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.
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).
References
[1] Baenninger R, Greco M. Some
antecedents and conse- quences of yawning. The
Psychol Rec 1991;41:453-460.
[2] Walusinski O. Yawning:
unsuspected avenue for a better understanding of
arousal and interoception. Med Hypotheses
2006;67:6-14.
[3] Melis MR, Argiolas A. Yawning:
role of hypothalamic paraventicular nitric
oxide. Zhongguo Yaoli Xuebao
1999;20:778-88.
[4] Aloe F. Yawning. Arquivos de
Neuro-psiquiatria 1994;52: 273-6.
[5] Askenasy JJ. Is yawning an
arousal defence reflex? J Psychol
1989;123:609-21.
[6] Jones JFX. Retrospective view of
the carotid body research of Ronan G. O'Regan.
Exp Physiol 2004;89:39-43, and references
therein.
[7] Kumar P, Bin-Jaliah I. Adequate
stimuli of the carotid body: more than an oxygen
sensor? Resp Physiol Neurobiol
2007;157:12-21.
[8] Prabhakar NR, Peng Y-J, Jacono
FJ, Kumar KG, Dick TE. Cardiovascular
alterations by chronic intermittent hypoxia:
importance of carotid body chemoreflexes. Clin
Exp Pharmacol Physiol 2005;32:447-9.
[9] Campanucci VA, Nurce CA.
Autonomic innervation of the carotid body: Role
in efferent inhibition. Resp Physiol Neurobiol
2007;157:83-92.
[10] Liljestrand G. The Nobel Prize
in Physiology or Medicine 1938, Presentation
Speech.
http://nobelprize.org/medcine/laureates/1938/press.html.
[11] Heymans CJF. The part played by
vascular presso- and chemo-receptors in
respiratory control. Nobel Lecture, December 12,
1945.
[12] Porkka-Heiskanen T, Strecker
RE, Thakkar M, Björkum AA, Greene RW,
McCarley RW. Adenosine: a mediator of the
sleep-inducing effects of prolonged wakefulness.
Science 1997;276:1265-8.
[13] Gallopin T, Luppi P-H, Cauli P,
Urade Y, Rossier J, Hayaishi O, et al. The
endogenous somnogen adenosine excites a subset
of sleep-promoting neurons via A2A receptors in
the ventrolateral preoptic nucleus. Neuroscience
2005;134: 1377-90.
[14] Ramesh V, Thatte HS, McCarley
RW, Basheer R. Adenosine and sleep deprivation
promote NF-jB nuclear translocation in
cholinergic basal forebrain. J Neurochem
2007;100: 1351-63.
[15] Anderson-Beck R, Wilson L,
Brazier S, Hughes IE, Peers C. Doxapram
stimulates dopamine release from the intact rat
carotid body in vitro. Neurosci Lett
1995;187:25-8.
[16] Dodt C, Breckling U, Derad I,
Fehm H, Born J. Plasma epinephirene and
norepinephirene concentrations of healthy humans
associated with nighttime sleep and morning
arousal. Hypertension 1997;30:71-6.
[17] Henson LC, Ward DS, Whipp BJ.
Effect of dopamine on ventilatory response to
incremental exercise in man. Resp Physiol
1992;89:209-24.
[18] Miller DB,
O’Callaghan JP. The
pharmacology of wakeful- ness. Metabol Clin Exp
2006;55:S13-9.
[19] Mignot E, Taheri S, Nishino S.
Sleeping with the hypothal- amus: emerging
therapeutic targets for sleep disorders. Nature
Neurosci Suppl 2002;5:1071-5.
[20] Lahiri S, Mitchell CH, Reigada
D, Roy A, Cherniack NS. Purines, the carotid
body and respiration. Resp Physiol Neurobiol
2007;157:123-9.
[21] Oldendorf WH. Brain uptake of
metabolites and drugs following carotid arterial
injections. Trans Am Neurolog Asso
1971;96:46-50.
[22] Niemi M. Hankala
hankakeränen. Duodecim 1997;113:
2461-2.
[23] Kovalzon VM, Strekalova TV.
Delta sleep-inducing peptide (DSIP): a still
unresolved riddle. J Neurochem 2006;97:
303-9.
[24] Dovedova EL, Khrustalev DA,
Khudoerkov RM. Effect of delta-sleep-inducing
peptide on activity of enzymes of biogenic amine
metabolism in the brain of Wistar and August
rats. Bull Exp Biol Med 2005;140:514-6.
