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17 septembre 2007
Medical Hypotheses
2008;70(3):488-492
Does yawning increase arousal through mechanical stimulation of the carotid body?
Jorma Matikainen, Hannu Elo
Department of Chemistry, University of Helsinki,
Faculty of Pharmacy, University of Helsinki

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Summary
 
Yawning is a stereotyped event that occurs in humans and animals from fish to mammals, but neither its mechanisms nor its functions are entirely known. Its widespread nature suggests that it has important physiological functions. It is associated with stretching of muscles in a large area, but the function of this stretching is understood far from completely. It has been proposed that yawning increases arousal and that it is an arousal defense reflex, whose aim is to reverse brain hypoxia. Whilst yawning has been speculated to have an important role in reversing hypoxia, there is a structure in the neck that is known to be intimately involved in the regulation of oxygen homeostasis, namely the carotid body. It senses acute changes in oxygen levels. In spite of this, a connection has never been proposed either between the carotid body and arousal, or between yawning and the carotid body. We propose that yawning stimulates mechanically the carotid body (and possibly other structures in the neck). We further propose that this stimulation gives rise to increased arousal, alertness and wakefulness and that one important physiological function of yawning is increase of arousal through this stimulation. We also propose that mechanical effects on the shunt system of the carotid body may be involved in this stimulation. Our hypothesis is supported by several facts. For example, yawning causes movements and compressions that may affect the carotid body that is situated strategically at the bifurcation of the common carotid artery. Thus, yawning may stimulate the carotid body. The carotid body is highly vascular and compressions may affect its shunt system and blood flow and for example give rise to release of hormones or other substances. Also several facts related to situations where people yawn or do not yawn support our hypothesis and are discussed. Further support comes from facts related to somnogenic substances, hormones and transmitters, and from facts related to the interconnection of homeostatic mechanisms, sleep arousal and ventilation.
carotid body
Introduction
 
Yawning is a stereotyped event that occurs fre- quently in humans as well as in animals from fish, amphibians, reptiles and birds to mammals [1‚2,3]. In spite of this, neither its mechanisms nor its functional role are entirely known [4]. Because of its widespread nature, it has been concluded that yawning obviously must have one ore more highly important physiological functions [2]. One important function of yawning is considered to be increased inspiration of air, resulting in reversal of hypoxia, exhalation of carbon dioxide and increase of the metabolic rate [4,5]. Yawning is commonly believed to occur under a variety of different conditions, including fatigue, boredom, lack of oxygen, and seeing other persons yawn [1]. According to Walusinski, there are three types of morphologically identical yawns occurring in three distinct situations: situations relative to circadian rest-activity rhythms, situations relative to feeding, and situations relative to sexuality or social interactions [2]. Baenninger and Greco [1] have concluded that "the fact that so many apparent mechanisms are associated with yawning, in so many different species, suggests that the act is of some general importance". It has been pointed out by Walusinski [2] that "In human, the expansion of the pharynx can qua- druple its diameter, while the larynx opens up with maximal abduction of the vocal cords.
 
These characteristics cannot be noticed in any other moment of life. Yawning is not just a matter of opening one's mouth, but generalized stretching of muscles, those of the respiratory tract (diaphragm, intercostal), the face and the neck". Importantly, he also points out that the function of the stretching is not well understood. So far, no specific cerebral structure has been identified as a yawning center. There are clinical and pharmacological arguments indicating that yawning involves the hypothalamus, especially the paraventricular nucleus (PVN). The PVN is an integration center between the central and peripheral autonomic nervous systems [2]. It has been proposed by Askenasy [5] that yawning is a complex arousal defense reflex located in the reticular brainstem with a peripheral and central arche, whose aim is to reverse brain hypoxia. The possibility that yawning increases arousal has been proposed also by Walusinski [2], Aloe [4] and others. Whilst yawning has been speculated to have a role, perhaps even a very important one, in reversing hypoxia, there is a structure in the neck that is well known to be intimately involved in the regulation of oxygen homeostasis, namely the carotid body (glomus caroticum) [6-9]. It is an oxygen sen- sor that possesses the ability to sense acute changes in physiological levels of oxygen [7,8,10,11]. Upon stimulation, the carotid body mediates almost all of the cardiorespiratory reflex responses to acute, systemic hypoxia, either directly or indirectly. A reduction in the arterial blood partial pressure of oxygen induces a characteristic response in the carotid body. This organ is stimulated also by hypercapnia, hypoglycaemia and a large number of other phenomena and sub- stances [7]. In spite of these facts, it appears that a connection has never been proposed either be- tween the carotid body and arousal, or between yawning and the carotid body. The hypothesis
 
We now propose that:
1. Yawning stimulates mechanically the carotid body (and possibly also other structures such as various receptors in the same anatomical area). This may be one major physiological function of yawning.
 
2. Said mechanical stimulation gives rise to increased arousal, alertness and wakefulness. One important physiological function of yawning is that it increases arousal and wakefulness through said mechanical stimulation of the caro- tid body. (This does not exclude the possibility that such mechanical stimulation gives rise to other effects as well, perhaps different under different conditions.)
 
3. Possibly, mechanical effects on the shunt system of the carotid body are involved in said stimulation.
 
Evaluation of the hypothesis
 
The hypothesis is supported by several facts. Some of these are related to the structure of the neck and the carotid body, and some to the situations where people yawn and to the situations where yawning does not occur. Further ones are related to somnogenic substances, to hormones, transmitters etc., and still further ones to the interconnection of homeostatic mechanisms, sleep and arousal, ventilation etc.
 
Facts related to the structure of the neck and the carotid body
 
Yawning causes by necessity movements and compressions in the neck and near-by structures and it is obvious that these may affect also the carotid body that is situated strategically at the bifurcation of the common carotid artery. So, it is understandable that yawning may activate or stimulate the carotid body. In spite of the obvious anatomical connection it has, to our best knowledge, never been proposed that yawning affects the carotid body. As far as we know, no connection has ever been proposed to exist between yawning and the carotid body or its physiological functions.
 
In this respect, it is interesting that, in the early 20th century, Sollmann and Brown had observed that stretching of the common carotid artery initiated respiratory reflexes [10]. Further, the carotid body is a highly vascular organ. The carotid body artery divides repeatedly to form extensive sinusoidal capillaries and thoroughfare arteriovenous anastomoses (A-V shunts). The total venous blood flow of the carotid body is a combination of flow shunted away from the organ and perfusion of the glomus [6].
 
The shunt system and the fact that the carotid body is a highly vascular organ suggest that this organ may be sensitive to mechanical stimulation. It is obvious that movements and compressions in the neck that target the carotid body may affect its shunt system and blood flow in it and may for example give rise to release of one or more hormones, transmitters or other substances. When the effect of the autonomic nervous system on the two types of venous blood flow of the carotid body was measured, it was found that local blood flow and tissue P(O2) were completely unaffected by both parasympathetic and sympathetic stimulation that was potent enough to alter total blood flow. This was interpreted to indicate that non-vascular mechanisms are responsible for the alterations in neural traffic seen during electrical stimulation of the autonomic nerves and that the brainstem is primarily concerned with regulation of shunt vessel diameter. The purpose of this focused regulation of shunt blood flow has been con- sidered obscure [6]. Facts related to the situations where people yawn and to the situations where yawning does not occur Tired people yawn. Those who are going to bed no longer need to yawn. When rising from bed in the morning, people may yawn. Sleeping people do not yawn. All of these facts support the hypothesis. Sleepy people who fight against sleep yawn. This is very important, since there is no evidence suggest- ing that they have hypoxia. Also bored people (who need or wish increased alertness, or whose alert- ness is decreased) yawn, although there is no evidence suggesting that they have hypoxia. Why should boredom alone cause hypoxia so that yawn- ing would be needed to increase ventilation? Those who by necessity suddenly have to wake through night tend to yawn (according to our hypothesis, subconsciously in order to prevent themselves from falling into sleep, or in order to maintain arousal). They would hardly be expected to have hypoxia. Interestingly, yawning does not normally occur during heavy physical exercise (such as running), although the metabolic rate and thus oxygen demand increase heavily. Under such circumstances, yawning would hardly be expected to be of any help, but a yawning athlete would be expected to be a looser. So, yawning is not necessarily needed for the inspiration of increased amounts of air. Because competing athletes such as runners hardly need an increase of arousal and wakefulness during a heavy exercise, they neither need yawning, if its physiological function is to increase arousal and wakefulness. Agitated, violent, excited or furious people and, more generally, people who are neither subjectively nor objectively in the need of increased arousal or wakefulness, are hardly expected to yawn. This is understandable if a central (or the main) function of yawning is to increase arousal. On the other hand, yawning occurs frequently in people who indeed are in the need of increased arousal and wakefulness, such as bored people, people who have to be able to wake and work night-time, and tired people who have to wake. All this constitutes strong support for our hypothesis. Facts related to somnogenic substances, to hormones, transmitters etc The proposal that stimulation of the carotid body leads to increased arousal or, at least, is involved in the regulation of the sleep-wakefulness cycle, is supported by several facts. For the first, adenosine, a neuromodulator considered to be the homeostatic sleep factor or an endogenous somno- gen [12-14], is known to stimulate the carotid body [7]. For the second, catecholamines are known to stimulate the carotid body [7]. On the other hand, hypoxia as well as the ventilatory stimulant doxapram seem to stimulate catecholamine release from the intact carotid body in vitro [15]. For the third, importantly, the carotid body is known to give rise to sympathoexcitatory responses such as augmentation of the pituitary-adrenocortical axis as well as augmentation of adrenomedul- lary catecholamine secretion [7]. Already in the earlier part of the 20th century, Heymans indicated that the adrenal medulla was probably influenced by reflexes arising from the carotid sinus, bringing it to increase or decrease epinephrine secretion into the blood [10,11]. Dodt et al. [16] have shown that, in healthy young men, the average epinephrine but not norepinephrine concentrations were significantly lower during nocturnal sleep than during wakefulness before and after sleep, and that the activities of the sympathoadrenal and noradrenergic branches of the sympathetic nervous system seem to be downregulated during rapid eye movement sleep, and further that awakening itself selectively enhances epinephrine levels.
 
Dopamine is an inhibitory neuromodulator in the carotid body [17]. There seems to be increasing evidence that dopamine plays an important role in promoting wakefulness [18]. Thus, if the dopamine concentration is high, the person is probably fully awake and alert and thus does not need increased arousal. So, in the light of our hypothesis, it is adequate that dopamine inhibits the carotid body. Facts related to the interconnection of homeostatic mechanisms, sleep and arousal, ventilation etc Indirect support for our hypothesis is lent also by the fact that the carotid body not only is a polymo- dal sensor but also initiates compensatory reflexes so as to maintain homeostasis [9]. The hypothalamus is now recognized as the key center for sleep regulation, and it is also a key regulator of homeostatic mechanisms, and an increased awareness of the close interaction between sleep and homeostatic systems is also emerging [19]. Thus, also the carotid body might well be involved in sleep regulation. The understanding of the complexities involved in detecting oxygen and processing the information by the carotid body has increased much, and while it is recognized as the primary site of oxygen sensing, responding to hypoxia without the need for new protein synthesis, a critical input from multi- ple signaling systems is now recognized. Extracellu- lar signaling by the purine derivatives ATP and adenosine seems to make a key contribution to the process. Endogenous adenosine stimulates receptors on the carotid body to increase the ven- tilation rate and may modulate the catecholamine release from the carotid sinus nerve [20]. This is very important taking into account the role of adenosine in sleep induction [12-14]. Other facts The carotid body is explicitly involved in control- ling oxygen availability and ventilation, and so is also yawning. Thus, it is obvious that they have a connection, especially as yawning involves the anatomical area, in which the carotid body is located. As pointed out by Walusinski [2], rapid eye movement sleep and the yawning-stretching syndrome are two opposite muscles tones. Also this is well in accord with our hypothesis on the role of yawning in increasing arousal. The carotid body is situated strategically at the bifurcation of the common carotid artery, from where substances released by the organ easily and very rapidly reach the brain (see the paper of Oldendorf [21]). Facts related to the results of glomectomy Since the late 1950's, glomectomy became popular as a treatment of asthma. After an initial relief of symptoms, a distinct and permanent worsening, however, occurred, and even fatalities due to hypoxia during sleep were reported [22]. These observations may be in line with our hypothesis since it is not impossible that the decreased ventilation during sleep actually might have been due to unusually and inappropriately deep sleep caused by the lack of one or both of the carotid bodies. Testing of the hypothesis There are several ways of testing the hypothesis. For example, measurement of the concentrations of epinephrine, norepinephrine and dopamine, as well as those of adrenocorticotropine and cortisol, in blood before and after intentional yawning in humans could be useful. Measurements of heart rate, ejection fraction and other cardiac parameters and (cerebral) blood flow before and after intentional yawning in humans might also be performed, as well as those of the concentrations of the delta sleep-inducing peptide [23,24] and adenosine [12-14] in blood. Physiological experiments could also be perormed, in which tired volunteers are divided into subgroups, and one group is allowed to sleep, one is kept sitting half-asleep and one is given tasks that require reasoning. The yawning frequency is recorded in order to see, whether it is increased in those subjects who are fighting against sleep, as compared to the others. The subjects are not told that the main goal is to do this comparison. During the experiments, blood samples could be taken (preferably using a catheter) for analyses of adenosine, epinephrine, norepinephrine, dopamine, cortisol, adrenocorticotropine, blood gases, glucose etc. Preferably, EEG measurements should also be performed. Measurements could also be performed on the effects of the administration of small amounts of epinephrine, norepinephrine, dopamine, synthetic stimulants, adrenocorticotropine or cortisol, on the frequency of yawning in experimental animals, or in humans under a variety of conditions (e.g., tired people after a short night or after having stayed awake for a long time, or people listening to very boring lectures, etc.), employing appropriate control groups. Some concluding remarks It must be pointed out that even if the physiological functions of yawning would not include enhancement of arousal, it is possible that yawning produces one or more of its physiological functions through mechanical stimulation of the carotid body. It is possible that the carotid body produces, contains and releases compounds (e.g., peptides) whose presence in it is not known at present, including novel compounds. It might also be worth- while to investigate these aspects. Studies in which the carotid body is mechanically stimulated and the release of compounds of interest is measured and possibly previously unknown compounds are sought for, either in vivo or using isolated carotid bodies, might also be useful. If it turns out that the carotid body indeed is deeply involved in the control of wakefulness, awareness and arousal, highly important practical applications can be expected. For example, it might then be possible to develop new therapies for various diseases that involve too low or too high degrees of arousal and wakefulness (for example, agitation states, excessive sleepiness, insomnia, perhaps even depression, and many others).
 
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