Introduction

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The act of yawning has been an intriguing enigma for centuries. Commonly associated with tiredness, stress, overwork, lack of stimulation and boredom, yawning has been shown to accompany numerous pathological conditions. These include frontal lobe tumours, epidemic encephalitis, supra-nuclear palsy, gastric diseases, brain stem lesions, epilepsy, motion sickness, narcotic withdrawal, chorea, strokes, and multiple sclerosis.1,2

Similar to breathing, blinking, sighing, yawning is often taken for granted and is a reflex consisting of the simultaneous inhalation of air and the stretching of the eardrums, followed by an exhalation of breath. Pandiculation is the act of yawning and stretching simultaneously which is not merely a simple opening of the mouth but a complex, coordinated movement bringing together a flexion followed by an extension of the neck and a wide dilatation of the pharyngolarynx with strong stretching of the diaphragm and anti-gravity muscles.3

Yawning is not just a human behaviour and is in fact morphologically similar in reptiles, birds, mammals and fish. Walusinski 4 identified 3 types of yawn:

(i) Universal yawning appears to be found in most vertebrates and is associated with sleep, arousal, hunger and satiety.5

(ii) Emotional yawning is seen in higher functioning vertebrates. For example, dogs yawn more when taken to the vets and chimpanzees yawns more when caged. This stress relationship appears in humans too – athletes yawn more when about to compete; actors yawn more before performances; and yawning increases more in parachutists about to jump.6 Some forms of yoga utilise yawning to increase relaxation and induce a calming effect.

(iii) Contagious yawning appears predominantly in great apes and humans,7 and is the process of mimicking with behaviour. Contagious yawning is reduced or even absent in some autistic conditions8 which may indicate a difficulty in expressing empathy. Indeed, fMRI scans shows yawning activates the brain structures implicated in the conveyance of empathy. As a neocortical activity (frontal and parietal lobes, insula and amygdala), communicative yawning seems to be a sign of involuntary empathy.9 Dr Gordon Gallup at the University of Albany in New York suggests that non-empathetic people do not contagiously yawn.10 This is contended since yawning is also dependent upon setting conditions such temperature of surroundings and possibly the way in which we perceive facial expressions.11

Schurmann et al.12 suggested that contagious yawning is related to the mirror-neuron system, activated when observing other motor acts and as a tool for understanding the behaviours of others behaviours. Platek et al.13 found negative correlation between susceptibility to contagious yawning and schizotypal personality traits.9 Contagious yawning may be a means in which humans gain an understanding of others whilst sharing similar feelings and emotions.2 It may also be dependent upon the way that the human face is perceived in terms of the portrayal of emotions.11

These types of yawning appear to indicate that yawning not only has numerous functions but is more complex in higher species in terms of the central nervous system and brain function as well as in the complexity of their social interactions. Yawning appears to have physiological significance13 and with advances in our understanding of biochemical activity over the last century, these have inevitably contributed to the understanding of the process of yawning from a neuropsychology perspective. Numerous neurotransmitters and hormones are likely implicated in the yawning process: dopamine (thought to activate oxytocin production in the hypothalamus and hippocampus), acetylcholine (known to be actively involved in memory functioning), serotonin (considered important in the feeling of well-being and pleasure), gamma amino butyric acid, pro-opiomelanocortin-derived peptides such as adrenocorticotrophic hormone, sexual hormones, and alpha-melanocyte stimulating hormone.2

Yawning Pathways

Yawning is mediated by at least three distinct pathways, and despite the diverse set of neurotransmitters involved, all appear to converge on cholinergic neurons within the hippocampus. The paraventricular nucleus of the hippocampus is thought to be important in the regulation of yawning with many neurotransmitters interacting with the oxytocinergic neurons within the hypothalamus (Figures 1-2).

Figure. 1_How Yawning and Cortisol Regulates the Attentional Network

Fig. 1: Theoretical pathways for the yawn reflex following fatigue

Figure. 2_How Yawning and Cortisol Regulates the Attentional Network

Fig. 2: Theoretical pathways for the contagious yawn reflex

The first international conference on yawning in Paris in 2010 brought together scientists to debate yawning and its manifestations.2 Walusinski et al.14 reported that brainstem stroke patients have been able to raise their paralysed arm during yawning. Termed parakinesia brachialis oscitans, this was first observed by the British Neurologist Sir Francis Walshe in 1923 and has since led to a number of similar reports.

In healthy people, during rest, the default-mode network is thought to be active but is switched to the attentional system with the increase in circulation of cerebrospinal fluid. This process increases clearance of somnogenic factors such as prostaglandin D(2), adenosine, and others accumulating in the cerebrospinal fluid.15

Curiously, patients with Locked-In Syndrome (LIS) commonly yawn with a reflex action known as reflexogen.16 LIS is a condition in which the patient is aware and awake but cannot move or communicate due to complete paralysis of nearly all of the voluntary muscles in the body except for the eyes. Askenasy17 suggests that the activatory reticular system remains unaffected, this has led to the speculation that the hypothalamus, brainstem, pontine and medullary regions play a role in yawning.18

Yawning and swallowing seem also to be physiologically related. Kimiko et al.19 were the first to suggest that yawning plays a role in eliciting rest swallowing which is demonstration of a temporal association between yawning and swallowing and thus extends current models of upper airway physiology.

Data is available prior to injury may hold the key to unwrapping the complex mechanisms involved in yawning. Williams20 reported the case of a woman experiencing excessive and spontaneous yawning months before the development of a bulbar or pseudo-bulbar palsy due to amyotrophic lateral sclerosis. This was caused by dysfunction of the upper motor neurons losing their inhibitory influence on the brainstem and lower motor neurons. Cattaneo et al.21 reported two similar cases who suffered from brainstem ischemia and both reported excessive yawning prior to any apparent neurological symptoms.

Yawning is implicated in thermoregulation in which the brain is cooled by yawning.22,23 Patients with central nervous system injury 24 and brain-injured patients 25 both display excessive brain temperature. Lesions within the central nervous system may also develop in areas which affect thermoregulatory control such as the hypothalamus.26 Excessive yawning has been seen in these patients. Temperature fluctuation is normally due to infection fever and is a common finding in stroke patients; 20-40% will suffer from fever.27 Stroke can induce mild elevations in body temperatures in humans; and animals also show spontaneous increases in body temperature following stroke. Sung et al.27 found that stroke resulting in destruction of the brainstem, directly and significantly influences body temperature. This could be a possibility as to why excessive yawning is implicated as a symptom in stroke patients.

Yawning and Multiple Sclerosis

Multiple sclerosis (MS) is a chronic and debilitating disease affecting the central nervous system and is characterised by autoimmune activated demyelination and axonal damage which consequently interrupts nerve transmission.

A common symptom of MS is excessive yawning.28 It has been postulated that thermoregulatory dysfunction is the main reason for this phenomenon together with a tendency towards over-fatigue.29,30 Davis et al.31 found that about 80% of MS patients experience a significant worsening of their clinical and neurological symptoms when exposed to an increase in ambient temperature.

It appears that the opposite is also true, with cooling alleviating temporarily some symptoms due to MS. Very small temperature changes of about 0.5 degrees centigrade was sufficient to make a change to symptom comfort. Temperature would appear to have effect on the sodium channels necessary for depolarisation of axons. An increase in temperature decreases the polarizing effect, whereas a decrease in temperature increases polarization.32

Sleep difficulties are often associated with MS. However, the cause of fatigue in MS is not well understood. In an evaluation of directed interactivity of an attentional network during intrinsic and phasic alerting tasks, it was hypothesised that neural circuits in the right hemisphere including the dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex, inferior parietal cortex and the thalamus were involved. Functional interactivity was significantly reinforced during the phasic alertness task and appeared to preferentially involve activity in the DLPFC region thus highlighting the role of this region in maintenance of a state of alertness and in temporal preparation during an alertness task.33

The focus of new research at Hpital Universitaire Amiens, Jules Verne Universit de Picardie, Universit Paris Ouest Nanterre La Dfense, France, in collaboration with Bournemouth University, UK led by the first author is fatigue and MS. Neuroscientist teams are testing the theory that intrinsic and phasic fatigue may be associated with cortisol levels and thus support the Thompson Cortisol Hypothesis.3436 It is well-established that yawning is linked with sleep deprivation 37 and it is speculated that fatigue is also signalled by yawning in MS.

According to Fleming and Pollak[38] the most common sleep disorders in MS patients are insomnia, nocturnal leg spasms, narcolepsy, REM sleep behaviour disorder, and sleep disordered breathing. Restless legs syndrome is also highly prevalent among MS patients revealing that among 156 MS patients examined, fifty-one per cent met the criteria and was associated with higher MS-related disability.38

Yawning and Epilepsy

Epilepsy is a group of long-term neurological disorders characterized by epileptic seizures. These seizures are episodes that can vary from brief and nearly undetectable to long periods of vigorous shaking. Seizures tend to recur, and have no immediate underlying cause while seizures that occur due to a specific cause are not deemed to represent epilepsy. The illness can be extremely debilitating and traumatic for the sufferer and family and friends. Epileptic seizures are occasionally followed by post-ictal yawning which lateralises the seizure to the right hemisphere.39 It has been speculated that endogenous opioids, considered part of a protective system that prevents seizures, may be expressed by yawning.40

Specchio et al.41 report on the incidence of yawning and seizures. Neuroscientists have also reported that chronic focal brain cooling suppresses seizures during wakefulness and achieves the effect without significantly affecting brain function. It is anticipated that this approach to seizure control may soon be available to humans. 42

Yawning and Cortisol

Cortisol is a steroid hormone, known as a glucocorticoid, made in the cortex of the adrenal glands and then released into the blood which transports it around the body. Almost every cell contains receptors for cortisol; therefore, it as many different actions dependent upon on the types of cells upon which it is acting on. These effects include controlling the bodys blood sugar levels and thus regulating metabolism, acting as an anti-inflammatory, influencing memory formation, controlling salt and water balance, influencing blood pressure and helping development of the foetus. In many species cortisol is also responsible for triggering the processes involved in giving birth.

Blood levels of cortisol vary dramatically, but generally are high in the morning on wakening, and then fall throughout the day. This is called the diurnal rhythm. In people who work at night, this pattern is reversed, so the timing of cortisol release is clearly linked to daily activity patterns. In addition, in response to stress, extra cortisol is released to help the body to respond appropriately.

The secretion of cortisol is mainly controlled by three inter-communicating regions of the body: hypothalamus, pituitary gland, and adrenal gland. This is called the hypothalamic-pituitary-adrenal axis. When cortisol levels in the blood are low, 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 and 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. As a result, the adrenocorticotropic hormone levels start to drop which then leads to a drop in cortisol levels. This is known as a negative feedback loop.

Not only have patients with low levels of cortisol been found to have a higher prevalence of asthenia, depression and fatigue 43 but clinical trials have also found increased self-report measures of energy and vigour. Cortisol has been linked with post-operative fatigue;44 however, feeling of wellbeing has also been associated with cortisol, and chronic fatigue syndrome is frequently addressed with cortisol treatment.45 Nater et al.46 found that hypocorticism was prevalent in their sample of patients with chronic fatigue syndrome and proposed that increased activation in the immune system was a result of low cortisol levels leading to fatigue.

The alexithymia trait, characterised by fatigue and low vigour, is associated with low cortisol levels 43 and is related to the fatigue experienced prior to disease onset 47 in a similar way as flattening daytime cortisol is associated with healthy individuals. This may suggest that cortisol levels change before disease symptoms are present, consequently offering great clinical value. Hence, there is scope and potential value in exploring the use of cortisol as a biomarker for detecting early signs of untoward and underlying neurological disease symptoms.48

The Thompson Cortisol Hypothesis, as well as complementing the thermoregulation hypothesis that suggests brain cooling occurs when yawning, has been supported in a number of studies.35,36,49 Yawning has also now been captured in terms of its electromyography trace 50 depicted as the yawning envelope. It seems that yawning is not just an expression of underlying activity but a mechanism for regulating temperature and immune system control but is also a warning of underlying symptoms.

Conclusions

Yawning has been seen in association with fatigue as well as in more recent reports in association with changes in cortisol levels. Fatigue is a common symptom of multiple sclerosis and has been proposed that the thermoregulatory hypothesis implicating the hypothalamus is also involved in the regulation of cortisol. Immune system and protection of neural brain activity, particularly seizure prevention, seems convincing in animal studies and it is likely that cortisol levels, expressed by yawning, may also protect against seizures in humans.

Cortisol is present throughout the body and appears to have different actions dependent upon the site of its receptors. In addition to influencing the hypothalamus-pituitary -adrenal axis, cortisol levels have been affected by the presence of yawning-provoking stimuli thus giving rise to the debate over contagious yawning and the interplay between environmental and social influences upon yawning and cortisol secretion.

It seems likely that cortisol could be a future biomarker of underlying neurological disease symptoms since it is representative of fatigue status in people with multiple sclerosis and because yawning is an important sign as well as an activist on brainstem ischaemic stroke patients in the elicitation of movement of hemiplegic limbs.

Locating the yawning site within the brain is dependent upon its activation of specific neurological pathways to determine movement. Therefore, it is specific to the origins of those pathways and it is proposed that they are likely to be the substructures within the brainstem and hypothalamus.