some inputs reach the cortex, where they are consciously perceived as visceral sensations (stomach emptiness or fullness) or symptoms such as nausea or abdominal pain ( Fig. 50.17 ).

From the SNS, splanchnic or spinal primary afferent neurons in the gastric wall mediate pain sensations. Cell bodies of these neurons lie in the dorsal horn of the spinal cord with second-order neurons that ascend via the spinothalamic and spinoreticular tracks in the dorsal columns. Sensory neurons are thin, myelinated A-delta or unmyelinated C fibers. Spinal afferents include a population of unmyelinated C fibers. Capsaicin-sensitive unmyelinated fibers contain neuropeptides such as calcitonin gene–related peptide, vasoactive intestinal peptide, somatostatin, substance P, and neurokinin A. These fibers are considered to be the primary route of transmission for various pain stimuli from the gut to the CNS. These nerve fibers may respond to inflammatory mediators that also awaken “silent” nociceptive fibers.

In addition to interacting with IPANs, vagal afferent axons have multiple connections with the enteric neurons and innervate the circular muscle fiber bundles via connections with ICCs. Vagal afferent neurons are also sensitive to chemostimuli via mucosal neurons and mechanosensitive neurons and ICCs in the muscle layers. CCK receptors on vagal afferent neurons are primarily activated by physiologic mechanical and chemical stimuli from the stomach during fasting and fed conditions. These vagal afferents mediate the sensory response to intraluminal acid and fat. Acid may have a direct action on the nerve endings themselves.

Nausea is a common sensation that is often attributable to stomach neuromuscular dysfunction. During the illusion of self-motion, gastric dysrhythmias develop as healthy individuals report nausea. Plasma vasopressin levels increase in the subjects who develop nausea but do not increase in those who experience no nausea. This brain-gut, gut-brain interaction during illusory self-motion illustrates the temporal relationships between the onset of gastric dysrhythmias in the periphery and acute, severe nausea experience of the subject. On the other hand, distention of the antrum, but not the fundus, with a balloon induces nausea sensations and gastric dysrhythmias in healthy individuals. These studies show that gastric dysrhythmias originate in the antrum in humans and that stretch of the antral wall is another mechanism that elicits gastric dysrhythmias and nausea sensations from the stomach. Distention of the gastric antrum and corpus by the water-load test (rather than a balloon) also elicits the gastric dysrhythmias and nausea in susceptible individuals.

The Stomach and the Regulation of Food Intake, Hunger, and Satiety

Hunger is a basic human drive, a stressful condition that is eliminated or reduced by the ingestion of food. Hunger is also described as an uncomfortable “emptiness” of the stomach. The ingestion of food elicits relaxation of the stomach musculature (receptive relaxation) and accommodation of the physical volume of the meal; as these gastric neuromuscular events occur, hunger disappears and the comfortable, postprandial sensations of stomach fullness are experienced.

The volume of food ingested suppresses hunger and stimulates the sense of fullness more than the calorie content of the meal. ^, Infusion of nutrients into the stomach induces a greater intensity of fullness or satiety compared with infusion of the same nutrients into the duodenum. The suppression of hunger is greater when nutrients are taken by mouth, indicating that CNS, oropharyngeal, and gastric neuromuscular factors are integrated to produce the comforts of normal postprandial stomach fullness.

Healthy individuals usually eat until they are reasonably full. The physiologic attributes of postprandial fullness are not completely known, but the physical stretch on the stomach walls (and changes in intragastric pressure) induced by ingestion of food and the secretion of gastric juice are in part responsible. ^, Subjects experience a dramatic change from the sensation of stomach emptiness at baseline to the sensation of stomach fullness after ingesting water over a 5-minute period. The average volume of water ingested to achieve fullness is 600 mL; in contrast, patients with functional dyspepsia (FD) ingest, on average, only 350 mL to feel full, indicating a disturbance in stomach wall relaxation and/or wall tension. Similarly, fullness and satiety can be achieved by ingesting a nutrient drink until achieving maximum tolerated satiety. The presence of acid or nutrients in the duodenum or an elevated blood glucose level decreases the stomach wall tension. ^,

The ingestion of a solid meal initially elicits fundic relaxation, and little emptying of the food occurs during the lag phase. Sensations of fullness continue during the lag phase when the food is being triturated. Once the linear phase of gastric emptying begins, there is a progressive perception of decreasing stomach fullness and increasing stomach emptiness over time. Four or 5 hours after a solid meal, the stomach is indeed empty and the healthy individual feels hungry once again.

The physiologic mechanisms of hunger and satiety (and stomach emptiness and fullness) are under intense investigation. In the fasting state plasma motilin levels increase during the phase 3 of the MMC, but correlations between the sensation of hunger and increases of motilin or onset of phase 3 have not been described. As discussed in Chapters 4 and 7 , ghrelin is a 28–amino acid peptide secreted from endocrine cells of the oxyntic glands in the gastric fundus. Ghrelin levels also increase in the plasma during fasting (hunger) and stimulate food intake, probably acting via vagal afferent nerves. Orexins or appetite-stimulating peptides are synthesized by neurons in the lateral hypothalamus, promote food intake, and stimulate gastric contractility (in the rat) by actions on the dorsal motor nucleus of the vagus with projections to the gastric fundus and corpus. After ingestion of food, ghrelin levels decrease and are profoundly suppressed after gastric bypass surgery. Ghrelin also has promotility effects on the stomach and is being evaluated for the treatment of gastroparesis. ^,

Other hormones are candidates for important roles in the sensation of fullness or satiety, and these hormones are released after the ingestion of meals. CCK is released from the duodenal mucosa exposed to fatty acids. CCK receptors participate in fullness and nausea sensations elicited by intraduodenal lipid and gastric distention. ^, Leptin is synthesized in the stomach and released after food ingestion; circulating leptin reduces food intake via CNS regulation of the arcuate nucleus. Glucagon-like polypeptide-1 enhances fullness after a standard meal, reduces antral motility, and increases gastric volume. ^, Apolipoprotein A-IV is released from the small intestine during absorption of TGs and decreases food intake and gastric motility, in part, via CCK and vagal afferent pathways. Polypeptide-YY is released from the ileocolonic area after meals and is an important mediator of the “ileal brake” effect and appetite suppression. ^,

The brain and these gut hormones are clearly linked in the regulation of food intake and the regulation of gastric neuromuscular activity that produces stomach emptying. ^, The cephalic phase of gastric physiology is well known but has not been reexplored for many years. The sight, smell, and taste of food stimulate central vagal efferent activity that increases gastric acid secretion, gastric contractility, and increases 3-cpm GMA. Sham feeding, during which the subject chews and spits out the test meal rather than swallowing it, elicits the cephalic-vagal reflex. Sham feeding a warm hot dog on a bun elicits enhanced 3-cpm activity on the EGG, whereas sham feeding a cold tofu dog, a food that the subjects considered disgusting, resulted in blunted or no increase in the 3-cpm myoelectrical activity ( Fig. 50.18 ). Thus, sensory and emotional attributes of food during the cephalic phase of ingestive behavior also affect the neuromuscular activity of the stomach.

Developmental Aspects of Gastric Neuromuscular Function

Gastric peristalsis appears between 14 and 23 weeks of gestation. Grouped or clustered peristaltic waves are evident by 24 weeks. The neuroregulatory mechanisms responsible for the coordination of antropyloroduodenal motility in gastric emptying are well developed by 30 weeks of gestation. EGG recordings show normal 3-cpm activity in preterm infants delivered at 35 weeks that are similar to EGG signals recorded in full-term infants. ^, On the other hand, EGG recordings from premature infants (<35 weeks’ gestation) showed considerable tachygastria. GMA matures further over the first 6 to 24 months of life and achieves full adult values by the end of the first decade.

The development of ICCs has been studied intensely because of the interest in gastric electrical rhythmicity, smooth muscle contractions, and gastric dysrhythmias. Labels for the tyrosine kinase receptor (c-Kit) and the availability of knock-out mice lacking c-Kit have led to increased understanding of the development of ICCs. The ICCs demonstrate differential development, with c-Kit expression on ICCs in the MY-ICCs developing before birth, whereas ICCs in the deep muscular plexus (IM-ICCs) develop after birth. ENS and ICC networks are not fully developed and are poorly coupled at birth, but progressive maturity of gastric rhythmicity and contractility occur during perinatal development. ^, The ENS and ICCs in the deep muscular plexus are closely related, whereas ICCs in the myenteric plexus can develop normally in the absence of the ENS. Loss of ICCs in the pylorus is associated with loss of the inhibitory neural activity that may contribute to the development of pyloric stenosis in infants (see Chapter 49 ).

Assessment of Gastric Neuromuscular Function