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Spontaneous yawning in patients with multiple sclerosis: A polygraphic study
Author’s Accepted Manuscript SPONTANEOUS YAWNING IN PATIENTS WITH MULTIPLE SCLEROSIS A Polygraphic Study Hülya Uluğut Erkoyun, Yeşim Beckmann, Nazlı Gamze Bülbül, Tülay Kurt İncesu, Nevin Gürgör Kanat, Cumhur Ertekin www.elsevier.com/locate/msard
PII: DOI: Reference:
S2211-0348(17)30145-1 http://dx.doi.org/10.1016/j.msard.2017.06.012 MSARD591
To appear in: Multiple Sclerosis and Related Disorders Received date: 6 June 2017 Revised date: 20 June 2017 Accepted date: 23 June 2017 Cite this article as: Hülya Uluğut Erkoyun, Yeşim Beckmann, Nazlı Gamze Bülbül, Tülay Kurt İncesu, Nevin Gürgör Kanat and Cumhur Ertekin, SPONTANEOUS YAWNING IN PATIENTS WITH MULTIPLE SCLEROSIS A Polygraphic Study, Multiple Sclerosis and Related Disorders, http://dx.doi.org/10.1016/j.msard.2017.06.012 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
SPONTANEOUS YAWNING IN PATIENTS WITH MULTIPLE SCLEROSIS A Polygraphic Study
Hülya Uluğut Erkoyun1*, Yeşim Beckmann2, Nazlı Gamze Bülbül3, Tülay Kurt İncesu2, Nevin Gürgör Kanat2, Cumhur Ertekin4
1
Department of Neurology, Cigli Region and Training Hospital, Izmir/ Turkey
2
Department of Neurology, Izmir Katip Celebi University Ataturk Research and Training Hospital, Izmir/Turkey
3
Department of Neurology, Mus State Hospital, Mus/Turkey
4
Departments of Neurology and Clinical Neurophysiology, Medical School Hospital Aegean University, Izmir/ Turkey
*
Corresponding author. Hülya Uluğut Erkoyun MD Address: Cigli Region and Training Hospital, Yeni Mahalle Mah., 8207. Sk. 71-2, 35620 AOSB, Cigli, Izmir/ TURKEY. Tel.: +90 505 6167580. [email protected]
ABSTRACT Background Patients with multiple sclerosis (MS) suffer from the repetitive yawning and sleep problems. Yawning is observed in MS and other central nervous system disorders and yawning and swallowing may be controlled by the network of the brain stem. Therefore it is important to investigate the MS patients with various clinical and radiological locations in order to understand the role of brainstem on the yawning mechanisms. One hour polygraphic recording would be crucial method for this purpose, because it is easy to observe spontaneous yawning (SY) and spontaneous swallowing (SS) together with their electrophysiologic counterparts. Previous studies reported that contagious yawn and swallow are temporally related and frequency of swallows was increased within 10 seconds of post yawn period in normal adult subjects. We have re-investigated this phenomenon by studying the SY and SS in polygraphic recording in normal subjects and patients with MS. Then we hypothesized that SY is expected to be increased in MS patients.
Methods 49 patients with MS and 19 control subjects were recruited in this study. We used a twelvechannel electroencephalography (EEG) device. Five channels were for electromyography (EMG) recording. We also used one channel for laryngeal sensor for vertical movements of the larynx during swallowing. Cardiac rhythm, respiration and sympathetic skin responses were synchronously recorded during swallowing. We evaluated rate of total SY, swallows inside the yawning, before and after 10 seconds of the yawning and yawning unrelated with swallowing. Results Patients with MS yawned more frequently than healthy controls (p=0,044). It was obvious that the yawning unrelated with spontaneous swallow was also significantly increased compared to normal controls (p=0,047), whereas swallowing inside the yawn or before and after 10 seconds of yawning were not significantly different in both groups. Among 49 MS patients, 16 (32.6%) had brainstem involvement. Yawning was observed in only 6 (37.5%) of them. Conclusion Yawning is significantly increased in MS patients compared to normal controls by using the polygraphic method. There is no direct relation of the brainstem and the origin of yawning in MS patients according to clinical picture and MRI findings. However safe swallows during yawning could suggest that there is still need to some brain stem mechanism and/or oropharyngeal reflexes. Difficulties must be emphasized to detect anatomic localization in MS because of relapsing pattern of disease
Keywords: Multiple sclerosis, yawning, swallowing, polygraphy
INTRODUCTION Spontaneous yawning (SY) is an involuntary and stereotyped behavior common to human being (Barbizet, 1958; Ertekin et al., 2015; O. Walusinski & Deputte, 2004). It is more likely to take place during wake-sleep and sleep-wake transitions (Provine et al., 1987). It can be easily recorded together with the spontaneous swallowing (SS) in the polygraphic study in lying position in one hour of the rest (Ertekin, 2014; Ertekin et al., 2013) or in all night sleep (Uludag, Tiftikcioglu & Ertekin, 2016) . Patients with multiple sclerosis (MS) suffer from the repetitive yawning and sleep problems (Gallup, Gallup Jr., & Feo, 2010; Sandyk, 1998; Thompson, 2014). Yawning is common in young female patients who are fully ambulatory with a relapsing-remitting course of disease (Sandyk, 1998). Yawning is observed in MS and other central nervous system disorders such as hypothalamus and cerebral cortical disorders and yawning and swallowing may be controlled by the network of the brainstem (Cattaneo et al., 2006; Postert et al., 1996; Thompson et al., 2016; Walusinski, 2009; Zilli, Giganti & Uga, 2008). There are some evidence that the brainstem is the origin of the spontaneous yawning behavior: 1-Excessive yawning behavior
is associated with the ischemic lesion in the brainstem
(Cattaneo et al., 2006; Singer et al., 2007) 2-Distorted yawning movements and complete volitional paralysis of the bulbar muscles are seen in Locked- in Syndrome (Bauer, Gerstenbrand & Hengl, 1980; Krasnianski et al., 2003). 3-Yawning movements persist in anencephalic infants (Daquin, Micallef & Blin, 2001).
4- Excessive yawning behavior is also observed in patient with motor neuron disease (Williams, 2000). Postert et al (1996) described excessive yawning as a symptom of the brainstem localization of MS. On the contrary diverse opinions were also reported (Gallup, 2014; Krestel et al., 2015; Platek, 2010; Thompson, 2014). Yawning may be related with the Central Pattern Generator (CPG) of the brainstem where the swallowing and respiration are controlled (Jean, 2001). If we look at yawning from the view of swallowing and respiration; there is a progressive slow opening of the mouth while the dilatation of pharynx, larynx, thorax and lowering of diaphragm muscle could be shown by the radiological methods (Barbizet, 1958). The increase of saliva flow was reported during yawning (Inomata et al., 2005). Furthermore SS occurs frequently in the period of SY (duration about 4-10 seconds) in normal subjects, patients with brainstem infarction and Parkinson’s disease (Ertekin et al., 2015). Therefore it is important to investigate MS patients with various clinical and radiological locations in order to understand the role of brainstem on yawning mechanisms. Yawning was evaluated by electrophysiological methods previously (Thompson, Frankham & Bishop, 2014; Thompson, Rose, & Richer, 2014; Thompson, 2013; Thompson & Bishop, 2012). However in these studies, association of SY and SS were not assessed and no muscle except masseter was recorded. One hour polygraphic recording would be crucial method for this purpose, because it is easy to observe SY and SS together with their electrophysiologic counterparts (Ertekin, 2014; Ertekin et al., 2013, 2015; Uludag et al., 2016). It is well known that yawning is classified into two types as spontaneous and contagious. Both are similar in their motor action and their triggering mechanism, although their evoluationary nature and social meaning are different (Baenninger, 1997; Provine & Hamernik, 1986). It was reported that contagious yawn and swallow are temporally related and frequency of
swallows was increased within 10 seconds of post yawn period in normal adult subjects (Abe et al., 2015). They concluded that swallows after contagious yawning were increased. We have re-investigated this phenomenon by studying the SY and SS in polygraphic recording in normal subjects and patients with MS. We investigated the SY and its association with SS within 10 seconds before and after yawning. We expected if this phenomenon is present, it may indicate a physiological linkage between brainstem swallowing and yawning, if not, there is no intimate relationship between the brainstem and yawning. Then we hypothesized that SY is expected to increase in MS patients. However the origin of yawning cannot strictly located to the brainstem uniquely, when clinical and radiological findings of the patients are compared. Difficulties must be emphasized to detect anatomic localization in MS because of relapsing pattern of disease. SS can be recorded inside of the yawning and increased rate of SS just before and after SY would demonstrate the relationship in between brainstem and yawning.
MATERIALS AND METHODS We investigated 49 patients (40 females and 9 males) with relapsing remitting multiple sclerosis (RRMS). The mean age of the patient sample was 37.9 years (range 18-58 years). Mean duration of disease was 28 months (range 8- 60 months). They have all typical clinical and radiologic (MRI) views diagnosing MS (Polman et al., 2011). Exclusion criteria were as follows: 1-They should not be younger than 18 and older than 85 years old, 2-They should not have sleep disorders like sleep apnea syndrome or sleep bruxism. 3-They should not have clinically overt dysphagia.
Nineteen healthy volunteers without any neurological disorder (13 females and 6 males) were enrolled (mean age 37.2 years, range 21–61 years) as a control group. Clinical evaluation of MS disability was performed with the Expanded Disability Status Scale (EDSS) (Kurtzke, 1983; Polman et al., 2011). All patients were assessed at any time during the remission period. All patients were thoroughly questioned with respect to dysphagia and aspiration along with neurological examination of their face, tongue, mouth, pharynx and larynx. Polygraphic recordings of Spontaneous Swallowing and Yawning The polygraphic recordings of spontaneous swallowing technique was previously described (Ertekin et al., 2013; Uludag et al., 2016). In this technique, the participants lay on comfortable examination table in a supine position with the head and neck resting at 30 degree angle from the table surface. Subjects were allowed to rest or fall asleep naturally. The room conditions were calm, quiet, and semi dark. Polygraphic investigations were performed with an electroencephalography apparatus (EEG; Nicolet One-EEG). We simultaneously recorded
EEG,
electrooculogram
(OCM),
respiration
(nasal
airflow)
(RESP),
electrocardiogram (ECG), electrodermal activity (EDA), vertical laryngeal movement (SENSOR), and electromyography (EMG) activities of the orbicularis oris (OR), masseter (MSS) and suprahyoid/submental muscle group (SM). Silver cup electrodes of 10-mm diameter were used for EEG, OCM, EDA, SENSOR and EMG recordings. They were recorded surface EMG electrodes bipolarly. Laryngeal movement is recorded by two electrodes placed 2 cm apart vertically over the thyroid cartilage. In polygraphic recording (on-line), the paper speed was 30 mm/s. During the recordings, all channels were filtered at an appropriate frequency response (high cutoff was 35–1,600 Hz), and all sensitivities were 100 microVolt /cm. However, because the data were recorded to external memory, these values could be changed in the off-line analysis. For example, the amplitude of each channel and the time base of all channels could be altered according to the
examiner’s requirements. Criteria for SS data in polygraphic recording was previously described (Ertekin et al., 2013; Uludag et al., 2016). One of the investigators cautiously inspected the swallowing and yawning periods. One yawning period was examined from beginning to the end, noted down by one of the investigators and extracted from the polygraphic recordings by another investigator. Total clinical and electromyographical duration of the yawning was measured from the EMG responses and the laryngeal movement sensor, while the related SSs were accepted and counted within the duration of yawning and 10 s before and after the end of yawning (Ertekin et al., 2015). Because all data were recorded to the external memory, the values could be changed in the offline analysis. For instance, the amplitude of each channel, the time base of all channels could be altered. This allowed us to carefully compare the SSs, SYs and coughs associated with swallowing muscles together with laryngeal and respiratory activities. In the offline mode, each swallow or the group of swallows could be analyzed by two directions of the recordings (backward and forward). Speech, snoring and sleep bruxism were carefully noticed by clinical and electrophysiological observations. Their electrographic shapes were clearly different from the swallowing and yawning (Uludag et al., 2016). The movements of other parts of the body including head, neck, eye, facial muscles, and limbs were also noted during yawning in all cases This study was approved by Izmir Katip Celebi University Clinical Trials Ethical Board (No:151) and a written informed consent was obtained from each study participant. Statistical Analysis Categorical variables were shown as percentages, continuous variables were shown as mean and standard deviation. Categorical variables were analyzed by chi-square test. When
assumptions of chi-square test could not be achieved Fisher's exact test was used. Continuous variables were analyzed using Student T test under parametric distribution assumptions. Mann Whitney-U test was used when parametric distribution assumptions were violated. Spearman correlation test was used to show the correlation between sleep duration and yawning. P value lower 0.05 was accepted as significant.
RESULTS During the polygraphic recording, subjects were free to rest or sleep. The mean sleeping time for normal controls (11.7±16.2 minutes; Mean± SD) and the patients with MS (5.4+11.2 minutes) was not statistically different from each other during the approximately 60-min recordings. Yawning was observed and recorded in 4 normal controls (22 % of all normal subjects) and total number of yawns were counted 11 times. Three of these did not slept, only one of them slept for 15 minutes. In all patients with MS, yawns were encountered in 20 patients (almost about 40 % of all cases). Number of yawning was counted 175 times. Thus the yawning was significantly increased in MS patients (p<0.044). It was interesting that in 5 patients, yawning were found more than 10 times (12-48 yawns among the 5 cases), but in 4 of them there was no clinical or electrophysiological sleep. In one of these MS patients the slow wave sleep occurred in 34 minutes and 38 yawns were almost equally distributed in awake (21 times) and in sleep (17 times). The longer sleeping time did not increased the amount of yawns significantly in between patients groups with and without yawning. There was no correlation between yawning and sleep duration (Spearman correlation coefficient: R=0.104, P=0.397). Relationship between yawning and spontaneous saliva swallowing
In Table 1 descriptive statistics of mean yawning classified according to its temporal relation with swallowing in patients and controls is shown. Figure 1 illustrates the samples recording from a patient with MS. It was obvious that the yawning unrelated with SS was also significantly increased compared to normal controls (p= 0.047), whereas occurring of swallows inside the yawn or before and after 10 seconds of the yawns were not different significantly in both groups. Yawning was recorded in 20 MS patients and 8 of them had only yawns without related swallowing. Eleven of MS patients had swallowing during yawning. Finally 2 of MS patients had swallowed within 10 seconds before and/or after the yawning. Among 49 MS patients, 16 (32.6%) had brainstem involvement. Yawning was observed in only 6 (37.5%) of them. There were remaining 14/20 patients with yawning who demonstrated a variety of localizations without brainstem involvement.
DISCUSSION: Yawning was significantly increased in MS patients. When we analyzed subgroups of yawning, there is no increase rate of the SS just before and after the SY within 10 seconds. Secondly, there was no direct relations for the brainstem and the origin of yawning in MS patients according to clinical picture and MRI findings. The mean sleeping time for normal controls and the patients with MS was not statistically different from each other during the approximately 60-min recordings. This was important because number of SS during sleep was known to be reduced in comparing to awake state (Afkari, 2007; Ertekin et al., 2013; Sato & Nakashima, 2006; Uludag et al., 2016). Yawning was significantly increased in MS patients compared to normal controls. This was well known finding and previously reported (Baker, 2002; Gallup et al., 2010; Postert et al.,
1996; Sandyk, 1998; Thompson, 2014). It is interesting that patients with MS suffer from thermoregulatory dysfunction, repetitive yawning and sleep problems (Gallup et al., 2010). Yawning is proposed that could be controlled by the network of brainstem (Cattaneo et al., 2006; Postert et al., 1996; Walusinski, 2009; Zilli et al., 2008). However, 14 of MS patients’ who were yawned MRI and clinical findings could not demonstrate the involvement of the brainstem. Only 6 of them had brainstem involvement. Our findings on MS patients without brainstem involvement were compatible to other previous studies which did not suggest yawning was under the control of the brainstem (Gallup, 2014; Krestel et al., 2015; Platek, 2010; Thompson, 2014). There are few theories that were developed for yawning and its origin, among these, the most recent and popular one is the cortical theory of Thompson (2014). Indeed the yawning, known to be associated with elevated cortisol levels; may also occur in association with fatigue; and this may explain why people with MS yawn when they are observed to be frequently fatigued (Thompson & Richer, 2015; Thompson, 2017; Thompson, 2014). Similarly plasma ACTH levels at night and just prior to awaking from sleep is also associated in humans with yawning and stretching behavior. Recurrent episodes of uncontrollable yawning and body stretching also occur in a subset of patients with MS during electromagnetic cranial stimulation. This kind of treatment was also found favorable to therapeutic response to magnetic stimulation (Sandyk, 1998). Our patients had never search any treatment for their yawning and stretching clinical responses. Although we could not observe any clinical improvement but this should also be investigated in further studies. Another physiological fact is the SS which was recorded inside of the SY, but this was not found statistically significant. However, it was reported that contagious yawn and swallow are temporally related and frequency of swallow was increased within 10 seconds of post yawn period in normal adult subjects (Abe et al., 2015). In SY, we could not found such a
relationship that the yawning after 10 seconds is able to increase rate of swallows. Thus our finding may not be compatible with finding of Abe (2014). SY and SS can often be seen together but not always associated with one another. Since the duration of yawning is about 4-10 seconds (Askenasy, 1989; Ertekin et al., 2015; Walusinski, 2009), SS could overlap with a yawning randomly and there is a mechanism for the safe swallow during yawning. Because SY associated with swallows seen to be safe for our patients and normal controls. We did not observe any clinical signs of aspiration such as coughing just after yawning, neither could we observed any graphical changes suggesting the laryngeal penetration. However this observation could not be contrary for the final relationship between yawning and brainstem where the origin of yawning could be different but the safe swallowing during yawning could be explained by some brainstem mechanism or/and related oropharyngeal reflexes. This point of view should be elucidated in further studies.
In Conclusion; 1-Yawning is significantly increased in MS patients compared to normal controls by using the polygraphic method. 2- The SY and the SS are sometimes associated and overlapped in both normal controls and MS patients without any aspiration into the airway. 3- There is no increased rate of SS just below and after the SY within 10 seconds. 4- There is no direct relation of the brainstem and the origin of yawning in MS patients according to clinical picture and MRI findings. However safe swallows during yawning could suggest that there is still need to some brainstem mechanism and/or oropharyngeal reflexes.
Acknowledgements We would like to appreciate Dr. Erdem Erkoyun for all his effort on statistical analysis and all workers in clinic electrophysiology laboratory of Izmir Katip Celebi University Atatürk Research and Training Hospital.
Founding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflict of Interest This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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Fig 1. Samples of yawning recording from a MS patient. A: Single swallow within yawn. B: Double swallow within yawn. OC: Orbicularis oculi, OR: Orbicularis oris, MSS: Masseter, SM: Submental, SENSOR: Sensor for laryngeal movement, RESP: Respiration
Highlights
Yawning is increased in MS patients. Relation between yawning and swallowing could not be shown directly in this study. Polygraphy is safe and objective method for assessing yawning and swallowing.
Fig. 1
PII: DOI: Reference:
S2211-0348(17)30145-1 http://dx.doi.org/10.1016/j.msard.2017.06.012 MSARD591
To appear in: Multiple Sclerosis and Related Disorders Received date: 6 June 2017 Revised date: 20 June 2017 Accepted date: 23 June 2017 Cite this article as: Hülya Uluğut Erkoyun, Yeşim Beckmann, Nazlı Gamze Bülbül, Tülay Kurt İncesu, Nevin Gürgör Kanat and Cumhur Ertekin, SPONTANEOUS YAWNING IN PATIENTS WITH MULTIPLE SCLEROSIS A Polygraphic Study, Multiple Sclerosis and Related Disorders, http://dx.doi.org/10.1016/j.msard.2017.06.012 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
SPONTANEOUS YAWNING IN PATIENTS WITH MULTIPLE SCLEROSIS A Polygraphic Study
Hülya Uluğut Erkoyun1*, Yeşim Beckmann2, Nazlı Gamze Bülbül3, Tülay Kurt İncesu2, Nevin Gürgör Kanat2, Cumhur Ertekin4
1
Department of Neurology, Cigli Region and Training Hospital, Izmir/ Turkey
2
Department of Neurology, Izmir Katip Celebi University Ataturk Research and Training Hospital, Izmir/Turkey
3
Department of Neurology, Mus State Hospital, Mus/Turkey
4
Departments of Neurology and Clinical Neurophysiology, Medical School Hospital Aegean University, Izmir/ Turkey
*
Corresponding author. Hülya Uluğut Erkoyun MD Address: Cigli Region and Training Hospital, Yeni Mahalle Mah., 8207. Sk. 71-2, 35620 AOSB, Cigli, Izmir/ TURKEY. Tel.: +90 505 6167580. [email protected]
ABSTRACT Background Patients with multiple sclerosis (MS) suffer from the repetitive yawning and sleep problems. Yawning is observed in MS and other central nervous system disorders and yawning and swallowing may be controlled by the network of the brain stem. Therefore it is important to investigate the MS patients with various clinical and radiological locations in order to understand the role of brainstem on the yawning mechanisms. One hour polygraphic recording would be crucial method for this purpose, because it is easy to observe spontaneous yawning (SY) and spontaneous swallowing (SS) together with their electrophysiologic counterparts. Previous studies reported that contagious yawn and swallow are temporally related and frequency of swallows was increased within 10 seconds of post yawn period in normal adult subjects. We have re-investigated this phenomenon by studying the SY and SS in polygraphic recording in normal subjects and patients with MS. Then we hypothesized that SY is expected to be increased in MS patients.
Methods 49 patients with MS and 19 control subjects were recruited in this study. We used a twelvechannel electroencephalography (EEG) device. Five channels were for electromyography (EMG) recording. We also used one channel for laryngeal sensor for vertical movements of the larynx during swallowing. Cardiac rhythm, respiration and sympathetic skin responses were synchronously recorded during swallowing. We evaluated rate of total SY, swallows inside the yawning, before and after 10 seconds of the yawning and yawning unrelated with swallowing. Results Patients with MS yawned more frequently than healthy controls (p=0,044). It was obvious that the yawning unrelated with spontaneous swallow was also significantly increased compared to normal controls (p=0,047), whereas swallowing inside the yawn or before and after 10 seconds of yawning were not significantly different in both groups. Among 49 MS patients, 16 (32.6%) had brainstem involvement. Yawning was observed in only 6 (37.5%) of them. Conclusion Yawning is significantly increased in MS patients compared to normal controls by using the polygraphic method. There is no direct relation of the brainstem and the origin of yawning in MS patients according to clinical picture and MRI findings. However safe swallows during yawning could suggest that there is still need to some brain stem mechanism and/or oropharyngeal reflexes. Difficulties must be emphasized to detect anatomic localization in MS because of relapsing pattern of disease
Keywords: Multiple sclerosis, yawning, swallowing, polygraphy
INTRODUCTION Spontaneous yawning (SY) is an involuntary and stereotyped behavior common to human being (Barbizet, 1958; Ertekin et al., 2015; O. Walusinski & Deputte, 2004). It is more likely to take place during wake-sleep and sleep-wake transitions (Provine et al., 1987). It can be easily recorded together with the spontaneous swallowing (SS) in the polygraphic study in lying position in one hour of the rest (Ertekin, 2014; Ertekin et al., 2013) or in all night sleep (Uludag, Tiftikcioglu & Ertekin, 2016) . Patients with multiple sclerosis (MS) suffer from the repetitive yawning and sleep problems (Gallup, Gallup Jr., & Feo, 2010; Sandyk, 1998; Thompson, 2014). Yawning is common in young female patients who are fully ambulatory with a relapsing-remitting course of disease (Sandyk, 1998). Yawning is observed in MS and other central nervous system disorders such as hypothalamus and cerebral cortical disorders and yawning and swallowing may be controlled by the network of the brainstem (Cattaneo et al., 2006; Postert et al., 1996; Thompson et al., 2016; Walusinski, 2009; Zilli, Giganti & Uga, 2008). There are some evidence that the brainstem is the origin of the spontaneous yawning behavior: 1-Excessive yawning behavior
is associated with the ischemic lesion in the brainstem
(Cattaneo et al., 2006; Singer et al., 2007) 2-Distorted yawning movements and complete volitional paralysis of the bulbar muscles are seen in Locked- in Syndrome (Bauer, Gerstenbrand & Hengl, 1980; Krasnianski et al., 2003). 3-Yawning movements persist in anencephalic infants (Daquin, Micallef & Blin, 2001).
4- Excessive yawning behavior is also observed in patient with motor neuron disease (Williams, 2000). Postert et al (1996) described excessive yawning as a symptom of the brainstem localization of MS. On the contrary diverse opinions were also reported (Gallup, 2014; Krestel et al., 2015; Platek, 2010; Thompson, 2014). Yawning may be related with the Central Pattern Generator (CPG) of the brainstem where the swallowing and respiration are controlled (Jean, 2001). If we look at yawning from the view of swallowing and respiration; there is a progressive slow opening of the mouth while the dilatation of pharynx, larynx, thorax and lowering of diaphragm muscle could be shown by the radiological methods (Barbizet, 1958). The increase of saliva flow was reported during yawning (Inomata et al., 2005). Furthermore SS occurs frequently in the period of SY (duration about 4-10 seconds) in normal subjects, patients with brainstem infarction and Parkinson’s disease (Ertekin et al., 2015). Therefore it is important to investigate MS patients with various clinical and radiological locations in order to understand the role of brainstem on yawning mechanisms. Yawning was evaluated by electrophysiological methods previously (Thompson, Frankham & Bishop, 2014; Thompson, Rose, & Richer, 2014; Thompson, 2013; Thompson & Bishop, 2012). However in these studies, association of SY and SS were not assessed and no muscle except masseter was recorded. One hour polygraphic recording would be crucial method for this purpose, because it is easy to observe SY and SS together with their electrophysiologic counterparts (Ertekin, 2014; Ertekin et al., 2013, 2015; Uludag et al., 2016). It is well known that yawning is classified into two types as spontaneous and contagious. Both are similar in their motor action and their triggering mechanism, although their evoluationary nature and social meaning are different (Baenninger, 1997; Provine & Hamernik, 1986). It was reported that contagious yawn and swallow are temporally related and frequency of
swallows was increased within 10 seconds of post yawn period in normal adult subjects (Abe et al., 2015). They concluded that swallows after contagious yawning were increased. We have re-investigated this phenomenon by studying the SY and SS in polygraphic recording in normal subjects and patients with MS. We investigated the SY and its association with SS within 10 seconds before and after yawning. We expected if this phenomenon is present, it may indicate a physiological linkage between brainstem swallowing and yawning, if not, there is no intimate relationship between the brainstem and yawning. Then we hypothesized that SY is expected to increase in MS patients. However the origin of yawning cannot strictly located to the brainstem uniquely, when clinical and radiological findings of the patients are compared. Difficulties must be emphasized to detect anatomic localization in MS because of relapsing pattern of disease. SS can be recorded inside of the yawning and increased rate of SS just before and after SY would demonstrate the relationship in between brainstem and yawning.
MATERIALS AND METHODS We investigated 49 patients (40 females and 9 males) with relapsing remitting multiple sclerosis (RRMS). The mean age of the patient sample was 37.9 years (range 18-58 years). Mean duration of disease was 28 months (range 8- 60 months). They have all typical clinical and radiologic (MRI) views diagnosing MS (Polman et al., 2011). Exclusion criteria were as follows: 1-They should not be younger than 18 and older than 85 years old, 2-They should not have sleep disorders like sleep apnea syndrome or sleep bruxism. 3-They should not have clinically overt dysphagia.
Nineteen healthy volunteers without any neurological disorder (13 females and 6 males) were enrolled (mean age 37.2 years, range 21–61 years) as a control group. Clinical evaluation of MS disability was performed with the Expanded Disability Status Scale (EDSS) (Kurtzke, 1983; Polman et al., 2011). All patients were assessed at any time during the remission period. All patients were thoroughly questioned with respect to dysphagia and aspiration along with neurological examination of their face, tongue, mouth, pharynx and larynx. Polygraphic recordings of Spontaneous Swallowing and Yawning The polygraphic recordings of spontaneous swallowing technique was previously described (Ertekin et al., 2013; Uludag et al., 2016). In this technique, the participants lay on comfortable examination table in a supine position with the head and neck resting at 30 degree angle from the table surface. Subjects were allowed to rest or fall asleep naturally. The room conditions were calm, quiet, and semi dark. Polygraphic investigations were performed with an electroencephalography apparatus (EEG; Nicolet One-EEG). We simultaneously recorded
EEG,
electrooculogram
(OCM),
respiration
(nasal
airflow)
(RESP),
electrocardiogram (ECG), electrodermal activity (EDA), vertical laryngeal movement (SENSOR), and electromyography (EMG) activities of the orbicularis oris (OR), masseter (MSS) and suprahyoid/submental muscle group (SM). Silver cup electrodes of 10-mm diameter were used for EEG, OCM, EDA, SENSOR and EMG recordings. They were recorded surface EMG electrodes bipolarly. Laryngeal movement is recorded by two electrodes placed 2 cm apart vertically over the thyroid cartilage. In polygraphic recording (on-line), the paper speed was 30 mm/s. During the recordings, all channels were filtered at an appropriate frequency response (high cutoff was 35–1,600 Hz), and all sensitivities were 100 microVolt /cm. However, because the data were recorded to external memory, these values could be changed in the off-line analysis. For example, the amplitude of each channel and the time base of all channels could be altered according to the
examiner’s requirements. Criteria for SS data in polygraphic recording was previously described (Ertekin et al., 2013; Uludag et al., 2016). One of the investigators cautiously inspected the swallowing and yawning periods. One yawning period was examined from beginning to the end, noted down by one of the investigators and extracted from the polygraphic recordings by another investigator. Total clinical and electromyographical duration of the yawning was measured from the EMG responses and the laryngeal movement sensor, while the related SSs were accepted and counted within the duration of yawning and 10 s before and after the end of yawning (Ertekin et al., 2015). Because all data were recorded to the external memory, the values could be changed in the offline analysis. For instance, the amplitude of each channel, the time base of all channels could be altered. This allowed us to carefully compare the SSs, SYs and coughs associated with swallowing muscles together with laryngeal and respiratory activities. In the offline mode, each swallow or the group of swallows could be analyzed by two directions of the recordings (backward and forward). Speech, snoring and sleep bruxism were carefully noticed by clinical and electrophysiological observations. Their electrographic shapes were clearly different from the swallowing and yawning (Uludag et al., 2016). The movements of other parts of the body including head, neck, eye, facial muscles, and limbs were also noted during yawning in all cases This study was approved by Izmir Katip Celebi University Clinical Trials Ethical Board (No:151) and a written informed consent was obtained from each study participant. Statistical Analysis Categorical variables were shown as percentages, continuous variables were shown as mean and standard deviation. Categorical variables were analyzed by chi-square test. When
assumptions of chi-square test could not be achieved Fisher's exact test was used. Continuous variables were analyzed using Student T test under parametric distribution assumptions. Mann Whitney-U test was used when parametric distribution assumptions were violated. Spearman correlation test was used to show the correlation between sleep duration and yawning. P value lower 0.05 was accepted as significant.
RESULTS During the polygraphic recording, subjects were free to rest or sleep. The mean sleeping time for normal controls (11.7±16.2 minutes; Mean± SD) and the patients with MS (5.4+11.2 minutes) was not statistically different from each other during the approximately 60-min recordings. Yawning was observed and recorded in 4 normal controls (22 % of all normal subjects) and total number of yawns were counted 11 times. Three of these did not slept, only one of them slept for 15 minutes. In all patients with MS, yawns were encountered in 20 patients (almost about 40 % of all cases). Number of yawning was counted 175 times. Thus the yawning was significantly increased in MS patients (p<0.044). It was interesting that in 5 patients, yawning were found more than 10 times (12-48 yawns among the 5 cases), but in 4 of them there was no clinical or electrophysiological sleep. In one of these MS patients the slow wave sleep occurred in 34 minutes and 38 yawns were almost equally distributed in awake (21 times) and in sleep (17 times). The longer sleeping time did not increased the amount of yawns significantly in between patients groups with and without yawning. There was no correlation between yawning and sleep duration (Spearman correlation coefficient: R=0.104, P=0.397). Relationship between yawning and spontaneous saliva swallowing
In Table 1 descriptive statistics of mean yawning classified according to its temporal relation with swallowing in patients and controls is shown. Figure 1 illustrates the samples recording from a patient with MS. It was obvious that the yawning unrelated with SS was also significantly increased compared to normal controls (p= 0.047), whereas occurring of swallows inside the yawn or before and after 10 seconds of the yawns were not different significantly in both groups. Yawning was recorded in 20 MS patients and 8 of them had only yawns without related swallowing. Eleven of MS patients had swallowing during yawning. Finally 2 of MS patients had swallowed within 10 seconds before and/or after the yawning. Among 49 MS patients, 16 (32.6%) had brainstem involvement. Yawning was observed in only 6 (37.5%) of them. There were remaining 14/20 patients with yawning who demonstrated a variety of localizations without brainstem involvement.
DISCUSSION: Yawning was significantly increased in MS patients. When we analyzed subgroups of yawning, there is no increase rate of the SS just before and after the SY within 10 seconds. Secondly, there was no direct relations for the brainstem and the origin of yawning in MS patients according to clinical picture and MRI findings. The mean sleeping time for normal controls and the patients with MS was not statistically different from each other during the approximately 60-min recordings. This was important because number of SS during sleep was known to be reduced in comparing to awake state (Afkari, 2007; Ertekin et al., 2013; Sato & Nakashima, 2006; Uludag et al., 2016). Yawning was significantly increased in MS patients compared to normal controls. This was well known finding and previously reported (Baker, 2002; Gallup et al., 2010; Postert et al.,
1996; Sandyk, 1998; Thompson, 2014). It is interesting that patients with MS suffer from thermoregulatory dysfunction, repetitive yawning and sleep problems (Gallup et al., 2010). Yawning is proposed that could be controlled by the network of brainstem (Cattaneo et al., 2006; Postert et al., 1996; Walusinski, 2009; Zilli et al., 2008). However, 14 of MS patients’ who were yawned MRI and clinical findings could not demonstrate the involvement of the brainstem. Only 6 of them had brainstem involvement. Our findings on MS patients without brainstem involvement were compatible to other previous studies which did not suggest yawning was under the control of the brainstem (Gallup, 2014; Krestel et al., 2015; Platek, 2010; Thompson, 2014). There are few theories that were developed for yawning and its origin, among these, the most recent and popular one is the cortical theory of Thompson (2014). Indeed the yawning, known to be associated with elevated cortisol levels; may also occur in association with fatigue; and this may explain why people with MS yawn when they are observed to be frequently fatigued (Thompson & Richer, 2015; Thompson, 2017; Thompson, 2014). Similarly plasma ACTH levels at night and just prior to awaking from sleep is also associated in humans with yawning and stretching behavior. Recurrent episodes of uncontrollable yawning and body stretching also occur in a subset of patients with MS during electromagnetic cranial stimulation. This kind of treatment was also found favorable to therapeutic response to magnetic stimulation (Sandyk, 1998). Our patients had never search any treatment for their yawning and stretching clinical responses. Although we could not observe any clinical improvement but this should also be investigated in further studies. Another physiological fact is the SS which was recorded inside of the SY, but this was not found statistically significant. However, it was reported that contagious yawn and swallow are temporally related and frequency of swallow was increased within 10 seconds of post yawn period in normal adult subjects (Abe et al., 2015). In SY, we could not found such a
relationship that the yawning after 10 seconds is able to increase rate of swallows. Thus our finding may not be compatible with finding of Abe (2014). SY and SS can often be seen together but not always associated with one another. Since the duration of yawning is about 4-10 seconds (Askenasy, 1989; Ertekin et al., 2015; Walusinski, 2009), SS could overlap with a yawning randomly and there is a mechanism for the safe swallow during yawning. Because SY associated with swallows seen to be safe for our patients and normal controls. We did not observe any clinical signs of aspiration such as coughing just after yawning, neither could we observed any graphical changes suggesting the laryngeal penetration. However this observation could not be contrary for the final relationship between yawning and brainstem where the origin of yawning could be different but the safe swallowing during yawning could be explained by some brainstem mechanism or/and related oropharyngeal reflexes. This point of view should be elucidated in further studies.
In Conclusion; 1-Yawning is significantly increased in MS patients compared to normal controls by using the polygraphic method. 2- The SY and the SS are sometimes associated and overlapped in both normal controls and MS patients without any aspiration into the airway. 3- There is no increased rate of SS just below and after the SY within 10 seconds. 4- There is no direct relation of the brainstem and the origin of yawning in MS patients according to clinical picture and MRI findings. However safe swallows during yawning could suggest that there is still need to some brainstem mechanism and/or oropharyngeal reflexes.
Acknowledgements We would like to appreciate Dr. Erdem Erkoyun for all his effort on statistical analysis and all workers in clinic electrophysiology laboratory of Izmir Katip Celebi University Atatürk Research and Training Hospital.
Founding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflict of Interest This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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Fig 1. Samples of yawning recording from a MS patient. A: Single swallow within yawn. B: Double swallow within yawn. OC: Orbicularis oculi, OR: Orbicularis oris, MSS: Masseter, SM: Submental, SENSOR: Sensor for laryngeal movement, RESP: Respiration
Highlights
Yawning is increased in MS patients. Relation between yawning and swallowing could not be shown directly in this study. Polygraphy is safe and objective method for assessing yawning and swallowing.
Fig. 1