The Neural/Cephalic Phase Reflexes in the Physiology of Nutrition

Home , Vagovagal reflex, Zafra (agriculture)

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Neuroscience and Biobehavioral Reviews 30 (2006) 1032–1044 www.elsevier.com/locate/neubiorev Review The neural/cephalic phase reﬂexes in the physiology of nutrition

Marı´ a A. ZafraÃ, Filomena Molina, Amadeo Puerto

Psychobiology, Department of Experimental Psychology and Physiology of Behavior. Campus de Cartuja, University of Granada, Granada 18071, Spain

Received 14 October 2005; received in revised form 15 March 2006; accepted 16 March 2006

Abstract

The cephalic phase of nutrition refers to a set of food intake-associated autonomic and endocrine responses to the stimulation of sensory systems mainly located in the oropharyngeal cavity. These reactions largely occur in the digestive system, but they have also been observed in other structures. Most published data indicate that cephalic responses are mediated by the efferent component of the vagus nerve, although other neurobiological components and brain centers must be involved. The physiological significance of all of these reactions has yet to be fully elucidated, but when the cephalic phase of digestion is obviated major physiological and behavioral dysfunctions can be observed. This has led numerous authors to propose that their function may be essentially adaptive, preparing the digestive system for the reception, digestion, and absorption of the food. Study of the neural/cephalic phase and the consequences of its absence may have clinical relevance in the setting of artificial nutrition, and may explain the difficulties of providing enteral nutrition to many of the patients that require it. r 2006 Elsevier Ltd. All rights reserved.

Keywords: Cephalic phase; Digestive enzymes; Gastric acid; Gastrointestinal hormones; Immunoglobulins; Vagus nerve; Dorsal motor nucleus of the vagus; Nucleus of the solitary tract; Lateral hypothalamus; Ventromedial hypothalamus; Orexins; Thyrotropin-releasing hormone; Enteral feeding; Disturbances of enteral nutrition

Contents

1. Introduction ...... 1032 2. Reﬂex responses during the cephalic phase...... 1033 2.1. Oral responses ...... 1034 2.2. Gastric responses ...... 1035 2.3. Intestinal responses ...... 1036 2.4. Pancreatic responses ...... 1036 2.5. Other cephalic responses ...... 1037 3. Neural mechanisms involved in cephalic responses ...... 1037 4. Disturbances induced by absence of cephalic phase...... 1039 5. Conclusion ...... 1041 Acknowledgments ...... 1041 References ...... 1041

1. Introduction

Studies of the physiological processes that participate in nutrition have demonstrated that food intake is dependent ÃCorresponding author. Fax: +34 58246239 on multiple and complex mechanisms involving both E-mail address: [email protected] (M.A. Zafra). central and peripheral nervous systems (Le Magnen,

0149-7634/$ - see front matter r 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.neubiorev.2006.03.005 ARTICLE IN PRESS M.A. Zafra et al. / Neuroscience and Biobehavioral Reviews 30 (2006) 1032–1044 1033

1992; Berthoud, 2002; Ritter, 2004). With regard to the post-absorptive consequences of food ingestion (Pav- peripheral mechanisms, researchers have underlined the lov, 1910; Brand et al., 1982; Davis, 1999). Because it is an importance of signals that originate at different levels of invasive technique, a modified sham feeding variant has the digestive system. Thus, emphasis has been placed on been developed for use in humans, in which the food is the role of the gustatory component of food, gastric tasted but not swallowed (Richardson et al., 1977; Jackson distension, gastric emptying rate, nutrient absorption rate, et al., 2001). The shortcoming of this approach is that and different gastrointestinal hormones (Le Magnen, 1992; pharyngeal and esophageal receptors are not stimulated, Phillips and Powley, 1998; Davis, 1999; Ritter, 2004). and it has been suggested that this stimulation may be With regard to oropharyngeal systems, it has been important for generating some secretions during the demonstrated over the past few decades that the stimula- cephalic phase (Brand et al., 1982). Nevertheless, both tion exerted by food at this level of the digestive tract is sham feeding and modified sham feeding allow the cephalic essential to different nutrition-related processes. Thus, phase to be isolated from subsequent phases, enabling these systems are relevant to satiety (Le Magnen, 1992; assessment of its participation in digestive events (Teff and Hetherington, 1996), appetite (Le Magnen, 1992; Davis, Engelman, 1996b). 1999), and the development of preferences and aversions (Deutsch et al., 1976; Sclafani et al., 1999; Zafra et al., 2. Reflex responses during the cephalic phase 2000, 2002, 2006; Mediavilla et al., 2005). Less attention has been paid to the fact that participation of orophar- Reactions to cephalic stimulation are generally rapid and yngeal systems in physiological digestive processes is transient responses mediated by the efferent component of required for optimal nutritive functioning (Brand et al., 1982; Mattes, 1997). Events that occur during food ingestion have usually been divided into different phases according to the part of the digestive system that is stimulated by the food, i.e. a neural/cephalic phase, gastric phase, and intestinal phase (Richardson et al., 1977; Naim et al., 1978; Brand et al., 1982). The neural phase of digestion refers to a set of physiological, endocrine and autonomic responses of the digestive system that result from stimulation of sensory systems at the cephalic level, especially in the oropharyngeal cavity. Although these responses are preferentially associated with the gustatory/olfactory properties of the food, the sight or anticipation of food or any other circumstance associated with food intake can also stimulate and trigger these responses (Pavlov, 1910; Powley, 1977; Nederkoorn et al., 2000). While the first observations date from 1878 (Moore and Schenkenberg, 1974; Brand et al., 1982), the characteristics of the digestive secretions of the cephalic phase were first documented by Ivan Pavlov (Brand et al., 1982; McGregor and Lee, 1998), who received the Nobel Prize in 1904 for his research on the physiology of digestion, widely known through his book ‘‘The Work of the Digestive Glands’’ (Pavlov, 1910). Although Pavlov introduced the term ‘‘psychic reflex’’ for these responses, subsequent authors agreed to use the designation ‘‘cephalic phase’’ in order to highlight the fact that, unlike gastric or intestinal phases, responses during this stage are essentially mediated by brain mechanisms and peripheral neural systems (Molina, 1978). Fig. 1. Main chemical substances released in the digestive system during Sham feeding is the most frequently used method for the cephalic phase. These secretions, essential for the correct digestion of studying processes related to the cephalic phase. Animals food, occur at both endocrine and exocrine levels. Endocrine secretions are allowed to ingest food in a normal manner but the food include the release of gastrin, leptin, and immunoglobulin from stomach is diverted by gastric or esophageal catheter so that it and of insulin, glucagon, PP, and CCK from pancreas. Exocrine secretions include the release of gastric acid and pepsinogen from stomach, digestive cannot accumulate in the gastric cavity, preventing enzymes from oral cavity, stomach, and pancreas, and bicarbonate from subsequent processing of food in remaining segments of small intestine and pancreas. PP, pancreatic poypeptide; CCK, cholecys- the gastrointestinal tract and allowing disassociation from tokinin. ARTICLE IN PRESS 1034 M.A. Zafra et al. / Neuroscience and Biobehavioral Reviews 30 (2006) 1032–1044

Table 1 Main responses during the cephalic phase and proposed actions and action mechanisms

Responses Actions and mechanisms

Oral cavity Saliva Lubricates and protects oral mucosa Dissolves food particles to be transported to the taste buds (essential for taste perception) Initiates breakdown of starch and fats (saliva contains enzymes such as amylase and lingual lipase) Stomach Hydrochloric acid Breakdown of foods Gastrin Contributes to gastric acid secretion Digestive enzymes (lipase) Breakdown of fats Immunoglobulins Protects gastric and intestinal mucosae against any exogenous microorganisms ingested with the food Leptin Contributes to satiation (by acting on leptin receptors in vagal afferents that play a major role in this process) Duodenum Bicarbonate Neutralization of gastric acid upon entry into the duodenum Pancreas Bicarbonate Neutralization of acid contents of duodenum Digestive enzymes (lipase, amylase, trypsin, chymotrypsin) Breakdown of fats, carbohydrates and protein Insulin Anticipatory metabolic role Glucagon To prevent hypoglycemia when protein-rich food is eaten Pancreatic polypeptide Cholecystokinin Other secretions Gallbladder ﬂow Secretin Enzymes in adipose tissue Other non-secretory responses Gastric motor activity Postprandial thermogenesis Cardiac response Respiratory quotient Absorption and transport of nutrients

the vagus nerve (see below) (Pavlov, 1910; Mattes, 1997; pancreatic enzyme system (Mattes, 2000; Pedersen et al., Powley, 2000). Most of these reactions imply the release of 2002). chemical substances in the digestive system (see Fig. 1), Saliva is released before food is present in the although some non-secretory responses have also been oropharyngeal cavity, since the mere sight of food or any observed (Pavlov, 1910; Powley, 1977; Brand et al., 1982; other food-related stimulus is sufficient to activate this see Table 1). mechanism. Nevertheless, the volume of saliva markedly increases once food reaches the oral cavity (Klajner et al., 2.1. Oral responses 1981; Richardson and Feldman, 1986; Mattes, 2000), implying that activation of receptors at this level is The first cephalic secretion, salivary flow, occurs in the especially important. Thus, although there are many oral cavity itself and is of great importance for digestion individual differences, the basal salivary flow can be (Tepper, 1992; Nederkoorn et al., 2000; Raudenbush et al., increased up to sixfold after only 15 m of sham-feeding 2003; Legenbauer et al., 2004). Besides its lubricating and (Richardson and Feldman, 1986; see Fig. 2). protective action, saliva is essential for taste perception The sensory receptors that participate in saliva release because it dissolves food particles for their transport to the are both mechanical (the mere act of chewing serves as taste buds, thereby facilitating the stimulation of taste adequate stimulant) and chemical in nature. With respect receptors (Pedersen et al., 2002). It also contains enzymes to the latter, it has been demonstrated that saliva secretion such as amylase and lingual lipase that are essential for is more influenced by the quality of a gustatory stimulus starch and fats breakdown, respectively (Giduck et al., than by its palatability. Thus, an acidic substance (e.g., a 1987; Mattes, 2000). The cephalic phase is therefore even lemon) stimulates a larger release compared with an more critical in children because of the immaturity of their appetizing foodstuff, in order to protect the oral mucosa ARTICLE IN PRESS M.A. Zafra et al. / Neuroscience and Biobehavioral Reviews 30 (2006) 1032–1044 1035

200 the volume of saliva, with sucrose or fructose, for example, saliva stimulating the release of amylase-rich saliva (Mattes, 2000; Pedersen et al., 2002). 160 2.2. Gastric responses 120 As Pavlov demonstrated, there is considerable secretion

ml/h at the gastric level in response to cephalic stimulation 80 (‘‘psychic’’ gastric secretions), including release of hydrochloric acid (Pavlov, 1910; Katschinski et al., 1992), pepsinogen (Janowitz et al., 1950; Preshaw et al., 1966), 40 gastrin (Feldman et al., 1979; Robertson et al., 2001) and digestive enzymes such as gastric lipase (Wojdemann et al., 0 2000). Some immunoglobulins (IgA) are also released from 0 15 30 37.5 the stomach during the cephalic phase, and although their physiological signiﬁcance is unknown, these antibodies 6 may contribute to protecting gastric and intestinal mucosae gastric acid against any exogenous microorganisms ingested with the 5 food (Fandriks et al., 1995). Likewise, in a recent animal study, Konturek et al. demonstrated a transient increase in 4 leptin in response to oropharyngeal stimulation (Konturek and Konturek, 2000). Since this hormone is known to be 3 synthesized in the gastric mucosa (as well as in adipocytes) and its release can be induced by vagus nerve stimulation

meq/15 min (Sobhani et al., 2002), it was proposed that the cephalic 2 leptin secreted from the stomach may contribute to the satiation process (Konturek and Konturek, 2000). In fact, 1 leptin receptors are present in vagal afferents and play a major role in this process (Buyse et al., 2001), as does the 0 vagus nerve itself (Phillips and Powley, 1998; Zafra et al., 0 15 30 37.5 2003, 2004a, b). 160 Gastrin rises rapidly above basal levels after starting a pancreatic polypeptide 30-min session modiﬁed sham feeding and remains elevated for a further 15 min, approximately (Feldman et al., 1979; 120 Robertson et al., 2001). This hormone is the most potent known stimulant of gastric acid secretion, and it has been suggested that the main role of the gastrin released during 80

pg/ml the cephalic phase is to contribute to gastric acid secretion, one of the most important cephalic responses (Feldman 40 and Richardson, 1981; Kovacs et al., 1997). In fact, the cephalic phase contributes approximately 50% of all acid secreted in the course of normal ingestion (Richardson 0 0 15 30 37.5 et al., 1977; Martı´ nez et al., 2002). In humans, release TIME (MIN) begins 3–5 min after sham feeding starts and usually lasts for 30–120 min after it ends (Janowitz et al., 1950). In basal peak animals, secretion lasts significantly longer: after sham- Fig. 2. Mean concentration at baseline (t ¼ 0) and maximal (peak) feeding for 15 min, gastric acid release continues for 2–4 h, concentration obtained for some typical cephalic phase responses. All data with a maximum secretion rate at 30–45 min after derive from humans undergoing 30 min of modified sham feeding (MSF) commencement of the feeding (Pavlov, 1910; Moore and of an appetizing meal (steak, french-fried potatoes, and water). The time of the start of the MSF session is considered as t ¼ 0. Data obtained from Schenkenberg, 1974; Richardson et al., 1977; Katschinski Richardson et al. (1977); Feldman et al. (1979); and Richardson and et al., 1992; see Fig. 2). Feldman (1986). The influence of the hedonic component of the nutritive stimulant on gastric release was also reported by Pavlov (1910), who stated: ‘‘If we give the dog, for example, (Giduck et al., 1987; Mattes, 2000). Likewise, it has been something else to eat which it does not relish to the demonstrated that the specific macronutrients present in same degree as flesh or bread, we find the initial increase the food determine the enzymatic composition rather than in quantity and strength of juice does not appear’’. ARTICLE IN PRESS 1036 M.A. Zafra et al. / Neuroscience and Biobehavioral Reviews 30 (2006) 1032–1044

Subsequent research confirmed his findings, revealing that tion of pancreatic exocrine secretory cells. Although the the volume of gastric acid released during the cephalic involvement of the vagus nerve is widely acknowledged, it phase is directly related to the desire for the food in is currently considered that part of the pancreatic response question (Janowitz et al., 1950; Brand et al., 1982). to cephalic stimulation may be due to secondary effects of Attempts have been made to demonstrate the individual some hormones (Preshaw et al., 1966; Behrman and Kare, contribution of each sensory system involved in cephalic 1968; Naim et al., 1978; Konturek and Konturek, 2000). phase gastric secretions. Feldman and Richardson (1986) Endocrine pancreatic secretions produced by the cepha- designed a study for this purpose after reports that it is not lic phase include insulin, glucagon, and pancreatic poly- necessary to taste the food for an increase in these peptide (PP), which are all mediated by the vagus nerve responses to be produced. The results showed that the (Schwartz et al., 1978; Berthoud and Powley, 1990; Teff sight, thought, or smell of appetizing food (without its and Townsend, 1999). taste) can provoke a significant increase in the concentra- Insulin release during the cephalic phase has been tion of gastric acid and gastrin. Nevertheless, this increase extensively studied in animal species and humans. Studies is much smaller than that produced when taste is also have generally demonstrated a rapid increase in the plasma included, as in modified sham feeding. Therefore, the content of this pancreatic hormone at 1 min after stimula- greater the stimulatory complexity of the foodstuff, the tion of the oral cavity with different types of nutrient greater is the response. These results also confirm that (Berthoud et al., 1980; Louis-Sylvestre, 1987; Strubbe, gustatory factors make an essential contribution to the 1992; Teff et al., 1993). This increase, which lasts for cephalic phase of gastric secretion. around 10 min, is produced in absence of increased glucose levels and is therefore a pre-absorptive effect (Berthoud 2.3. Intestinal responses and Powley, 1990; Secchi et al., 1995; Teff et al., 1995). The insulin released during the cephalic phase depends on the Duodenal neutralization of the acid that results from functional integrity of the vagus nerve, especially of its gastric emptying is an especially important mechanism for hepatic and gastric branches (Berthoud and Powley, 1990; protecting the mucosa of this segment of the intestine. Herath et al., 1999; Ahre´ n and Holst, 2001). Several animal and human studies have revealed the release The hedonic qualities of the gustatory stimulus again of bicarbonate (the main neutralization agent) from show a major influence on the release (Giduck et al., 1987; duodenal mucosa during the cephalic phase of digestion Stockhorst et al., 2000). Thus, rats fed saccharin-contain- (Ballesteros et al., 1991; Glad et al., 1997). This increase, ing diets show signs of a greater preabsorptive insulin which can be around 35%, persists for around 15 min after response compared with those on a diet without saccharin the end of oropharyngeal stimulation (Ballesteros et al., (Giduck et al., 1987; Louis-Sylvestre, 1987), and the sweet 1991). taste alone of saccharin is sufficient to produce the cephalic phase of insulin secretion (Berthoud et al., 1980; Woods 2.4. Pancreatic responses and Bernstein, 1980). In humans, however, this is not the case. The sampling of food, which activates additional It was long assumed that the release of substances from sensory modalities such as touch and smell, is required in the pancreas was so small and for such a short period as to order to produce a stronger increase in pre-absorptive be without significance. However, the cephalic phase is now insulin secretion (Teff et al., 1995). known to have important effects on pancreatic secretion The physiological significance of the insulin released (Preshaw et al., 1966; Behrman and Kare, 1968), which is during the cephalic phase has not been elucidated. A considered to occur at two levels: exocrine secretion of possible anticipatory metabolic role has been proposed, substances released by the pancreas to the duodenum; and since insulin secretion is associated with a decrease in endocrine secretions of hormones directly released by the baseline glycemic levels (Proietto et al., 1987; Storlien and gland into the bloodstream (Konturek and Konturek, Bruce, 1989; Secchi et al., 1995). 2000). The release of glucagon is not as well documented as Exocrine pancreatic release in response to oropharyngeal that of insulin. It occurs when food is tasted or even when stimulation include pancreatic digestive enzymes (amylase, it is seen or smelled, although the latter two sensory lipase, trypsin. or chymotrypsin) and bicarbonate (Naim modalities are much less powerful (Secchi et al., 1995; Teff et al., 1978; Katschinski et al., 1992; Hiraoka et al., 2003). and Engelman, 1996a). Glucagon has several known In dogs, this pancreatic juice begins to flow 2–3 min after physiological effects, including the stimulation of gluco- initiating sham feeding and reaches a maximum peak at genesis, lipolysis, and insulin release; and the inhibition 15 min (Pavlov, 1910; Preshaw et al., 1966). The precise of gastric acid and exocrine pancreatic secretions, and nature of the mechanism involved in exocrine pancreatic peristaltic intestinal activity (Bataille, 1989). No data are secretions is controversial. Some authors interpret them as currently available on the precise role of the glucagon a secondary effect of hormones released as a consequence secreted during the cephalic phase, although it has of cephalic phase gastric secretions, whereas for others, been suggested that it can prevent hypoglycemia when including Pavlov, they resulted from direct vagus stimula- protein-rich food is eaten (Teff and Engelman, 1996a) ARTICLE IN PRESS M.A. Zafra et al. / Neuroscience and Biobehavioral Reviews 30 (2006) 1032–1044 1037 and contribute to postprandial thermogenesis (LeBlanc, duced by the energy required for digestion, absorption, and 2000). utilization of ingested foods. The first phase lasts for An increase in pancreatic polypeptide (PP) release is 30–40 min and is proposed to result from the actions of observed after stimulation of cephalic receptors (Taylor hormones released during the cephalic phase, such as et al., 1978; Feldman et al., 1979; Jackson et al., 2001; insulin or glucagon (LeBlanc, 2000). Robertson et al., 2001; see Fig. 2). In humans, the cephalic Other reactions observed during the cephalic phase phase of PP secretion appears as early as 10 min after the include an anticipatory increase in the cardiac response start of the meal and remains elevated for at least another and a rise in the respiratory quotient in response to intake 30 min after ending sham feeding (Hoentjen et al., 2001). In (Giduck et al., 1987; McGregor and Lee, 1995, 1998; fact, the PP secreted during the cephalic phase constitutes Nederkoorn et al., 2000), as well as changes in the 16% of the total PP released during a normal ingestion absorption and transport of nutrients, gallbladder empty- episode (Taylor, 1989) and, unlike gastric juice secretions ing, release of secretin, and release of enzymes in adipose during the cephalic phase, swallowing the food may be an tissue (Giduck et al., 1987; Louis-Sylvestre, 1987; Hoentjen influential factor, but does not appear to be indispensable et al., 2001; Khan et al., 2005). for PP secretion (Brand et al., 1982; Schwartz, 1983; Taylor, 1989). Although this hormone has various known 3. Neural mechanisms involved in cephalic responses physiological effects (inhibition of pancreatic exocrine secretion and bile duct motility) (Schwartz, 1983; Taylor, Except for salivary release, which is partly controlled by 1989), the specific role of the PP released during the sympathetic and non-vagal parasympathetic fibers origi- cephalic phase has yet to be determined. nating in the salivary nuclei of the brain stem (Ramos and The release of cholecystokinin (CCK) has also been Puerto, 1988; Ramos et al., 1988a, b, 1989a; Mattes, 2000), reported during the cephalic phase of digestion. Release of it is accepted that digestive events during the cephalic phase this intestinal hormone appears to be under control of the are mediated through the vagus nerve, as first demon- vagus, given that prior administration of atropine com- strated by Pavlov (1910) and confirmed by numerous pletely blocked this response (Schafmayer et al., 1988). studies. Thus, vagotomy or administration of the muscarinic antagonist atropine interrupts physiological responses 2.5. Other cephalic responses caused by oropharyngeal stimulation, whereas stimulation of the vagus reproduces most of these responses (Brand Although the most noteworthy consequences of the et al., 1982; Richardson and Feldman, 1986; Ramos et al., cephalic phase are the digestive secretions, other physiolo- 1989b; Katschinski et al., 1992). gical processes are also involved (Louis-Sylvestre, 1987; Vagal efferents distributed throughout the digestive Stern et al., 1989; Katschinski et al., 1992). Thus, several system are known to originate in the dorsal motor nucleus studies showed a cephalically stimulated anticipatory of the vagus (DMNX) and in the nucleus ambiguus increase in gastric motor activity (Stern et al., 1989; (Norgren and Smith, 1988; Loewy and Spyer, 1990; Powley Katschinski et al., 1992; Chen et al., 1996). Stern et al. et al., 1992). However, available data indicate that the measured gastric myoelectric activity in healthy human responses evoked during the cephalic phase of digestion are subjects and vagotomized patients. In the healthy indivi- mediated by fibers from the DMNX (Powley, 2000). In duals, the stimulation produced by sham feeding and order to trigger cephalic digestive events, these vagal normal ingestion produced similar increases in the ampli- efferents can be activated by upper centers of the brain tude and power of this activity, whereas no change in this (stimulated by oropharyngeal or visual inputs, etc.) or activity was observed in vagotomized patients, suggesting directly by visceral afferents (Brand et al., 1982; Giduck et that this response to sham feeding is vagally mediated al., 1987; Powley, 2000). Thus, it has been demonstrated (Stern et al., 1989). A study confirmed this hypothesis and that DMNX neurons receive visceral information either also proposed that CCK participates in the gastric but not directly via vagal afferents, giving rise to monosynaptic duodenal motor response (Katschinski et al., 1992). vago-vagal reflexes (Kalia and Sullivan, 1982; Rogers et al., Although the above responses have been the most 1995), or indirectly via interneurons of the nucleus of the documented, other effects of oropharyngeal stimulation solitary tract (NST), the main central relay of vagus nerve have been demonstrated in recent decades. Giduck et al. sensory fibers (Norgren and Smith, 1988; Altschuler et al., (1987) suggested that these reactions may be secondary 1989; Loewy and Spyer, 1990; Powley et al., 1992). In fact, effects of central and vagus activation induced by cephalic the DMNX is located parallel to the NST and has highly stimulants rather than direct responses to cephalic stimula- profuse dendritic branches that extend toward it, establish- tion. One of these effects, postprandial thermogenesis, has ing numerous synaptic contacts (Powley et al., 1992). been especially emphasized (Storlien and Bruce, 1989, Besides receiving information from visceral vagal affer- McGregor and Lee, 1995; Nederkoorn et al., 2000). Two ents, the NST is a gustatory relay of facial and phases of postprandial thermogenesis have been described: glossopharyngeal nerves and, to a lesser degree, of vagal a ‘‘cephalic’’ phase, considered to occur in response to afferents (Hamilton and Norgren, 1984; Altschuler et al., orosensory stimulation; and an ‘‘obligatory’’ phase, pro- 1989). Since NST gustatory neurons establish synaptic ARTICLE IN PRESS 1038 M.A. Zafra et al. / Neuroscience and Biobehavioral Reviews 30 (2006) 1032–1044 contact with DMNX nerve cells, it has been proposed that this circuit mediates, albeit partially, cephalic responses triggered by the gustatory component of food (Powley, 2000). As mentioned above, the DMNX also receives direct projections from upper brain structures (brainstem areas, diencephalic and telencephalic regions), some of which have been widely implicated in nutrition or in the physiology of the digestive system. These include projections from the parabrachial nucleus, mesencephalic peria- queductal gray, paraventricular and dorsomedial nucleus of the hypothalamus, lateral hypothalamus, central nucleus of amygdala, bed nucleus of stria terminalis, insular cortex, anterior cingulate cortex, and orbitofrontal cortex (Loewy and Spyer, 1990; Rogers et al., 1995; Zhang et al., 1999; Liubashina et al., 2000; Ro´ nai et al., 2002; De Araujo et al., 2003; see Fig. 3). Thus, it has been suggested that olfactory and visual information, also important in the cephalic phase, may indirectly reach the dorsal motor nucleus of the vagus via the central nucleus of the amygdala or the orbitofrontal cortex, among other structures (Powley, 2000). It should be taken into account that the NST projects not only to the nucleus of the DMNX but also to other brainstem structures and prosencephalic centers (e.g., parabrachial, hypothalamus or amygdala) that subse- quently project to the DMNX (Hamilton and Norgren, 1984). Consequently, cephalic responses could equally be triggered by this other circuit. However, it is not known which specific brain structures control each individual response that occurs during the cephalic phase. Some authors suggested that these responses may be mainly organized by the lateral hypothalamus and inhibited by the ventromedial hypothalamus (Klajner et al., 1981). Thus, animals with lesions to the ventromedial hypothalamus show an enhancement of cephalic reflexes (Powley, 1977; Klajner et al., 1981) while electrical stimulation of the lateral hypothalamus triggers some of these responses, e.g., gastric acid release (Takaha- shi et al., 1999). In this context, it has been shown that lateral hypothalamus neurons are activated by the sight or taste of food and that their response is modulated by the degree of food deprivation (Burton et al., 1976). This fact could also be interpreted as a possible involvement of the lateral hypothalamus in cephalic responses. Some advances have recently been made in our knowl- edge of the neurochemical systems by which central structures control cephalic responses. Takahashi et al. reported that orexins, neuropeptides synthesized almost exclusively in the lateral hypothalamus (Ishii et al., 2005; Kirchgessner, 2002), may participate in the gastric acid secretion induced in response to cephalic stimulation Fig. 3. Schematic representation of the neural mechanism involved in (Takahashi et al., 1999; Yamada et al., 2005). This cephalic responses. ACC, anterior cingulate cortex; BNST, bed nucleus of hypothesis was supported by observations that central stria terminalis; CeA, central nucleus of amygdala; DMNX, dorsal motor but not peripheral administration of orexin-A significantly nucleus of the vagus; LH, lateral hypothalamus; NTS, nucleus of the stimulates gastric acid release in animals and that this solitary tract; PVN, paraventricular nucleus of hypothalamus; VMH, response can be blocked by vagotomy (Takahashi et al., ventromedial hypothalamus; OFC; orbitofrontal cortex. ARTICLE IN PRESS M.A. Zafra et al. / Neuroscience and Biobehavioral Reviews 30 (2006) 1032–1044 1039

1999). Moreover, orexin-containing fibers of the lateral continues in the stomach through the action of salivary hypothalamus have been found to project to the DMNX, amylase (Guyton and Hall, 1996). Therefore, the absence whose neurons have shown orexin receptors (Ferguson and of saliva is expected to delay gastric release and to slow Samson, 2003). carbohydrate digestion, because the necessary enzyme is Thyrotropin-releasing hormone (TRH) has also been not present. proposed as a candidate for the central control of gastric As demonstrated by Pavlov, the lack of secretions in acid release during the cephalic phase (Tache´ and Yang, intragastric feeding indeed delays and prolongs digestion. 1994; Takahashi et al., 1999; Martı´ nez et al., 2002). Nerve In one study, a catheter was used to administer food into terminals and receptors for TRH (mainly TRH1 receptors) one animal’s stomach and the same treatment was given to are abundant in the DMNX, and this neuropeptide another animal that also underwent a short session of sham increased the firing rate of DMNX neurons in vivo and feeding. The degree of digestion undergone by the food was in vitro. Direct administration of TRH into the DMNX evaluated after 1.5 h, with the striking finding that 6% of but not into other structures (lateral hypothalamus, area the food was digested in the former compared with 30% in postrema or NST) stimulates gastric responses, including the sham-fed animal (Pavlov, 1910). Absence of orophar- secretion of gastric acid and pepsin and an increased blood yngeal stimulation also indirectly delays the appearance of flow and motor activity, and all of these responses are other digestive responses. For instance, the release of dependent on the vagus nerve (Tache´ and Yang, 1994; pancreatic juices is determined by the level of hydrochloric Martı´ nez et al., 2002). Because the TRH fibers that acid in the stomach (Pavlov, 1910; Guyton and Hall, 1996), innervate the DMNX solely originate in the raphe nuclei and there is no significant accumulation of this acid in the (pallidus, obscurus and magnus) and the parapyramidal gastric cavity in absence of cephalic stimulation, markedly region of the ventral medulla, either of these structures delaying pancreatic release (Pavlov, 1910). could participate in these cephalic responses. Currently According to these classic studies, therefore, when food available data lend support to involvement of the raphe arrives at the stomach in absence of cephalic phase, the nuclei, since electrical or chemical stimulation of their gastric secretions that promote its breakdown are not neurons is known to activate these gastric functions (Tache´ available, prolonging its digestion for hours in comparison and Yang, 1994). with digestion in presence of oropharyngeal stimulation (Pavlov, 1910). This implies that the gastric and intestinal 4. Disturbances induced by absence of cephalic phase phases alone do not have the capacity to produce adequate digestion. Oropharyngeal stimulation induces responses The relevance of cephalic responses to nutrition and that rapidly and effectively initiate the physiological and digestion becomes apparent when the cephalic phase is enzymatic transformation of the food, which is continued absent, e.g., when food is directly administered into the by the action of further secretions during subsequent stages gastric cavity or other segments of the digestive tract, of the digestive process. obviating the orosensory receptors (Puerto, 1977; Zafra, The effect on food digestion is not the only anomaly 2000). Animal, human, and clinical studies have demon- produced by absence of the cephalic phase. Thus, Tordoff strated that the enteral administration of food gives rise to et al. demonstrated that significant damage to the intestinal numerous disruptions of digestive processes and functions mucosa is produced by the intestinal administration of related to absorption or metabolism. Pavlov was again one nutrients (fats) at concentrations used in behavioral studies of the first authors to document the changes induced by and with the same characteristics (e.g., pH and infusion removal of the cephalic phase, based on dog studies that rate), which may explain the reduction in subsequent ingeniously demonstrated the importance of the passage of intake observed in these studies (Friedman et al., 1996; foods through the oral cavity for their subsequent Horn et al., 1996; Ramirez et al., 1997). digestion. Thus, he reported that no release of gastric juice It has also been demonstrated that intragastric feeding was produced for the first hour or even longer after the produces an acceleration of gastric emptying (Molina et al., direct administration of some foods (e.g., bread or cooked 1977; Ramirez, 1986; Friedman et al., 1996; Kaplan et al., egg) into the stomach, although the direct injection of other 1997), which may cause discomfort, as in the case of foods (e.g., meat) produced a small amount of gastric dumping syndrome (Molina et al., 1977). This syndrome, secretion, but with weak digestive power and after a delay observed in individuals who have undergone abdominal of 20–40 min. These observations contrasted sharply with vagotomy, is characterized by a rapid gastric emptying, the rapid and abundant release of gastric juices when the producing nausea and epigastric pain (Snowdon, 1970). oropharyngeal cavity was stimulated by intake of the same Anomalies resulting from absence of oropharyngeal/ food under normal or sham feeding conditions (Pavlov, cephalic stimulation also extend to post-absorptive stages. 1910). Food administered intragastrically also lacks Thus, it has been demonstrated that intolerance to glucose salivary secretions. Pavlov (1910) demonstrated that saliva (i.e., a rise in plasma levels) is induced by its intragastric stimulates the release of gastric juices when it reaches the administration, which also produces a reduction in blood stomach cavity, and it was more recently found that the levels of certain hormones (e.g., glucagon). These changes digestion of carbohydrates that begins in the oropharynx are not observed when this treatment is accompanied by ARTICLE IN PRESS 1040 M.A. Zafra et al. / Neuroscience and Biobehavioral Reviews 30 (2006) 1032–1044 orosensory stimulation via modified sham feeding (Proietto physiological methods of feeding. They do not elicit the et al., 1987; Teff and Engelman, 1996a). In this context, cephalic phase responses (Stratton and Elia, 1999), result- Bruce et al. (1987) demonstrated that if tease feeding (sight, ing in numerous disturbances. Unlike enteral nutrition, smell, and expectation of a meal) of humans is combined parenteral feeding is associated with an increased risk of with a non-nutritive sweet taste (aspartame) a rise in serum thromboembolism, severe metabolic fluctuations, hyper- or insulin and a significant fall in blood glucose levels can be hypoglycemia, infections, gastrointestinal mucosal atro- observed within 5 mins of the food presentation. These phy, and, especially, translocation of bacteria and endo- data suggest that non-nutritive sweeteners may be useful in toxins from the gut lumen into the portal circulation, one the treatment of the hyperglycemia usually present in of the main causes of septicemia (Heymsfield et al., 1979; intragastric nutrition (Teff and Engelman, 1996a). Moore et al., 1992; Kudsk, 1994; Howard et al., 1995). For Likewise, intragastric feeding has been shown to slow this reason, it is now accepted that nutritional support lipolysis, with the amount of fatty acids in plasma reaching should be given enterally, whenever possible, reserving levels above those observed in animals that orally ingest the parenteral nutrition for patients with intestinal failure same food (Molina et al., 1977). This phenomenon may (Heymsfield et al., 1979; Moore et al., 1992). Nevertheless, explain the increased body weight observed after intragas- enteral administration is not without drawbacks. Regard- tric feeding, as suggested by several researchers on this field less of the disease of patients, enteral nutrition is frequently (Rothwell and Stock, 1978; Yamashita et al., 1993). Thus, associated with disturbances that can be considered Rothwell and Stock (1978) demonstrated that animals reactions of the gastrointestinal tract to the administration intragastrically administered with a small amount of the of different diets. These include discomfort, flatulence, daily diet reduced their oral ingestion so that the amount of difficulty in breathing, heartburn, gastric distension, energy consumed did not differ from that consumed by swelling and cramping of the abdomen, pain, vomiting, control animals receiving the entire diet orally. Despite nausea, diarrhea (Heymsfield et al., 1979; Henderson et al., their similar caloric intake, however, the weight gain of the 1992; Moore et al., 1992; Kandil et al., 1993; Elia, 1994), experimental animals was much higher than that of the metabolic disorders (Meguid and Campos, 1996), and, if control animals. These results were replicated in studies in enteral feeding is very prolonged, ulcers (Henderson et al., which the experimental paradigm was partially modified. 1992). The intolerance shown by some patients can even Thus, Yamashita et al. reported a significantly higher prevent them from receiving nutrients by enteral adminis- weight gain in intragastrically fed animals compared with tration (He´ buterne et al., 1995). those fed via catheter into the oral cavity. The weight rise Therefore, both clinical and animals studies show that corresponded to an increase in adipose tissue and a large the administration of food directly into the gastric cavity accumulation of triglycerides in the liver, anomalies that gives rise to disturbances that do not occur when the are themselves the result of lipid metabolism disturbances oropharyngeal cavity is stimulated. Although the reasons (Yamashita et al., 1993). Since the only difference between for these anomalies have not been fully elucidated, they can the groups was the feeding modality (oral vs. enteral), it perhaps be generally attributed to the fact that the arrival can be concluded that these disorders may result from of food to the digestive tract is non-physiological, i.e., it absence of oral stimulation. does not undergo the neuroendocrine transformations The above data indicate that the cephalic phase not only induced during the cephalic phase. participates in food digestion but also in processes related One approach to resolving or minimizing the problems to the absorption and metabolism of nutrients. This action associated with enteral nutrition may be to overcome the may be secondary to the release of gastrointestinal absence of secretions normally induced during cephalic hormones, whose release is stimulated by the anticipation stimulation. Thus, the rewarding nature of intragastric or presence of food in the oropharyngeal cavity (Giduck feeding has been demonstrated in animals by the admin- et al., 1987). istration of partially digested rather than natural foods. Problems associated with the absence of cephalic phase These foods are obtained by gastric aspiration from orally responses can also be observed in the clinical setting. Many fed donor animals after remaining in their stomach for a patients cannot feed themselves during the course of their certain time period (Puerto et al., 1976a, b; Puerto, 1977; disease, and nutritional support is usually provided either Zafra, 2000; Zafra et al., 2002, 2005). Similar results have intravenously (parenteral nutrition) or by direct adminis- been observed in the clinical setting, as in the well-known tration of a liquid diet into the gastric or intestinal cavity ‘‘Tom case’’ (Wolf and Wolf, 1947; Powley, 1977). This (enteral nutrition). In the USA, it is estimated that 1% of patient suffered complete esophagus obstruction through- all healthcare dollars (i.e., around $7–8 billion in 1992) is out his childhood after ingesting boiling hot food, and he used for nutritional support of patients at home (20%) or could only be fed through a gastric catheter (Wolf and in hospital. The estimated cost of all home parenteral and Wolf, 1947). When his food was directly deposited in the enteral nutrition in that year was just over $1 billion gastric cavity, optimal digestion was not possible and the (Howard, 1993; Howard et al., 1995). patient was not adequately satiated. However, when he was Because part or all of the gastrointestinal tract is allowed, on his request, to taste and chew the food before bypassed, both enteral and parenteral nutrition are non- being intragastrically fed, he gained in weight and ARTICLE IN PRESS M.A. Zafra et al. / Neuroscience and Biobehavioral Reviews 30 (2006) 1032–1044 1041 developed a good appetite (Wolf and Wolf, 1947; Powley, System, Section 6, vol. 2. American Physiological Society, Oxford 1977). University Press, New York, pp. 455–474. This rewarding effect may be related to specific secre- Bates, D., 2005. The vegetative state and the Royal College of Physicians guidance. Neuropsychological Rehabilitation 15, 175–183. tions induced by the cephalic phase, which are closely Behrman, H.R., Kare, M.R., 1968. Canine pancreatic secretion in linked to the taste and nature of the foods, as mentioned response to acceptable and aversive taste stimuli. Proceedings of the above (Pavlov, 1910; Teff et al., 1995; Mattes, 2000; Society for Experimental Biology and Medicine 129, 343–346. Hiraoka et al., 2003), and to the chain of secretory actions Berthoud, H.-R., 2002. Multiple neural systems controlling food intake generated by the saliva itself (Pavlov, 1910). and body weight. Neuroscience and Biobehavioral Reviews 26, 393–428. With the above background, it can be proposed that Berthoud, H.-R., Powley, T.L., 1990. Identification of vagal preganglio- some of the disturbances associated with enteral feeding nics that mediate cephalic phase insulin response. American Journal of could be avoided if the foods used were subjected to the Physiology 258, R523–R530. neuroendocrine processes of the cephalic phase, as in the Berthoud, H.R., Trimble, E.R., Siegel, E.G., Bereiter, D.A., Jeanrenaud, case of partially digested foods. This would allow nutrients B., 1980. Cephalic-phase insulin secretion in normal and pancreatic to reach the gastrointestinal system in physiological islet-transplanted rats. American Journal of Physiology 238, E336–E340. conditions similar to those of normal ingestion, enabling Brand, J.G., Cagan, R.H., Naim, M., 1982. Chemical senses in the release their adequate digestion, of considerable value for physi- of gastric and pancreatic secretions. Annuual Review of Nutrition 2, cally impaired patients unable to receive food normally. 249–276. This would be especially relevant in patients in a vegetative Bruce, D.G., Storlien, L.H., Fuler, S.M., Chisholm, D.J., 1987. Cephalic or minimally conscious state (estimated prevalence of phase metabolic responses in normal weight adults. Metabolism 36, 721–725. 20–120 per million; Bates, 2005), in whom stimulation of Burton, M.J., Rolls, E.T., Mora, F., 1976. Effects of hunger on the cephalic responses is not possible. responses of neurons in the lateral hypothalamus to the sight and taste of food. Experimental Neurology 51, 668–677. 5. Conclusion Buyse, M., Ovesjo¨ , M.-L., Goı¨ ot, H., Guilmeau, S., Pe´ ranzi, G., Moizo, L., Walker, F., Lewin, M.J.M., Meister, B., Bado, A., 2001. Expression and regulation of leptin receptor proteins in afferent and In conclusion, the studies reviewed examined the efferent neurons of the vagus nerve. European Journal of Neuroscience characteristics and role of the neuroendocrine processes 14, 64–72. of the cephalic phase in both normal nutritional behavior Chen, J.D.Z., Pan, J., Orr, W.C., 1996. Role of sham feeding in and in clinically relevant situations. These physiological postprandial changes of gastric myoelectrical activity. Digestive Diseases and Science 41, 1706–1712. responses appear necessary to prepare the digestive system Davis, J.D., 1999. 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