Physiology of Nausea

Location of nausea

Percentage of patients

Epigastrium only

Epigastrium + substernal

Periumbilical

Substernal only

Lower abdomen

Head

Why do we experience nausea? From a homeostasis viewpoint, nausea is a warning signal of (a) danger in the external environment often related to food or motion, and (b) damage or dysfunction in an area or areas of the internal milieu related to digestive tract organs and other organ systems. For example, nausea protects the organism from ingesting potentially harmful foods. The external cues that stimulate nausea include the sight of food that evokes disgust, the smell of foods that evoke disgust, and the taste of bitter foods that evoke disgust. These disgusting, visual, olfactory, and taste stimuli result in or are associated with nausea and protect the individual from ingesting foods that may in fact contain poisons or toxins.

Various movements of the body or the illusions of movement are external stimuli during which otherwise healthy individuals may develop nausea. During movement or during the illusion of movement, visual, vestibular, and proprioceptive sensory organs are stimulated (and/or mismatched) and result in nausea that ranges from mild to severe in susceptible individuals [4]. Racial and gender differences contribute to susceptibility to motion sickness. For example, subjects of Asian ancestry are much more susceptible to the illusion of motion than Caucasians or African Americans [5, 6].

In regards to the internal milieu, ingested foods can elicit nausea and vomiting once they have entered the esophagus, stomach, duodenum, and small intestine. If vagal afferent nerves in the mucosa of these organs are activated by noxious foods or food-related toxins, then nausea and vomiting are elicited to expel the ingested harmful agents. Toxins that are absorbed through the gastrointestinal tract mucosa and enter the blood stream may be sensed in the area postrema and an additional level of defense, the central nervous system, is activated to stimulate nausea and vomiting [7].

Diseases of various organs of the digestive tract commonly result in nausea. Inflammation or obstruction in virtually every gastrointestinal (GI) organ, ranging from esophagitis to gastritis to small bowel bacterial overgrowth to constipation, can stimulate some degree of nausea. Most GI diseases that present with nausea also present with some degree of abdominal discomfort or pain. The noxiousness of nausea is very different from the noxiousness of visceral or somatic pain. Somatic pain is localized, the cause more obvious and treatments more available compared with visceral pain, which is usually difficult to localize to specific organs in the digestive tract and may be difficult to diagnose and treat. Nausea has similarities to pain. Nausea comes in waves or is constant and unremitting and can occur during day or night. But nausea often disappears, at least temporarily, after vomiting. Nausea alone can overwhelm one’s ability to think, to work, and to function, sapping energy and often forcing the individual to lie down, curl up, and strive to avoid moving and vomiting. In many patients, nausea may be difficult or impossible to reduce or to eradicate with drugs, devices, or complementary medicine approaches, all of which results in the irremediable suffering of nausea.

The physiology and pathophysiology of nausea are poorly understood, in part, because there are many different pathways to nausea. Treatment of nausea tends to be generic, and the specific mechanism driving the nausea is often unknown. Thus, current medications are often ineffective. The author recalls interviewing a patient with unexplained nausea and asking the patient to describe their nausea. The patient responded, “Which one?” to which the author replied, “How many do you have?” The patient thought for about one second and said, “Seven.” The author was incredulous at the time, but clearly and certainly, individual patients can indeed suffer from several different types of nausea.

In this chapter, studies of the pathophysiology of nausea will be reviewed with an emphasis on associations of nausea and gastric neuromuscular dysfunction. Dysfunction in other GI organs can also cause nausea and an organ-based review of the peripheral and central mechanisms of nausea is a major purpose of this book. There are many mechanisms driving nausea. Ultimately, however, the stomach is the organ which is involved in any form of nausea that culminates in vomiting, whether the nausea was evoked by motion or food or disease.

The Physiology of Nausea: From Motion to Emotion

Nausea and Motion

The nausea of motion sickness occurs naturally in otherwise healthy people. In susceptible individuals, nausea is evoked during motion experienced in cars, trains, planes, ships, and microgravity. In addition, the illusion of motion experienced watching big screen or 3-D movies or in a laboratory-based rotating optokinetic drum can induce nausea, sweating and headache, and epigastric discomfort associated with motion sickness [4]. These motion or illusion of motion-induced symptoms are evoked acutely, but mimic in many ways the chronic nausea experienced by patients with GI diseases as discussed in later chapters.

The physiology of nausea, especially nausea related to motion sickness, can be studied in the controlled conditions of a laboratory. Nausea is reliably induced with a rotating, optokinetic drum (Fig. 1.1). The inner surface of the drum is painted with black and white stripes. The rotation of the drum at approximately ten revolutions per minute evokes the sensation of self-motion in one to two minutes. The illusion of motion is associated with the neurosensory mismatch of visual, vestibular, and proprioceptive afferent nerve inputs to the brain. This neurosensory mismatch creates stress for the organism in that there is conflict between the sensation of movement from visual stimuli and no actual movement from proprioception and vestibular sensory inputs to the brain. This is a critical computational problem for any organism. In susceptible subjects, the “stress” of the neurosensory mismatch during the illusion of body motion results in cold sweating, pallor, epigastric discomfort, and nausea [8]. When nausea escalates to an unacceptable intensity, the drum is stopped at the subject’s request. After the drum rotation is stopped, visual, vestibular, and proprioceptive stimuli are congruent, homeostasis is reestablished, and nausea disappears.

Fig. 1.1

Rotation of an optokinetic drum with black and white stripes on the inner surface evokes the illusion of self-motion and the nausea of motion sickness in susceptible subjects

During onset of nausea, the normal three cycles per minute (cpm) gastric myoelectrical activity (GMA) shifts to gastric dysrhythmias such as tachygastrias [4]. Tachygastrias are abnormal gastric electrical events ranging from 3.5 to 10 cpm [9]. Changes in GMA were studied in healthy subjects during optokinetic drum rotation. Subjects were positioned within the optokinetic drum. At baseline, the subjects had no nausea and normal 3 cpm GMA was recorded. In subjects who became nauseated during drum rotation, the normal GMA abruptly shifted to tachygastria (Fig. 1.2). During this time, parasympathetic tone decreased and sympathetic tone increased as shown by changes in heart rate variability and skin conductance measures [10, 11]. Nausea was reported by the subjects approximately one minute after the gastric dysrhythmias developed suggesting that the gastric dysrhythmia needed to be established for some duration of time before the change in gastric rhythm status was appreciated consciously as an unpleasant nausea sensation. Over the next ten minutes of drum rotation, nausea frequently increased in intensity and gastric dysrhythmias continued until the drum was stopped. During drum rotation, those subjects who became nauseated also had significantly increased plasma vasopressin, cortisol, and epinephrine compared with subjects who reported no nausea during drum rotation [12, 13]. Asian subjects had particularly intense nausea symptoms, more frequent vomiting episodes, and higher levels of vasopressin compared with African American and Caucasian subjects, indicating racial and genetic differences in susceptibility to nausea in these conditions [13]. Subjects who did not develop nausea during illusory self-motion remained in the 3 cpm GMA pattern (Fig. 1.2) and neurohormonal measures were similar to baseline. Thus, in this laboratory model of nausea, the illusion of motion resulted in an acute neuroendocrine stress response and an acute peripheral gastric response—tachygastria.

Fig. 1.2

Running spectral analyses of gastric myoelectrical activity (GMA) recorded before and after rotation of the optokinetic drum (Drum On). The left figure shows the running spectral analysis (RSA) of the GMA recorded from a subject who did not develop nausea during drum rotation. The X-axis is the frequency of the GMA, the Y-axis represents time, and the Z-axis shows the power of the frequencies. This subject remained in the normal 3 cpm GMA as shown by the peaks in the normal 3 cpm range and did not develop nausea. The right figure shows the RSA of GMA from a healthy subject who developed nausea during Drum On. GMA shifts from normal 3 cpm peaks to multiple peaks in the 3.5–9 cpm tachygastria range during drum rotation (Drum On) in the subject who became “queasy”

The increase in epinephrine and cortisol indicated adrenal sympathetic nervous system activation and a stress response. The increase and subsequent decrease in vasopressin correlated with the increasing nausea during drum rotation and then the decreasing nausea symptoms after the drum was stopped. Increased vasopressin levels also occurred during nausea induced by morphine sulfate infusions [14]. Infusion of vasopressin also stimulates canine tachygastrias and results in delayed gastric emptying [15]. Thus, release of various neurotransmitters and hormones, such as vasopressin and epinephrine in addition to gastric dysrhythmias, have a role in the physiology of nausea.

Figure 1.3 illustrates central and peripheral neuro-gastric interactions during the induction of nausea based on studies of the nausea of motion sickness. There are several contributing central nervous system (CNS), hormonal, and GMA events involved in the nausea induced by motion. The nausea induced by motion represents stimulation of visual, vestibular, and proprioception sensory pathways that elicit sympathetic nervous system stress responses, but this is not the classic “fight or flight” sympathetic response that energizes subjects to spirited action. Rather, the stress response associated with nausea is accompanied by fatigue, efforts to avoid vomiting, and a strong desire to lie down and be still, the ultimate behavioral effects of nausea.

Fig. 1.3

Peripheral and central pathways activated during the shift from normal 3 cpm gastric myoelectrical activity (GMA) to tachygastria and CNS interactions during the nausea of motion sickness are shown. Tachygastria-related changes in vagal afferent activity are transmitted through the nucleus tractus solitarius to higher centers of the brain, ultimately reaching the cortex where nausea is recognized and reported by the subject. During motion sickness, increased levels of vasopressin are released from the posterior pituitary and increased epinephrine is released from the adrenal glands while the sympathetic nervous symptom tone increases, indicating a stress response. As homeostasis is reestablished after the drum is stopped, GMA returns to the normal 3 cpm pattern as shown in the electrogastrogram rhythm strips and nausea disappears

The stomach is a key peripheral organ in the physiology of nausea elicited during motion sickness. GMA normally ranges from 2.5 to 3.5 cpm in healthy subjects [16, 17]. When the interstitial cells of Cajal (ICCs), the gastric pacemaker cells, are present in normal numbers in the corpus and antrum of the stomach then the normal 3 cpm GMA is recorded by cutaneous and serosal myoelectrical recordings [16, 17]. Gastric enteric nerves, smooth muscle, parasympathetic and sympathetic inputs, and hormonal fluxes can temporarily affect ICC function and thus the rhythmicity of GMA. If activity in one or more neuro-hormonal elements is disturbed, as during the development of in the nausea of motion sickness nausea, then a shift from normal 3 cpm GMA to gastric dysrhythmias occurs and nausea symptoms are experienced. The acute tachygastrias during the nausea of motion sickness develops in the setting of increased sympathetic activity and vagal withdrawal [10, 11]. The presence of the gastric dysrhythmias is necessary, but may not be sufficient to evoke nausea. Other factors such as the increase in epinephrine and vasopressin may also be needed for the full expression of nausea and related symptoms like cold sweating, dry mouth, etc. The presence of nausea is also associated with loss of gastric smooth muscle tone [18]. The change in gastric rhythm and tone affects vagal afferent activity and other sensory neurons within the wall of the gastric corpus and antrum [19]. These changes in GMA and tone during nausea are sensed by vagal afferent activity and transmitted to the nucleus tractus solitarius and higher brain centers. Ultimately, these peripheral inputs from the stomach reach the cortex and nausea is perceived and reported.

Nausea evoked during drum rotation usually proceeds from mild to severe over the course of time (15-min rotation limit), presumably due to an escalation of the stimulation or the neuro-hormonal responses described above [12, 13]. The pathophysiology of the escalation of nausea intensity is complex because countermeasures are continually evoked to attempt to regain homeostasis even as nausea intensity increases. Napadow et al. described areas in the brain using functional magnetic resonance imaging (fMRI) that are activated during illusory self-motion while patients described increasing severity of nausea [20]. During the transition from mild to moderate to severe nausea, more brain regions, including insular, anterior cingulate, orbitofrontal, somatosensory, and prefrontal cortices were activated. During strong nausea, the linkage of anterior insula and midcingulate was sustained. Activation of these diverse regions reflects the extensive physiological responses in blood pressure and respiratory changes and shifts in GMA that are intimately associated with nausea and the accompanying symptoms features. The exact sequence of the countermeasures in the autonomic nervous and endocrine systems in response to activation of these CNS areas have not been fully elucidated.

The progression from the state of feeling comfortable (and no nausea) to experiencing mild to severe nausea during the illusion of motion in a drum or in an fMRI device represents important laboratory-induced nausea conditions that have implications for understanding chronic nausea. Patients often have low intensity, intermittent nausea that then flares into severe acute episodes that are similar to the acute and severe nausea elicited by illusory self-motion. Therapeutic approaches to prevent or counteract the physiological responses that mediate acute nausea may be helpful for patients with chronic nausea syndromes. More laboratory-based studies of the physiology of nausea are needed to further understand these relationships.

Nausea and Emotion/Disgust

Emotional states such as disgust are often associated with nausea and can also be induced in the laboratory. Disgust is associated with effects on GMA. Healthy subjects viewed neutral to highly arousing pictures used to elicit disgust while GMA was recorded. Analyses showed the percentage of bradygastria (1.0–2.5 cpm) predicted the disgust ratings evoked in the highly arousing picture condition [21]. The onset of bradygastria was considered a prodromal sign for vomiting during disgust, although the presence of nausea was not reported in these studies. In another study, video clips were used to induce ingestive disgust in healthy subjects who underwent electrogastrogram and electrocardiogram recordings and fMRI studies [22]. Groups who reported high and low disgust were identified and separated for analysis. Results showed that disgust ratings were dependent on tachygastria activity and that the brain areas activated during disgust were the posterior and anterior insula, basal ganglia, thalamus, and bilateral somatosensory and somatomotor cortices. The presence of tachygastria was related to significant activation of mid-anterior insula on the right and the cingulate cortex [23]. The conclusion was that the peripheral physiological changes in the stomach, the tachygastrias, directly contributed to the activation CNS areas (insular cortex) and the emotional responses of ingestive disgust. Thus, the visual stimulation of disgusting foods disrupted the GMA and evoked nausea and disgust. Was peripheral tachygastria the key? It would have been interesting to ask these subjects where they “felt” or where they “located” their nausea in these experiments. As listed in Table 1.1, would they have chosen “Head” or “Epigastrium” or some other location?

Sham feeding stimulates the cephalic vagal phase of digestion during which gastric acid secretion increases and the amplitude of 3 cpm GMA increases, although the chewed food does not actually enter the stomach, because it is spit out [24]. Sham feeding elicited by chewing and spitting out a warm hotdog increased the amplitude of normal 3 cpm GMA in healthy subjects; but during sham feeding using a cold, white, tofu dog, some subjects reported this was a disgusting experience. The GMA shifted from normal 3 cpm pattern to bradygastria in those subjects who reported disgust [25]. In another set of experiments in healthy subjects, n-propylthiouracil strips were placed on the tongue to produce an intense bitter taste. The intense bitter taste also evoked nausea and gastric dysrhythmias [26]. Thus, special sensory organs responding to motion stimuli, disgusting visual stimuli, or noxious taste stimuli can lead to nausea and disruption of normal GMA and the development of bradygastrias and tachygastrias. These motion and emotion studies show the relationship between the acute onset of nausea and the acute onset of gastric dysrhythmias.

Despite exhaustive testing with standard diagnostic procedures such as radiographic studies and endoscopy and gastric emptying studies, many patients have unexplained and chronic nausea. Some of these patients have gastric dysrhythmias and abnormalities of gastric relaxation or tone. Chronic neuromuscular dysfunction of the stomach or of non-gastric GI organs may result in chronic gastric dysrhythmias and chronic nausea syndromes. The pathophysiology of unexplained nausea in these patients is discussed below.

The Pathophysiology of Nausea and Gastric Neuromuscular Dysfunction

In this section, the pathophysiology of chronic nausea related to gastric neuromuscular diseases and disorders will be reviewed. The pathophysiology of nausea originating in the stomach includes gastric mucosal inflammation due to acid or H. pylori. Vagal afferent sensory nerves convey the information of mucosal injury and inflammation to the NTS and higher centers where ultimately the nausea sensations are appreciated. This mechanism of nausea related to mucosal diseases is very common and easily diagnosed and treated. The majority of patients with unexplained nausea and vomiting, however, have normal gastric mucosa at endoscopic examination [27]. Thus, neuromuscular abnormalities of the stomach may be the mechanisms of nausea in many of these patients.

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