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Le bâillement : de l'éthologie à la médecine clinique
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La parakinésie brachiale oscitante
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Warum gähnen wir ?
 
Fetal yawning assessed by 3D and 4D sonography
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mise à jour du
13/01/2014
 Brain Struct Funct
2015;220(2):803-812
 
Scholarpedia
Insular and caudate lesions release
abnormal yawning in stroke patients
 
Krestel H, Weisstanner C, Hess CW, Bassetti CL, Nirkko A, Wiest R.
 
Department of Neurology, Inselspital, Bern University Hospital, Switzerland

Chat-logomini

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 3 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 and Stroke
Bâillements et accidents vasculaires cérébraux
 
 
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.
 
Gallup AC.
 
Front Neurosci. 2014
 
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.