Joshi S, Bayat A, Gagnon L, Shields DC,
Koubeissi MZ.
1. Introduction
The function of yawning is not clear.
Physiological and communicative functions have
been hypothesized [1]. Some authors have
hypothesized it to be physiologically important
in oxygenation [2], arousal and
vigilance [3,4], thermoregulation
[5], and stress [6]. Others
argue that because of its contagious nature,
yawning serves a communicative function,
specifically that it is an expression of empathy
[7]. A number of anatomical structures
including the brainstem and hypothalamus have
been implicated in yawning [3,8,9],
whereas the role of the striatum remains
controversial [10,11,12]. Most evidence
for the neural substrates of yawning come from
pharmacological investigations of the roles of
such neurotransmitters as acetylcholine,
serotonin, dopamine, oxytocin, and other
excitatory neuropeptides [9]. To our
knowledge, there have been no reports from
humans in which electrical stimulation of a
brain region induced yawning, and reports from
animals are minimal [13,14]. Here, we
report a unique case of electrical stimulation
of the putamen consistently inducing yawning in
a patient with depth electrodes implanted for
evaluation of intractable epilepsy.
2. Methods
A 46-year-old woman with pharmacoresistant
seizures underwent implantation of depth
electrodes for identification of the seizure
focus. She had automotor seizures with
alteration of awareness. Because her scalp-EEG
monitoring had suggested bilateral temporal
seizure foci, 8 multi contact intracerebral
depth electrodes (Ad-Tech, Park Ridge, IL, USA,
10 contact electrodes; 0.5-cm inter electrode
distance) were stereotactically implanted in
bilateral hippocampi as well as extra temporal
structures that are connected with the medial
temporal lobes, including the insulae. Two
contacts of one depth electrode that aimed at
sampling the left insular cortex were in the
putamen. Her invasive monitoring concluded
bilateral independent hippocampal onsets. As
part of the comprehensive intracranial EEG
evaluation, electrocortical stimulation mapping
was done on the third and the fourth day post
implantation. Electrode placement was determined
by coregistering preoperative MRI with
postoperative CT (Fig. 1). Stimulation current
ranged from 2 to 10 mA, using 0.2-ms pulse width
at a frequency of 50 Hz and 3- to 10-second
train durations.
3. Results
Stimulation of the two putamen contacts at
intensities of 2 mA or 4 mA did not result in
any discernible behavioral phenomena. At 6 or 8
mA, however, stimulation consistently elicited
yawning. The patient was assigned a reading task
during mapping, and, upon stimulation at 6 mA,
her reading pace slowed, and she yawned 5.5 s
following the onset of the train. She was
stimulated on two other occasions at 6 mA and
yawned within 4.5 and 5.5 s after stimulation
onset. She was stimulated 6 times at 8 mA.
During the first three stimulations, she
exhibited the same behavioral changes noted at
6mA, namely a decrease in her reading pace
accompanied with yawning 4.5&endash;6 s
following stimulation onset. Following the third
stimulation,when askedwhether she was sleepy,
she affirmed.
We then tested the hypothesis whether
engagement in complex verbal and motor tasks
could modify the elicited yawning response.
Thus, attempts at 8 mA were done while engaging
the patient in cognitive and motor tasks before
stimulation onset. The tasks included following
repetitive verbal commands (e.g., point to the
window and touch your nose) and solving simple
arithmetic problems. It appeared that these
tasks abolished yawning. However, on two
occasions, she would take a deep inspiration,
suggestive of yawning onset, though without
evolution into a complete yawn. She remained
alert and followed all commands throughout the
rest of the mapping session and did not yawn
spontaneously. Stimulation of other electrodes
that day did not elicit yawning.
When the same putamen contacts were
stimulated at 6 mA the following day, the
patient again consistently yawned a few seconds
after the onset of the stimulation train. No
other motor or memory deficits were apparent
during mapping, and the patient consistently
returned to baseline upon cessation of
stimulation. Again, stimulation of other
electrodes including ones in the insula and the
posterior cingulate gyrus did not elicit
yawning. The EEG did not show any seizure
activity or afterdischarges.
4. Discussion
Although many have explored the
neuroanatomical substrates of yawning, the
direct involvement of the striatum has remained
unconfirmed [10,11,12]. Here, we provide
direct evidence, through electrical stimulation,
of the involvement of the putamen in yawning. We
found that putamen stimulation on two separate
days consistently elicited yawning - a response
thatwe foundmodifiable by paying full attention
to cognitive and motor tasks. We, thus, propose
that the putamen play a key role in the
execution of motor movements of yawning. Among
the basal ganglia, the putamen has been most
associated with motor control, and it is
possible that putaminal stimulation activates
the motor network of yawning [15]. The
4.5- to 6-second latency between stimulation
onset and yawning suggests further processing of
an action that is encoded in the putamen across
other motor execution networks. Whether
putaminal stimulation is related to sleep itself
is unlikely, although it cannot be totally ruled
out based on this case. While the patient
reported that she was sleepy during stimulation,
she did not fall asleep and maintained full
attention to assigned tasks. The above
considerations may be supported by the known
extensive anatomical connectivity of the putamen
to cortical and brainstem areas and its role in
motor control.
Animal studies have suggested roles for the
paraventricular nucleus (PVN) of the
hypothalamus, brainstem, and hippocampus, but
not the putamen, in yawning [3,8,9]
There are proposed roles for a number of
neurotransmitters in yawning, including
acetylcholine, serotonin, oxytocin, and dopamine
(DA), among others. The primary site of action
of these neurotransmitters has been hypothesized
to be the PVN [9]. While injections of
DA receptor agonists, such as apomorphine, in
the PVN can induce yawning [9],
bilateral striatal lesions can abolish this
response [11]. Additionally, high-dose
injections of DA receptor agonists into the
striatum or septum induced yawning in rats
[12]. A subtype of rats, "high-yawning"
rats, has the highest labeling of D1-like DA
receptors in the caudate and putamen. This
finding could possibly explain the increased
yawning (and grooming) behaviors of these rats
in comparison with the "low-yawning" rats
[16]. In rhesus monkeys, it was shown
that quinpirole, a DA agonist, induced yawning.
Furthermore, through PET imaging, the
researchers found that a D3R (D2-like receptor)
preferring radioligand shows highest binding
potential in the putamen, ventral pallidum,
globus pallidus, and hippocampus [17].
Moreover, functional imaging studies have
implicated the anterior dorsal insula in
task-level control and attention [18].
It is possible that attention, such as that
elicited by solving arithmetic questions and
commands to carry out motor tasks, also
activates the anterior dorsal insula which, in
turn, inhibits the putaminal processing of
yawning. This relationship between the insula
and the putamen is supported by reports that
patients with insular strokes present with
pathological yawning [19].
But why do we yawn? Many speculations have
been put forth, though no clear scientific
evidence favors one over the other. Itwas
initially believed that yawning functioned to
increase oxygenation levels in the blood
[2]. However, this was discredited since
it was found that breathing high levels of
either CO2 or O2 did not affect yawning
frequency [20]. Some believe that
yawning serves as an arousal mechanism,
particularly during times of little external
stimulation where lack of vigilance can prove
harmful [2]. This idea has been extended
to propose that yawning represents an
interoceptive process, one that increases
self-awareness and arousal [8]. The
thermoregulatory theory of yawning posits that
yawning serves to reduce brain and body
temperature [5]. Indeed, there have been
reported cases of pathological yawning in
disorders of thermoregulation [21,22].
Furthermore, disappearance of yawning was
reported in disorders with decreased DA neurons
in the PVN, such as Parkinson's disease
[23]. Lastly, yawning has been connected
with increased blood cortisol levels and,
therefore, is associated with stress and fatigue
[6].
On the other hand, someargue that yawning
serves a primarily communicative function.
Contagious yawning was reported to be more
common among kin and friends than strangers and
was, therefore, interpreted as a representation
of empathy [7]. This has been
corroborated by studies revealing engagement in
contagious yawning of the mirror neuron system
(MNS), a system implicated in higher-level
cognitive processing, such as empathy
[24]. Functional MRI findings revealed
activation of the right inferior frontal gyrus,
a part of the MNS, when participants exhibited
contagious yawning, thereby supporting the idea
of empathetic yawning [25]. Furthermore,
EEG findings have revealed that mu suppression
on the EEG, an index utilized to represent MNS
activation, was greater for participants viewing
or hearing yawns than for controls [26].
These findings support the notion that
contagious yawning is an expression of empathy
and that the MNS may play a key role in this
expression. In reference to the proposed
theories, we hypothesize that the putamen's
widespread connectivity with cortical and
subcortical regions allows it to receive input
regarding alterations in physiologic or social
needs and initiate the motor execution of
yawning, an action that can similarly be
inhibited by other brain regions, possibly
including the insula.
5. Conclusion
Whether yawning has a social communicative
function or a physiological significance, or
both, is a question that remains to be answered.
Here, we illustrate the role of the putamen
through direct electrical stimulation and
corroborate previous findings suggesting a role
for the striatum in yawning. We hope that
findings from this report contribute to future
research investigating yawning.
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