Yawning
and cortisol levels in multiple sclerosis:
Potential new diagnostic tool
Thompson SBN, Coleman A, Williams N.
Faculty of Science &
Technology, Bournemouth University
Abstract
Yawning is a significant behavioural
response and, together with cortisol, is
potentially a new diagnostic marker of
neurological diseases. Evidence of an
association between yawning and cortisol was
found which supports the Thompson Cortisol
Hypothesis and thermoregulation hypotheses,
indication that brain cooling occurs when
yawning.
117 volunteers aged 18-69 years were
randomly allocated to experimentally controlled
conditions to provoke yawning. Thirty-three had
been diagnosed with multiple sclerosis. Saliva
cortisol samples were collected before and after
yawning or after stimuli presentation in the
absence of yawning. Hospital Anxiety and
Depression Scale, General Health Questionnaire,
demographic and health details were collected.
Comparisons were made of yawners and
non-yawners, healthy volunteers and MS
participants.
Résumé
Le bâillement est une réponse
comportementale significative et, avec son lien
avec le cortisol, en fait potentiellement un
nouveau marqueur diagnostique de maladies
neurologiques. Des preuves d'une association
entre le bâillement et le cortisol ont
été trouvées, semblant
confirmer les hypothèses de Thompson sur
le cortisol au cours du bâillement et son
lien avec la thermorégulation (le cerveau
se refroidirait durant le
bâillement).
117 volontaires âgés de 18
à 69 ans ont été
répartis au hasard dans des conditions
contrôlées expérimentalement
pour provoquer le bâillement. Trente-trois
avaient reçu le diagnostic de
sclérose en plaques. Des
échantillons de cortisol salivaire ont
été recueillis avant et
après le bâillement ou après
la présentation des stimuli en l'absence
de bâillements. Échelle
d'anxiété et de dépression,
questionnaire général sur la
santé, données personnelles et sur
la santé ont été
recueillies. Des comparaisons ont
été faites entre les
bâilleurs et les non-bâilleurss, les
volontaires sains et les participants
affectés de SEP.
Thompson
Cortisol Hypothesis : all the
publications
1. Introduction
The first evidence-based report of cortisol
level rises in multiple sclerosis (MS) together
with observed yawning is presented as a
potential new diagnostic indicator of signs
associated with the onset of MS.
MS is a chronic debilitating condition that
is progressive and affects the fatty tissue
sheath surrounding nerves. Incomplete
innervation due to loss of the myelin sheath is
considered to be responsible for uncoordinated
movements (Thompson, 2017). Brain temperature
fluctuations are seen in people with MS together
with symptoms of fatigue and especially when
carrying out mentally or physically demanding
tasks. These are also associated with excessive
yawning (Gallup and Gallup, 2008; Gallup and
Eldakar, 2013). Yet the cause of fatigue in MS
is not fully understood.
Attempts to clarify brain recruitment during
fatigue in MS has revealed involvement of the
dorsolateral prefrontal cortex, inferior
parietal cortex, anterior cingulate cortex and
the thalamus (Périn et al., 2010).
Fatigue in MS has been investigated using
variations in inducing fatigue together with MRI
scans to determine functional areas of brain
activation. For example, Thompson et al. (2016)
discovered that cortisol levels were found to be
higher during mental versus motor (physical)
tasks. Recruitment of brainstem and hypothalamus
regions, important in cortisol activity, was
affected differently (Fig 1). At low cortisol
levels, mental task participants had less
activity in the hypothalamus than their physical
task counterparts (Fig 2). When cortisol levels
were higher, wider spread recruitment of both
the hypothalamus and brainstem was observed in
the mental task participants, and for the
physical task participants, the spread was at
comparative low levels of cortisol.
The authors concluded that cortisol is
implicated in these brain regions and that brain
region recruitment is likely to be dependent
upon factors such as perception of stress in the
task. It is likely that the mental tasks were
perceived more stressful than the physical tasks
and therefore required higher cortisol levels to
promote wider spread brain region activity.
The hormone cortisol has been associated
with yawning and fatigue and described in the
Thompson Cortisol Hypothesis (Thompson, 2014).
Threshold level rises of cortisol appear to
trigger the yawn which is proposed to be part of
a complex mechanism for lowering brain
temperature (Thompson and Richer, 2015). Brain
temperature rises dramatically in people with MS
(Gallup and Gallup, 2010) and it has been
proposed that cortisol is able to regulate brain
temperature because of its role within the
hypothalamus-pituitary-adrenal (HPA-axis)
(Thompson et al., 2014), even in the foetus and
in young babies (Giganti et al., 2007).
Secretion of cortisol is controlled by three
inter-communicating regions of the brain:
hypothalamus, pituitary and adrenal glands.
During low levels of cortisol in the blood, the
hypothalamus releases corticotrophin-releasing
hormone causing the pituitary gland to secrete
adrenocorticotropic hormone into the
bloodstream. High levels of adrenocorticotropic
hormone are detected in the adrenal glands which
stimulate the secretion of cortisol, causing
blood levels of cortisol to rise. As the
cortisol levels rise, they start to block the
release of corticotrophin- releasing hormone
from the hypothalamus and adrenocorticotropic
hormone from the pituitary (Thompson and Richer,
2015). As a result, the adrenocorticotropic
hormone levels start to fall resulting in a fall
in cortisol levels. This mechanism is known as a
negative feedback loop.
Cortisol has been noted during exposure to
stressful events and may even be modulated by
contagious yawning (Eldakar et al., 2017).
Yawning has also been observed to reduce facial
temperature in rats (Eguibar et al., 2017) but
substantive evidence of brain cooling in humans
has been elusive to date.
Thompson (Thompson, 2010, 2011) presented
the Thompson Cortisol Hypothesis which is the
first evidence-based report linking cortisol
with yawning in healthy participants and
demonstrates that cortisol rises when we yawn.
Other researchers have postulated that yawning
may promote increased clearing of central
nervous system-derived fluid into the central
venous structures (Dolkart, 2017; Walusinki,
2014). Produced by the zona fasciculate of the
adrenal cortex within the adrenal gland
(Schillings, 2008), it is suggested that the
rise in cortisol level triggers the yawning
response in healthy people. When we become
fatigued either mentally or physically, and in
particular in MS, yawning becomes important for
regulating cortisol. We believe that cortisol
also affects the hypothalamus temperature
regulation within the HPA-axis and may signal
brain cooling particularly when elevation in
brain temperature is common such as in MS.
In addition to the hypothalamus, evidence of
the effects of cortisol has been found in the
brainstem and motor cortex (Sale et al., 2008).
Hasan et al. (2013) found sophisticated motor
receptors in mice. The efficiency of
cortisol-specific receptors and the
communication between sensory and primary motor
neurons is enhanced during motor learning. It is
postulated that the link between the established
sites within the HPA-axis and those of the motor
cortex and brainstem may be less intimately
linked by neural networks but instead by hormone
system. This would help in our understanding of
why brainstem lesion stroke patients may raise
their affected arm during yawning where the
yawning response is possibly triggered by
threshold levels of cortisol. Cortisol-specific
receptors on the motor end plates would give
rise to muscle movements in the arm.
In stroke patients, cortisol levels may be
inadequately detected and due to incomplete
innervation, the brainstem may fail to act on
changes in cortisol levels to prevent arm
movement resulting in the observed parakinesia
brachialis oscitans seen in brainstem ischaemic
patients (Wimalaratna and Capildeo, 1988;
Walusinski et al., 2010). Whilst it is accepted
that hormones work within a system that
comprises other hormones and complex neural
circuitry, it is often through direct
observation that pathways can be understood. It
is hoped that such observation of people with MS
(and yawning and cortisol) might provide us with
an increased understanding of why brain
temperature fluctuates with fatigue. This might
have greater implications for people with a wide
range of neurological disorders and
cortisol-insufficiency syndromes such as
Cushing's disease (AAES - American Association
of Endocrine Surgeons, 2013). It may also be a
potential diagnostic tool for detecting the
signs of MS in the future.
4. Discussion
There are several interesting findings of
this study. Of those participants who did not
yawn, the cortisol samples at rest and then at
the end of stimuli presentations was not
significantly different within each group of
participants. This is perhaps not surprising
since it is known that cortisol levels rise
during episodes of stress, whether perceived to
be mentally fatiguing or if they are physically
demanding. It may be that for those who did not
yawn, the tasks were not demanding in mental or
physical terms.
It is interesting that those participants
with MS who did not yawn also had no significant
difference in their cortisol levels which tends
to suggest that, in the absence of yawning,
cortisol levels in these participants did not
significantly change by the end of the testing
session. Perhaps of more scientific interest is
the finding that participants who yawned had
elevated cortisol levels. Previous studies by
the research team have found that in healthy
participants who yawn their cortisol levels rise
significantly (Giganti et al., 2007; Thompson
and Simonsen, 2015). People who have MS often
become fatigued and yawning are often observed
as a common symptom of MS (Gallup and Gallup,
2010). Therefore, it is of note that in those MS
participants who did yawn during the stimuli
presentations, their cortisol levels
significantly raised in levels greater than
their resting levels. It is also of note that
not all of the participants yawned; this may be
because their symptoms of MS were not identical
to those who did yawn. Alternatively, it may be
due to threshold levels of cortisol not being
reached, as compared with healthy participants
who did not yawn.
It is proposed that people with threshold
levels of cortisol yawn, whether they have MS or
not; however, changes in cortisol levels after
yawning were not significantly different between
the healthy and MS participants although there
was a significant difference between the groups
in their second saliva sample for the
non-yawners. This is interesting because
significant difference in levels between healthy
participants and those with MS might suggest
that cortisol levels are important in MS; and
when associated with excessive yawning, these
levels may signal MS symptoms. It will be
interesting to see if the effects of these
cortisol levels are directly correlated to
lowering brain temperature since yawning seems
to lower temperature.
These findings tend to support the Thompson
Cortisol Hypothesis (Thompson, 2017, 2014) that
proposes yawning occurs when threshold levels of
cortisol are reached in order to reduce brain
temperature. This is shown in both the healthy
and MS participants. Communication with the
motor cortex via cortisol-specific receptors may
also explain how involuntary movement of the arm
in brainstem ischaemic patients can occur partly
due to incomplete innervation and irregulation
of cortisol within the HPA-axis which has been
extensively discussed elsewhere (Thompson, 2017;
Wimalaratna and Capildeo, 1988; Walusinski et
al., 2010; Walusinski, 2007).
The picture in neurological and biological
diseases is complex because they present with a
range of symptoms and severity. However,
cortisol features in many disorders as well as
the body's natural stress hormone. Hence it is
suggested that it may provide an important key
to our understanding of the way many
neurological disorders are linked. It may also
provide scientists and practitioners in the near
future with a potential identifier or even
diagnostic indicator of underlying and untoward
neurological disease systems including MS.
