Krestel H, Weisstanner C, Hess CW, Bassetti
CL, Nirkko A, Wiest R.
Department of Neurology,
Inselspital, Bern University Hospital,
Switzerland
Abstract
Abnormal yawning is an underappreciated
phenomenon in patients with ischemic stroke. We
aimed at identifying frequently affected core
regions in the supratentorial brain of stroke
patients with abnormal yawning and contributing
to the anatomical network concept of yawning
control. Ten patients with acute anterior
circulation stroke and ³3 yawns/15 min without
obvious cause were analyzed. The NIH stroke
scale (NIHSS), Glasgow Coma Scale (GCS), symptom
onset, period with abnormal yawning, blood
oxygen saturation, glucose, body temperature,
blood pressure, heart rate, and modified Rankin
scale (mRS) were assessed for all patients.
MRI lesion maps were segmented on
diffusion-weighted images, spatially normalized,
and the extent of overlap between the different
stroke patterns was determined. Correlations
between the period with abnormal yawning and the
apparent diffusion coefficient (ADC) in the
overlapping regions, total stroke volume, NIHSS
and mRS were performed. Periods in which
patients presented with episodes of abnormal
yawning lasted on average for 58 h. Average GCS,
NIHSS, and mRS scores were 12.6, 11.6, and 3.5,
respectively. Clinical parameters were within
normal limits. Ischemic brain lesions overlapped
in nine out of ten patients: in seven patients
in the insula and in seven in the caudate
nucleus. The decrease of the ADC within the
lesions correlated with the period with abnormal
yawing (r = -0.76, Bonferroni-corrected p =
0.02).
The stroke lesion intensity of the common
overlapping regions in the insula and the
caudate nucleus correlates with the period with
abnormal yawning. The insula might be the long
sought-after brain region for serotonin-mediated
yawning.
Yawning is termed abnormal or excessive if
it is more frequent than generally perceived as
normal, compulsive and/or not triggered by
appropriate stimuli such as fatigue, boredom or
contagion. At present, no definite consensus
exists as to the frequency of yawns considered
abnormal. The threshold of abnormality found in
literature ranges from 2 yawns/10 min (Singer et
al. 2007) to 30 yawns/10 min (Cattaneo et al.
2006). Abnormal yawning (or chasm) seems to be
an underappreciated neurobiological phenomenon.
Its cause in humans is unknown, but it can be
observed in a variety of medical conditions
(e.g., Thompson 2010). In contrast,
physiological yawning is a ubiquitous behavioral
phenomenon that can be observed across species
barriers in most mammals and, according to some
authors, also inmost classes of vertebrates
(Baenninger 1997;Guggisbergetal. 2011).Agood
number of clinical and pharmacological studies
indicate that yawning involves the hypothalamus,
particularly the paraventricular nucleus (PVN),
the brainstem, and the cervical medulla (phrenic
nerveC1&endash;4 andmotor supply of
intercostalmuscles). The neuroanatomical
localization of the brainstem motor pattern that
orchestrates yawning is still disputed (Askenasy
1989; Walusinski 2006). At least three distinct
neural pathways have been identified that
participate in the induction (and control) of
yawning. These are (1) subsets of oxytocinergic
neurons in the PVN that either project to the
hippocampus or to the brainstem; (2) neurons in
the PVN that are activated by
adrenocorticotropic hormone and
a-melanocyte-stimulating hormone (a-MSH), and
project to the medial septum where they activate
cholinergic septohippocampal neurons; (3) direct
activation of septohippocampal/hippocampal
neurons; and (4) a serotonergic-cholinergic
pathway (e.g., to the hippocampus) whose brain
localization has not been identified yet
(Collins and Eguibar 2010; Sato-Suzuki et al.
1998; Argiolas and Melis 1998).
Abnormal yawning may also occur in
association with cerebrovascular disease.
Patients who experienced abnormal yawning with
supratentorial cerebral or brainstem infarctions
have been consistently reported (Singer et al.
2007; Cattaneo et al. 2006; Chang et al. 2008;
Krasnianski et al. 2003; Walusinski et al.
2010). Some authors postulated a ''denervation
hypersensitivity'' mechanism as cause of
abnormal yawning. By theory, this mechanism
would disconnect the putative yawning center in
the brainstem from (inhibitory) control of more
cranial structures, in analogy to the theories
about excessive yawning in ALS patients
(Williams 2000) or manifestation of enduring
hiccups after medullary infarction (Park et al.
2005). Although abnormal yawning during anterior
circulation (AC) stroke has been reported in the
literature, investigations about the putative
lesion topography and extension are still
lacking. In addition, the clinical experience of
abnormal yawning in cerebral ischemia has not
been statistically substantiated in the
literature. Here, we aimed at identifying stroke
lesions in common overlapping areas of the
ACthat facilitate abnormal
yawning.Wehypothesized that the severity rather
than the extension of ischemic stroke in a
circumscribed strategic lesion correlateswith
abnormal yawning. We also aimed at identifying
different neuronal pathways besides the
oxytocinergic neurons in the PVN that are
involved in the induction of yawning.
Discussion
In this observational study, we investigated
the spatial topography of stroke lesions linked
to abnormal yawning. We present the first
statistically substantiated evidence that
ischemic lesions in the posterior insula and
caudate nucleus facilitate abnormal yawning.
Within these two regions, the ischemia
intensity&emdash;as measured by the extent of
the ADC signal drop&emdash;correlated with the
period of abnormal yawning after stroke onset.
Significant correlations were further observed
between the period of abnormal yawning and
clinical stroke severity as measured by NIHSS,
and a trend for correlation with mRS that did
not pass significance correcting for multiple
testing. Total stroke volume did not correlate
at all with the duration of yawning, further
supporting the specificity of the two identified
small regions of overlap as opposed to the
extent of the whole stroke.
Abnormal yawning in anterior circulation
stroke A previous study by Singer et al. (2007)
identified supratentorial lesions in patients
with extended AC strokes and implicated "hat
excessive yawning can be a sign of
supratentorial lesions affecting the MCA (medial
cerebral artery, comment ours) territory". They
hypothesized that supratentorial lesions may
release the hypothalamic PVN from neocortical
control mechanisms along the hippocampus and
periamygdalar region, thereby increasing its
activity and leading to abnormal yawning. The
authors identified no ischemic diencephalic
lesions in their CT study, however, exclusion of
additional affections of the brainstem failed
due to the methodological limitations of CT
technology (Chalela et al. 2007; Masdeu et al.
2006). The current MR-study adds further
evidence to the hypothesis that ischemic lesions
of the AC are related to abnormal yawning
without evidence of brainstem lesions. We also
ruled out lesions of the PVN, thereby supporting
the hypothesis that ischemic lesions of the AC
cause disinhibition of subcortical nuclei or
networks that control yawning (Singer et al.
2007). In contrast, the extension of ischemic
areas to more than one-third of the MCA
territory, as previously suggested (Singer et
al. 2007) could not be confirmed as being
causative for abnormal yawning in our study. Our
patients were less severely affected by MCA
stroke extension according to the DWI stroke
extent, the NIHSS, and mRS scores than
previously reported (Singer et al. 2007). Our
positive correlation between clinical stroke
severity (NIHSS) and the period with abnormal
yawning may merely correspond to an
epiphenomenon representing the higher
probability of strokes involving deep brain
areas such as the basal ganglia/caudate
manifesting with severe deficits, as opposed to
strokes confined to more peripheral regions of
the brain.
Abnormal yawning due to caudate nucleus
lesions
Abnormal yawning was observed in case
reports with isolated caudate lesions by
Renau-Lagranja et al. (2010; stroke in caudate)
and Auer et al. (1987; cysticercosis lesion in
caudate), and is supported by our data. As
hypothesis, we ascribe this clinico-anatomical
association to an excess release of dopamine and
acetylcholine due to ischemic damage in the
caudate nucleus. The striatum, including the
caudate nucleus, encompasses a high density of
dopaminergic and cholinergic terminals. The
caudate nucleus is highly innervated by dopamine
neurons that originate mainly from the ventral
tegmental area and the substantia nigra pars
compacta. Animal studies demonstrated a release
of dopamine and glutamate neurotransmitter
levels during ischemic stroke (Richards et al.
1993). Furthermore, animal experiments
demonstrated the dependence of yawning frequency
on dopaminergic neurotransmission by an
activation of D2/D3 receptors (Baladi et al.
2010; Depoorte`re et al. 2009). The negative
correlation between decreased ADC in the caudate
nucleus and prolonged periods with abnormal
yawning is thus in favor of a disruption of
dopaminergic projections with subsequent
uncoordinated release of dopamine levels that
may facilitate abnormal yawning.
Abnormal yawning due to insular
lesions
The insula is not known to be a direct
target of the mesotelencephalic dopamine system.
It is intensively connected with other cortical
and subcortical regions via a
cortico-striato-thalamic network (linking the
insula also to the caudate nucleus; see Metzger
et al. 2010), with the lateral hypothalamus
(Jasmin et al. 2004), the hippocampus [at
least with the entorhinal cortex (Mesulam and
Mufson 1982)], and the brainstem via
corticobulbar pathways (Jasmin et al. 2004;
Ruggiero et al. 1987). We refer for further
review of the neuroanatomy and function of the
insula to the classical work by Mesulam and
Mufson (1985) and an excellent new work by
Nieuwenhuys (2012). Monosynaptic trajectories
from the posterior insula or the caudate nucleus
head are not known to directly project to the
hypothalamic PVN. Therefore, our data support
the involvement of additional
pathways/mechanisms in control of the yawning
motor pattern. In line with our hypothesis that
abnormal yawning is mainly caused by a
denervation hypersensitivity mechanism or
excessive neurotransmitter release (or both) due
to targeted and intensive disruption of core
areas within the AC, we envisage three
scenarios. First, a (GABAergic?) disinhibition
of insular targets such as the entorhinal
cortex, lateral hypothalamus or the brainstem
might lead to abnormal yawning. Interestingly,
mono-/oligosynaptic projections from the
posterior insula to the Raphe nucleus and the
nucleus tractus solitarius (NTS) exist (Allen et
al. 1991; Saper 1982, 2000). As the NTS is
located in the vicinity of the
Pre-Bo¨tzinger complex (a neuronal
respiratory rhythm generator in the
ventrolateral medulla) and the cranial nerve
nuclei V, VII, IX, X and XII [which are
involved in yawning; see Smith et al. (1991);
Abdala et al. (2009)], it is conceivable
that ischemic lesions in the posterior insula
may not only affect swallowing, taste and
cardiovascular events (Cereda et al. 2002;
Brandt et al. 1995), but also the frequency of
yawning. Second, the pharmacology of the insula
contains a series of neurotransmitters and
receptors (albeit with sometimes indirect
evidence), including GABA, glutamate,
acetylcholine and serotonin (Jasmin et al. 2004;
Chen et al. 2010; Van De Werd et al. 2010;
Tuerke et al. 2012). Interestingly, infusion of
serotonin agonists into the insula induced
gaping in awake rats, which was interpreted as
conditioned disgust (Tuerke et al. 2012), but
can also be part of the yawning event without
stretching. It is tempting to speculate that
ischemia of variable severity with only
partially destructive neuronal lesions in the
insula leads to excessive serotonin release and
induction of yawning. Serotonin-mediated yawning
is known to occur independently of the PVN. The
brain regions responsible for serotonin-mediated
yawning had not been identified yet. Third, the
actually responsible regions may not be the
insula itself, but the adjacent white matter
tracts (capsula extrema) or the claustrum, which
may not necessarily be reliably separated from
the insular cortex with the resolution of the
spatial renormalization techniques, which were
needed to identify inter-individual overlaps,
and because the underlying regions are likely to
be involved to a similar degree due to the
common vascular supply including common
collateralization pathways.
Finally, it was previously stated
(Walusinski 2006) that another function of
yawning may be to check for the homeostasis of
inner organs and perceive a feeling of
wellbeing, based on the observations that
visceral afferents arrive in posterior insular
cortex while processing of selfawareness takes
place in the anterior insula (von Economo
neurons), and because the insula may be
(indirectly) activated in the yawning process.
We have not systematically analyzed our patients
for their retained or lost ability to check for
their wellbeing of inner organs, but this idea
may be explored in future studies.
Abnormal yawning due to other
etiologies
Our own study only assessed yawning in
ischemic stroke. The literature also mentions a
few cases of yawning associated with stroke in
the insula or the caudate nucleus. Other
(non-stroke) etiologies for yawning in the
literature involve traumatic brain injury
(Laurent-Vannier et al. 1999), brain surgery
(Martino et al. 2012), and complex focal
seizures (Penfield and Jasper 1954). However, we
have failed to identify a study that reported
hyperammonemia inducing abnormal yawning.
......
Conclusions
We provide the first statistically
substantiated study that ischemic stroke in two
specific regions within the AC can indeed be
associated with abnormal yawning in few cases.
We add to the existing evidence that (a) strokes
do not necessarily have to be severe (high
NIHSS) to elicit abnormal yawning; (b) in
general, the intensity but not the extent of
ischemia in core regions within the AC
correlates with duration of abnormal yawning;
(c) additional pathways and/or mechanisms
besides the hypothalamus may be involved in
abnormal yawning. The as yet unknown brain
region of serotonin-mediated yawning might be
the insula. The hypothesis of excessive
uncoordinated neurotransmitter release due to
ischemic lesions might be one explanation why
the other neurological stroke deficits caused by
the same stroke frequently outlast abnormal
yawning. This transient nature of abnormal
yawning might also be the explanation why it is
perceived as rare phenomenon in acute
neurological disorders.
Abnormal
yawning in stroke patients: the role of brain
thermoregulation.
A commentary on Insular and caudate
lesions release abnormal yawning in stroke
patients
by Krestel, H., Weisstanner, C., Hess, C. W,
Bassetti, C. L., et al.
Krestel et al. (2013) recently investigated
the potential contributing factors associated
with abnormal yawning (defined as 3 yawns/15 mm)
in 10 patients with acute anterior circulation
stroke. Though frequent yawning had previously
been observed in stroke patients (Cattaneo et
al., 2006; Singer et al., 2007), this study
attempted to assess the influence of specific
physiologic and lesion topographic variables
contributing to this association. AH patient
parameters were taken within 1 h after admission
and emergency nurses recorded a single axillary
body temperature with a digital thermometer
(Krestel, personal communication). Using MRI
lesion maps, and reportedly finding no
associations between various physiologic
measures, including blood oxygen saturation,
glucose, body temperature, blood pressure, and
heart rate, the authors concluded that ischemic
lesions in the posterior insula and caudate
nucleus might facilitate high frequency yawning
in stroke patients. While this report improves
our neurological understanding regarding the
association between frequent yawning in stroke
patients, limitations in the analysis and
interplay of temperature need to be
addressed.
Yawning is characterized by a powerful
gaping of the jaw with inspiration, a brief
period of peak muscle contraction, and a passive
closure of the jaw with shorter expiration
(Barbizet, 1958). The localized circulatory
changes resulting from this action pattern have
led researchers to hypothesize that yawns may
function to cool the brain (Gallup and Gallup,
2007). For example, yawns produce increases in
blood flow to the skull and enhanced venous
return (Bhangoo, 1974), while the deep
inhalation during yawning can modify the
temperature of venous blood draining from the
nasal and oral orifices into the cavernous
sinus, which surrounds the internal carotid
artery (Zenker and Kubik, 1996). Together, these
processes act like a radiator removing
hyperthermic blood from brain while introducing
cooler arterial blood to the brain. Moreover,
the flexing of the musculature during yawning
may encourage the evaporation of the sinus
mucosa (see Gallup and Hack, 2011). Research
supporting the brain cooling hypothesis has
accumulated over the past 5 years, including
evidence for predicted brain and body
temperature fluctuations surrounding yawning
events, indirect manipulations of brain
temperature causing a reduction in yawn
frequency, and an altered expression of yawning
which appears to be driven by ambient
temperature manipulation/variation (reviewed by
Gallup and Eldakar, 2013). For example, by
directly monitoring continuous changes in
prelimbic cortex temperature of rats it was
shown that yawning is preceded by intermittent
and rapid increases in brain temperature (i.e.,
"-'O.l°C/min), and that following the
completion of a yawn the slope of the
temperature change reverses and quickly returns
to baseline (Shoup-Knox et al., 2010).
While the breadth of physiologic measures
taken by Krestel et al. (2013) is laudable, a
single measure of axillary temperature taken
long after the onset of the yawning episode is
inadequate for assessing this relationship.
Since distinct brain temperature changes in rats
occur before and after single yawns on a rather
short temporal scale; i.e., 60-90 s (ShoupKnox
et al., 2010), and isolated bouts of excessive
yawning in humans have been shown to reduce
skull temperature by as much as 0.4°C
(Gallup and Gallup, 2010), it remains possible
that the pathological yawning experienced by
these patients was accompanied by recurrent
changes in temperature that were never recorded.
Furthermore, temperature measures taken from the
skull (e.g., oral, tympanic, forehead) would be
more informative since the motor pattern of
yawning and the associated circulatory changes
are localized to this area. That said, even
these measurements could miss important
temperature fluctuations confined to particular
brain regions.
The use of MIII lesion maps to establish a
relationship between ischemic lesions in the
posterior insula and caudate nucleus and the
duration of abnormal yawning is certainly of
great importance (Krestel et al., 2013). At this
point, however, it is premature to declare that
there was "no evidence of other potential
causes" related to abnormal yawning in these
patients. To the contrary, frequent or abnormal
yawning in stroke patients may be a consequence
of thermoregulatory dysfunction associated with
the brain injury (Gallup and Gallup, 2008).
Given the close temporal association between
yawning and changes in brain/skull temperature,
future research monitoring patients with
abnormal or excessive yawning bouts should take
continuous temperature measures from areas
proximate to the cranium in order to properly
assess this relationship.
