Le bâillement, du réflexe à la pathologie
Le bâillement : de l'éthologie à la médecine clinique
Le bâillement : phylogenèse, éthologie, nosogénie
 Le bâillement : un comportement universel
La parakinésie brachiale oscitante
Yawning: its cycle, its role
Warum gähnen wir ?
Fetal yawning assessed by 3D and 4D sonography
Le bâillement foetal
Le bâillement, du réflexe à la pathologie
Le bâillement : de l'éthologie à la médecine clinique
Le bâillement : phylogenèse, éthologie, nosogénie
 Le bâillement : un comportement universel
La parakinésie brachiale oscitante
Yawning: its cycle, its role
Warum gähnen wir ?
Fetal yawning assessed by 3D and 4D sonography
Le bâillement foetal

mystery of yawning 



mise à jour du
20 décembre 2020
J Parkinons Dis
On the Emergence of Tremor
in Prodromal Parkinson's Disease


Fearon C, Lees AJ, McKinley JJ, McCarthy A,
Smyth S, Farrell M, Lynch T.


Parakinésie brachiale oscitante
Parakinesia brachialis oscitans
Clinical, neuropathological and neuroimaging research suggests that pathological changes in Parkinson's disease (PD) start many years before the emergence of motor signs. Since disease-modifying treatments are likely to be most effective when initiated early in the disease process, there has been significant interest in characterizing prodromal PD. Some people with PD describe autonomic symptoms at the time of diagnosis suggesting that autonomic dysfunction is a common feature of prodromal PD. Furthermore, subtle motor signs may be present and emerge prior to the time of diagnosis.
The authors present a series of patients who, in the prodromal phase of PD, experienced the emergence of tremor initially only while yawning or straining at stool and discuss how early involvement of autonomic brainstem nuclei could lead to these previously unreported phenomena. The hypothalamic paraventricular nucleus (PVN) plays a central role in autonomic control including bowel/bladder function, cardiovascular homeostasis and yawning and innervates multiple brainstem nuclei involved in autonomic functions (including brainstem reticular formation, locus ceruleus, dorsal raphe nucleus and motor nucleus of the vagus).
The PVN is affected in PD and evidence from related phenomena suggest that the PVN could increase tremor either by increasing downstream cholinergic activity on brainstem nuclei such as the reticular formation or by stimulating the locus ceruleus to activate the cerebellothalamocortical network via the ventrolateral nucleus of the thalamus. Aberrant cholinergic/noradrenergic transmission between these brainstem nuclei early in PD couldlead to tremor before the emergence of other parkinsonian signs, representing an early clinical clue to prodromal PD.
La recherche clinique, neuropathologique et en neuroimagerie suggère que les changements pathologiques de la maladie de Parkinson (MP) commencent plusieurs années avant l'apparition des signes moteurs. Étant donné que les traitements de fond sont susceptibles d'être plus efficaces lorsqu'ils sont initiés tôt dans le processus de la maladie, il y a un intérêt significatif pour caractériser la MP prodromique.
Certaines personnes atteintes de MP décrivent des symptômes autonomes au moment du diagnostic, suggérant que le dysfonctionnement autonome est une caractéristique commune de la MP prodromique. De plus, des signes moteurs subtils peuvent être présents et apparaître avant le moment du diagnostic.
Les auteurs présentons une série de patients qui, dans la phase prodromique de la MP, ont remarqué initialement l'émergence de tremblements uniquement en bâillant ou en allant aux selles. Ils discutent de la façon dont l'implication précoce des noyaux du tronc cérébral autonome pourrait conduire à ces phénomènes auparavant non signalés. Le noyau paraventriculaire hypothalamique (PVN) joue un rôle central dans le contrôle autonome, y compris la fonction intestinale / vésicale, l'homéostasie cardiovasculaire et le bâillement. Il innerve plusieurs noyaux du tronc cérébral impliqués dans les fonctions autonomes (y compris la formation réticulaire du tronc cérébral, le locus ceruleus, le noyau du raphé dorsal et le noyau moteur du vague). Le PVN est affecté dans la MP et les preuves issues de phénomènes connexes suggèrent que le PVN pourrait augmenter le tremblement soit en augmentant l'activité cholinergique en aval sur les noyaux du tronc cérébral comme la formation réticulaire, soit en stimulant le locus ceruleus pour activer le réseau cerebello-thalamo-cortical via le noyau ventrolatéral du thalamus. Une transmission cholinergique / noradrénergique aberrante entre ces noyaux du tronc cérébral au début de la MP pourrait entraîner des tremblements avant l'apparition d'autres signes parkinsoniens, ce qui représente un indice clinique précoce de la MP prodromique.
Cartoon showing afferent and efferent projections of the paraventricular nucleus (PVN) salient to yawning (red), tremor (blue) and parakinesia brachialis oscitans (green). DA, dopamine; LRN, Lateral reticular nucleus, OXT, oxytocin; VLpv, ventrolateral nucleus of the thalamus pars ventralis.
The diagnosis of Parkinson's disease (PD) is centered on the identiÞcation of a predominantly motor phenotype. Converging evidence from clinical, neuropathological and neuroimaging research, however, suggests that pathological changes in people with Parkinson's disease (PwP) start years before the emergence of core motor signs [1, 2]. A recent hypothesis in PD is that alpha-synuclein may spread from the peripheral autonomic nervous system to lower brainstem nuclei and only thereafter to areas salient to movement [2&endash;4]. In particular, a body-Þrst subtype of PD has been recently described whereby multimodal imaging supports cardiac and colonic denervation which may occur in prodromal PD [5]. Hence, it is not surprising that PwP report autonomic symptoms at the time of diagnosis [6]. Since disease-modifying treatments are likely to be most effective when initiated early in the disease process, there has been interest in identifying and character rising prodromal PD [7]. REM-sleep behavior disorder (RBD), the proto- typical prodromal syndrome in PD, has complex pathophysiology involving GABAergic, glutamatergic and cholinergic mechanisms centered on a number of critical brainstem nuclei [8]. Post-mortem, animal and imaging studies suggest that cholinergicdegen- eration of the mesopontine tegmentumplays a central role in RBD [9, 10]. Other prodromal markers of PD are regulated by the autonomic nervous system and include constipation, orthostatic hypotension, uri- nary and erectile dysfunction [7]. In parallel, some cholinergic, serotoninergic and noradrenergic brain- stem nuclei which regulate these autonomic functions are selectively vulnerable in PD [11]. These include the dorsal motor nucleus of the vagus, dorsal raphe nuclei, locus ceruleus and subceruleus and brainstem reticular formation.
Subtle motor signs are present before a deÞni- tive diagnosis of idiopathic PD is made [12, 13]. At diagnosis, rest tremor is the most common present- ing symptom of PD [14]. Charcot and Gowers both described ephemeral tremors preceding the onset of parkinsonism but this phenomenon has not been well described in the modern era [15, 16]. Tremor has been identiÞed in two studies as a prodromal sign of PD (in some cases up to 10 years prior to diagnosis) [12, 17] but whether these represent the well-documented relationship between essential tremor and PD [18, 19] or distinct prodromal parkinsonism is unclear. The pathogenesis of tremor is poorly understood, and serotoninergic, dopaminergic, noradrenergic and cholinergic mechanisms may all contribute. SpeciÞc brainstem nuclei implicated in the generation of parkinsonian tremor include the locus ceruleus [20], ventral tegmental area [21], and dorsal raphe nuclei [22]. Stress and cognitive load can unmask tremor in PwP [23] and this may be mediated by the locus ceruleus via connections to the ventrolateral nucleus of the thalamus [20]. The ability of other activities to unmask parkinsonian tremor has not been well described to date. We present a series of patients who, in the prodromal phase of PD, experienced the emergence of tremor while yawning or straining at stool up to 20 years prior to their diagnosis. We present a hypothesis on how the early involvement of critical diencephalic and brainstem nuclei could lead to these previously unreported phenomena.
Clinical cases
We present a series of patients who, in the prodromal phase of PD, experienced the emergence of tremor initially only while yawning or straining at stool. Although at Þrst glance, yawning and straining appear to have opposing physiological effects, the two processes are not entirely at odds with each other physiologically.
Studies have indicated that yawning leads to an increase in heart rate, lung volume and skin conductance and reduced venous return which may be med- iated by mechanical stimulation of the carotid body [24, 25]. The Valsalva maneuvre engages both sympathetic and parasympathetic pathways during four separate phases of the response [26]. Hemodynamic responses to the Valsalva maneuvre are well deÞned and also include an increase in heart rate and reduced venous return (mirroring those which occur during yawning). This same physiological response can also be stimulated by carotid sinus massage. This suggests that similar central autonomic activation may occur during both yawning and Valsalva maneuver during straining at stool [25]. The baroreceptor reþex described above activates a distributed central autonomic network which includes the supraoptic and paraventricular nuclei, posterior hypothalamus, par- aventricular and dorsomedial hypothalamic nuclei, preoptic-anterior hypothalamic region, the periaqueductal gray, the central nucleus of the amygdala, and the insular cortex [27]. Of these, the area which may be of most interest in PD is the paraventricular nucleus of the hypothalamus, as outlined below.
Yawning and the paraventricular nucleus of the hypothalamus
In order to understand how yawning could activate tremor in a patient with prodromal PD, the physiology of yawning must be considered. Yawning is a common physiological phenomenon occurring up to 20&endash;30 times per day in healthy humans [28]. However, the pathophysiology of yawning is poorly understood, as is its role in neurological disease. Several hypotheses have been proposed as to why we yawn. These include regulation of arousal and sleep, thermoregulation, brain perfusion/oxygenation and a communicative/social tool [29].
The precise underlying neuroanatomical structures which mediate yawning are also unknown. Anencephalic infants yawn suggesting that the structures which execute the motor action of yawning reside in the brainstem [30]. Other lesion studies have localized this to near the reticular activating system [31]. It is clear that a number of structures modulate the yawning mechanism in a top-down fashion, most notably, the hypothalamic paraventricular nucleus (PVN) [28]. The PVN is located in the ventral diencephalon and is composed of magnocellular neurons, parvocellular neuronsand long-projecting neurons. These long-projecting neurons include oxytocinergic cells which project to the hippocampus, spinal cord and brainstem, including multiple autonomic brainstem nuclei (e.g., nucleus of the solitary tract, reticular formation, locus ceruleus, dorsal raphe nuclei and motor nucleus of the vagus). The pro- posed roles of the PVN are therefore wide-ranging from cardiovascular, gastrointestinal and respiratory homeostasis, through feeding and metabolism, to penile erections and sexual behavior [32, 33].
Yawning in Parkinson's disease
Yawning has been reported in parkinsonism as early as initial reports of encephalitis lethargica, both in acute and post-encephalitic stages [34]. However, its role in idiopathic PDis predominantly related to dopaminergic therapy. Goren & Friedman Þrst reported yawning as an aura signaling the levodopa- induced "on" period in two PwP [35]. Transient yawning preceded the clinical transition from "off" to "on" by approximately 5 minutes in a reproducible fashion. The authors hypothesized that dopaminergic and cholinergic mechanisms may be at play [36, 37]. This letter prompted responses from other groups stating that the majority of PwP who are administered subcutaneous apomorphine (a direct D1/D2 dopamine receptor agonist) experience transient yawning coincident with onset of the motor response [38, 39] and in some patients, with transient penile erections [40]. Given that oxytocin release from the PVN mediates yawning and penile erections in rats following apomorphine administration, the PVN is assumed to play a similar role in apomorphine-induced yawning in these PwP [33, 41]. The number of oxytocinergic neurons in the PVN is reduced (by over 20%) in PwP [42]. The nuclear volume of the remaining neurons is increased suggesting a compensatory activation. This may result in altered sensitivity of these remaining neurons to dopaminergic stimulation. Initial studies examining ubiquity nation suggested that Lewy bodies were not present in the PVN [42], however more recently alpha-synuclein immunohistochemistry has demonstrated that the PVN is directly involved, not only in conÞrmed PD cases but also in the incidental Lewy body disease group (Braak stage< = 2) [43]. Importantly this suggests that Lewy body aggregation may occur in the PVN in the prodromal phase of PD.
Apomorphine injected into the PVN can induce yawning at concentrations 5&endash;40 times lower than that required to induce yawning at the level of the striatum implying that the PVN is the primary site of action for dopaminergic yawning [44]. Furthermore, lesioning of the PVN and administration of oxytocin antagonists suppresses apomorphine-induced yawning [41, 45]. D2-like antagonists do not sup- press oxytocin-induced yawning, suggesting that the dopaminergic effect is upstream from oxytocin [46, 47]. Yawning induced by D2-agonists is sup- pressed by D2-like antagonists as expected. However, D2-agonist-induced yawning is also inhibited by anticholinergics [35, 48]. Cholinesterase inhibitors and muscarinic receptor agonists can also induce yawning which can be suppressed by anticholinergics but not dopamine receptor antagonists [36, 48]. Thus, the dopaminergic effect on yawning is likely executed by downstream cholinergic transmission, probably via M1 muscarinic receptors. In summary, the primary yawning mechanism is likely via oxytocinergic long-projecting neurons in the paraventricular nucleus enhancing cholinergic transmission in the hippocampus and multiple brainstem sites including the reticular formation.
Defecation, valsalva and Parkinson's disease
Our fourth patient experienced prodromal emergence of tremor while straining at stool. Bowel dysfunction is a common prodromal feature of PD. During defecation in PwP, paradoxical sphincter con- traction occurs, leading to signiÞcantly higher anal pressure than occurs in control subjects [49]. As a result, a greater rise in intra-abdominal pressure is required for evacuation in PwP. Abdominal straining and hence, Valsalva can achieve this. The degree of paradoxical sphincter contraction on defecation is similar in early and late PD, indicating that this phenomenon is an early Þnding in PD and may even occur in the prodromal phase [50]. However, straining is impaired in PwP due to poorly coordinated glottal closure [51]and Valsalva maneuvers in PwP lead to a smaller increase in intraabdominal pressure com- pared with controls [52], suggesting a greater degree of straining is required for defecation in PwP. Furthermore, the vagal response to Valsalva maneuver is reduced in PwP, particularly in the setting of ortho- static hypotension (another prodromal PD syndrome) [53]. This implies abnormal and possibly aberrant vagal responses may occur during straining at stool and Valsalva maneuvers, even in the prodromal phase of PD.
The PVN, which densely innervates the dorsal vagal nuclei, clearly plays a central role in yawning but it may also play a crucial role in vagal control of gut motility. Stimulation of the PVN modulates the activity of gut-sensitive neurons in the vagal com- plex and may also modulate vago-vagal reþexes [54]. Excessive PVN activity may therefore be required to compensate for the deÞcient downstream regulation of defecation. Furthermore, vagal afferents can stim- ulatePVNneuronsinthesettingofchangesinvolume load as occurs during a Valsalva maneuvre [55]. In this way, straining at stool in PD could lead to similar activation of the PVN-brainstem axis as we have hypothesized occurs during yawning above. However, we have yet to discuss how either process could lead to the emergence of tremor in these patients.
Unmasking paradoxical movement and tremor
The striking feature of our cases is that they developed yawning- or straining-associated rest tremor ears before a diagnosis of PD was made. The emergence of tremor while yawning or straining at stool in PwP has not been previously described. However, involuntary movement occurring synchronously with yawning has been previously described herein patients with acute hemiplegia may experiencere þex elevation of the paralyzed arm during yawning [56&endash;59]. This phenomenon of parakinesia brachialis oscitans has been reported in patients with vascular, demyelinating, infectious and degenerative lesions affecting the corticospinal tract, basal ganglia or brainstem and consists of reproducible involuntary elevation or abduction of the paretic limb coincident with jaw opening during yawning [59]. The paretic limb falls again when the yawn ends. The most com- mon causes are lesions of the internal capsule and lentiform nucleus/caudate nucleus or ponto medullary lesions. The precise pathophysiology is unknown but it is hypothesized to occur as a reþex activity of brain- stem structures when released from rostral inhibitory control, similar to the emergence of palatal tremor with uncontrolled activity of the olivary nucleus [59]. Walusinski has presented a number of possible hypotheses for parakinesia brachialis oscitans [29, 56, 59, 60]. Regulation of automatic respiratory activity such as diaphragmatic movement and stretching occurs via the coordinated activity of the pre-Botzinger complex in the ventral medulla and the adjacent lateral reticular nucleus (under modulatory control from the hypothalamus) [61, 62]. The lateral reticular nucleus (LRN) plays a crucial role in integrating descending and ascending signals to regulate limb movements [63]. The Þbers which project from the LRN to the deep cerebellar nuclei exert a direct excitatory effect on descending motor pathways via the reticulospinal and vestibulospinal tracts [63]. Even when corticospinal motor control is lost, the LRN continues to receive afferent stimulation from the ventral spinocerebellar tract. A strong afferent signal from contraction of respiratory muscles during yawning (or a strong Valsalva maneuver during straining at stool), could therefore lead to involuntary automatic limb movement through this spinoreticulocerebellar pathway [59].
Although parkinsonian tremor is a much more common phenomenon than parakinesia brachialis oscitans, its precise pathophysiology is equally poorly understood. Unlike rigidity and bradykinesia, parkinsonian tremor often takes longer to respond to dopaminergictherapyandsomecasesrequiredhigher doses [64]. Animal studies of selective dopaminergic basal ganglia lesions (e.g., MPTP) do not pro- duce the characteristic parkinsonian tremor [65] and involvement of other brainstem areas such as the locus ceruleus or ventral tegmental area may be required to cause tremor [21]. Tremor severity is not related to nigral dopamine deÞciency making dop- amine unlikely to be the sole neurotransmitter involved in tremor generation. Serotoninergic deÞcits in midbrain raphe nuclei have been demonstrated with positron emission tomography (PET) and these correlate with tremor scores [22]. Importantly, the raphe nuclei receives input from the PVN. However, the effect of anticholinergic agents on parkinsonian tremor cannot be ignored. Antimuscarinic agents were the Þrst pharmacological treatment for PD and still widely used for management of tremor. NeostriatalM4muscarinicreceptorshavebeenimpli- cated in generation of this tremor in rat models and tropicamide (which has a modest effect on M4 receptors) suppresses the tremor [66, 67]. Multiple brainstem areas can be involved in generation of parkinsonian and non-parkinsonian tremor (includ- ing dentate-rubro-olivary pathways [68, 69], dorsal raphe nuclei [70], bulbar reticular formation [71], nucleus ambiguous [72], locus ceruleus and ventral tegmental area [21]). Many of these regions receive projections from the PVN (Fig. 1). In particular, the PVN projects to the reticular nuclei, raphe nuclei, ventral tegmental area, locus ceruleus and nucleus ambiguous [32].
Ephemeral tremors prior to the emergence of PD have been described by both Charcot and Gowers, however these were predominantly in the setting of acute stressors (emotional shock, prolonged anxiety, trauma or cold weather) [15, 16].
Gowers noted that "the tremor subsides when the alarm is over" suggesting a brief physiological change may mediate these tremors. Trauma was noted to be the inciting cause in a number of cases, in particular trauma at the site in which tremor subsequently persisted. Although there may be a bias here (tremor in the traumatized limb being more notable than tremor elsewhere), it raises the possibility of sensory feedback modulating tremor thresh- olds. The spinoreticular pathway and brainstem ret- icular formation may play a role in parakinesia brachialis oscitans. However, this pathway is also in- volved in processing emotional response to pain [73]. Hence, the reticular formation may provide a com- mon pathway to explain those tremors caused by emotional stress and those cause by physical trauma. Gowers also described the remarkable case of young lady, who when startled by water suddenly pouring onto her hand, developed tremor in that hand which subsequently spread, developing into typical PD. It is worth noting that in all of our cases, the tremor which occurred during yawning or straining was on the side in which persistent tremor eventually emerged. This supports the idea that our patients were displaying true prodromal parkinsonian tremor rather than an unrelated phenomenon.
Cognitive load is another common exacerbator of tremor. Dirkx and colleagues examined the effect of cognitive load on tremor in PwP using synchronous electromyography and functional MRI [20]. In a similar manner to what we observed, parkinsonian tremor can emerge or be ampliÞed when patients experience a cognitive load such as being asked to carry out mental arithmetic under pressure in the consulting room. Dirkx and colleagues demonstrated that cognitive load correlated with tremor amplitude, pupillary diameter, heart rate and activity in the cog- nitivecontrolnetwork[20]. Theauthorshypothesized that cognitive load can increase tremor through a bottom-up noradrenergic ascending arousal system which activates the ventrolateral nucleus of the thalamus pars ventralis (VLpv) and hence the cerebel- lothalamocortical network driving tremor. Tremor- predominant PwP show less degeneration of the locus ceruleus than other PwP [74] and the locus ceruleus sends noradrenergic projections to the VLpv as well as other nodes of the cerebellothalamocortical network [75, 76]. Dirkx and colleagues therefore con- cluded that the locus ceruleus mediates the increase in tremor amplitude, as well as the pupillary and heart rate changes. Since the PVN is a major sym- pathetic premotor nucleus of the pupillary reþex (via the intermediolateral column of spinal cord) [77] and modulates heart rate, it is possible that this nucleus may play a role in their Þndings. Given the dense connectivity between the PVN and the locus ceruleus, a similar activation of the cerebellothalamocortical network might enhance tremor during yawning or Valsalva while straining at stool in our patients.
Hence, it is possible that aberrant brainstem trans- mission during yawningor Valsalva maneouvre could activate the cerebellothalamocortical network either via the lateral reticular nucleus (and the deep cerebellar nuclei) or via the locus ceruleus (and the VLpv). The brainstem reticular formation and locus ceruleus have previously been implicated in the pathophysiology of RBD, the only well characterized prodromal syndrome in PD.
Horsager et al. recently used the presence or absence of premotor RBD to dichotomize PD patients into "brain-Þrst" and "body-Þrst" subtypes [5]. Body-Þrst patients demonstrate a wide range of abnormalities on functional imaging including cardiac denervation and cholinergic denervation of the colon. Given the widespread role of the PVN both in cardiovascular homeostasis as well as well as regulation of bowel function, it seems likely that the PVN may be involved in many of these "body-Þrst" patients.
Our hypothesis is speculative and future work is required to clarify the involvement of the PVN in prodromal PD and its clinical correlates. Only a single study to date has examined alpha-synuclein immunohistochemistry in the PVN. It is clear that well-designed neuropathological studies examining the frequency and extent of involvement of the PVN in clinically well-characterised patients with PD (such as body-Þrst subtypes) as well as patients with idiopathic RBD are needed. As we are on the thresh- old of diagnostic tests for the synucleinopathies, in particular with respect to Real-Time Quaking- Induced Conversion (RT-QuIC) in tissues such as skin and cerebrospinal þuid, it may be able to test this hypothesis in vivo in patients such as those presented herein [78, 79]. With potential disease modifying treatments in evolution, this may also have impor- tant implications in helping to deÞne prodromal PD patients who may beneÞt from early treatment with such agents. Although the exact mechanisms under- lying the emergence of tremor in prodromal PD are undeÞned, it clearly represents an important Þnding as it may help identify PwP at an earlier stage of disease than is currently possible. Vigilance for this phenomenon, for example in newly diagnosed PwP or in patients with idiopathic RBD, may lead to greater appreciation of its prevalence and the breadth of its spectrum.
The identiÞcation of a new clinical syndrome in prodromal PD has important implications for target- ing early therapeutic interventions. The emergence of tremor coincident with yawning and straining at stool up to 20 years before a diagnosis of PD in our patients represents an important therapeutic window. A greater understanding of the pathophysiology of this phenomenon is required. The PVN likely plays a central role, either by increasing downstream cholinergic activity on critical brainstem nuclei such as the reticular formation, by stimulating the locus ceruleus to activate the cerebellothalamocortical network or by another autonomic mechanism. Aberrant cholinergic/noradrenergic transmission between these non-dopaminergic brainstem nuclei early in PD could lead to tremor before the emergence of other (dopaminergic) parkinsonian signs, representing an early clinical clue to incipient PD.