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Yawning induced by focal electrical stimulation in the human brain
Epilepsy & Behavior 66 (2017) 1–3
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Brief Communication
Yawning induced by focal electrical stimulation in the human brain Sweta Joshi a, Arezou Bayat a, Linda Gagnon a, Donald C. Shields b, Mohamad Z. Koubeissi a,⁎ a b
Department of Neurology, George Washington University, 2150 Pennsylvania Avenue, 9th Floor, Washington, D.C. 20037, USA Department of Neurological Surgery, George Washington University, 2150 Pennsylvania Avenue, Suite 7-420, Washington, D.C. 20037, USA
a r t i c l e
i n f o
Article history: Received 18 August 2016 Accepted 7 September 2016 Available online xxxx Keywords: Yawning Putamen Electrical stimulation Epilepsy Insula
a b s t r a c t The primary function of yawning is not fully understood. We report a case in which electrical stimulation of the putamen in the human brain consistently elicited yawning. A 46-year-old woman with intractable epilepsy had invasive depth electrode monitoring and cortical stimulation mapping as part of her presurgical epilepsy evaluation. The first two contacts of a depth electrode that was intended to sample the left insula were in contact with the putamen. Stimulation of these contacts at 6 mA and 8 mA consistently elicited yawning on two separate days. Engagement in arithmetic and motor tasks during stimulation did not result in yawning. When considering the role of the putamen in motor control and its extensive connectivity to cortical and brainstem regions, our findings suggest that it plays a key role in the execution of motor movements necessitated by yawning. Furthermore, given the role of the anterior insula in attention and focused tasks, activation of this area while engaged in arithmetic and motor tasks could inhibit the putaminal processing necessary for yawning. Many have hypothesized the function of yawning; however, it remains debatable whether yawning serves a primarily physiological or communicative function or perhaps both. © 2016 Elsevier Inc. All rights reserved.
1. Introduction The function of yawning is not clear. Physiological and communicative functions have been hypothesized [1]. Some authors have hypothesized it to be physiologically important in oxygenation [2], arousal and vigilance [3,4], thermoregulation [5], and stress [6]. Others argue that because of its contagious nature, yawning serves a communicative function, specifically that it is an expression of empathy [7]. A number of anatomical structures including the brainstem and hypothalamus have been implicated in yawning [3,8,9], whereas the role of the striatum remains controversial [10,11,12]. Most evidence for the neural substrates of yawning come from pharmacological investigations of the roles of such neurotransmitters as acetylcholine, serotonin, dopamine, oxytocin, and other excitatory neuropeptides [9]. To our knowledge, there have been no reports from humans in which electrical stimulation of a brain region induced yawning, and reports from animals are minimal [13,14]. Here, we report a unique case of electrical stimulation of the putamen consistently inducing yawning in a patient with depth electrodes implanted for evaluation of intractable epilepsy. 2. Methods A 46-year-old woman with pharmacoresistant seizures underwent implantation of depth electrodes for identification of the seizure focus. She had automotor seizures with alteration of awareness. Because her ⁎ Corresponding author at: 22nd & I Street NW, 9th Floor, Washington, D.C. 20037, USA. E-mail address: [email protected] (M.Z. Koubeissi).
http://dx.doi.org/10.1016/j.yebeh.2016.09.006 1525-5050/© 2016 Elsevier Inc. All rights reserved.
scalp-EEG monitoring had suggested bilateral temporal seizure foci, 8 multicontact intracerebral depth electrodes (Ad-Tech, Park Ridge, IL, USA, 10 contact electrodes; 0.5-cm interelectrode distance) were stereotactically implanted in bilateral hippocampi as well as extratemporal structures that are connected with the medial temporal lobes, including the insulae. Two contacts of one depth electrode that aimed at sampling the left insular cortex were in the putamen. Her invasive monitoring concluded bilateral independent hippocampal onsets. As part of the comprehensive intracranial EEG evaluation, electrocortical stimulation mapping was done on the third and the fourth day postimplantation. Electrode placement was determined by coregistering preoperative MRI with postoperative CT (Fig. 1). Stimulation current ranged from 2 to 10 mA, using 0.2-ms pulse width at a frequency of 50 Hz and 3- to 10-second train durations.
3. Results Stimulation of the two putamen contacts at intensities of 2 mA or 4 mA did not result in any discernible behavioral phenomena. At 6 or 8 mA, however, stimulation consistently elicited yawning. The patient was assigned a reading task during mapping, and, upon stimulation at 6 mA, her reading pace slowed, and she yawned 5.5 s following the onset of the train. She was stimulated on two other occasions at 6 mA and yawned within 4.5 and 5.5 s after stimulation onset. She was stimulated 6 times at 8 mA. During the first three stimulations, she exhibited the same behavioral changes noted at 6 mA, namely a decrease in her reading pace accompanied with yawning 4.5–6 s following
2
S. Joshi et al. / Epilepsy & Behavior 66 (2017) 1–3
Fig. 1. Electrode location. Preoperative MRI superimposed with postoperative CT shows placement of the electrode contacts whose stimulation elicited yawning. Coronal, sagittal, and axial cuts reveal the first (top) and second (bottom) contacts within the left putamen.
stimulation onset. Following the third stimulation, when asked whether she was sleepy, she affirmed. We then tested the hypothesis whether engagement in complex verbal and motor tasks could modify the elicited yawning response. Thus, attempts at 8 mA were done while engaging the patient in cognitive and motor tasks before stimulation onset. The tasks included following repetitive verbal commands (e.g., point to the window and touch your nose) and solving simple arithmetic problems. It appeared that these tasks abolished yawning. However, on two occasions, she would take a deep inspiration, suggestive of yawning onset, though without evolution into a complete yawn. She remained alert and followed all commands throughout the rest of the mapping session and did not yawn spontaneously. Stimulation of other electrodes that day did not elicit yawning. When the same putamen contacts were stimulated at 6 mA the following day, the patient again consistently yawned a few seconds after the onset of the stimulation train. No other motor or memory deficits were apparent during mapping, and the patient consistently returned to baseline upon cessation of stimulation. Again, stimulation of other electrodes including ones in the insula and the posterior cingulate gyrus did not elicit yawning. The EEG did not show any seizure activity or afterdischarges. 4. Discussion Although many have explored the neuroanatomical substrates of yawning, the direct involvement of the striatum has remained unconfirmed [10,11,12]. Here, we provide direct evidence, through electrical stimulation, of the involvement of the putamen in yawning. We found that putamen stimulation on two separate days consistently elicited yawning — a response that we found modifiable by paying full attention to cognitive and motor tasks. We, thus, propose that the putamen play a key role in the execution of motor movements of yawning. Among the basal ganglia, the putamen has been most associated with motor control, and it is possible that putaminal stimulation activates the motor network of yawning [15]. The 4.5- to 6-second latency between stimulation onset and yawning suggests further processing of an action that is encoded in the putamen across other motor execution networks. Whether putaminal stimulation is related to sleep itself is unlikely, although it cannot be totally ruled out based on this case.
While the patient reported that she was sleepy during stimulation, she did not fall asleep and maintained full attention to assigned tasks. The above considerations may be supported by the known extensive anatomical connectivity of the putamen to cortical and brainstem areas and its role in motor control. Animal studies have suggested roles for the paraventricular nucleus (PVN) of the hypothalamus, brainstem, and hippocampus, but not the putamen, in yawning [3,8,9] There are proposed roles for a number of neurotransmitters in yawning, including acetylcholine, serotonin, oxytocin, and dopamine (DA), among others. The primary site of action of these neurotransmitters has been hypothesized to be the PVN [9]. While injections of DA receptor agonists, such as apomorphine, in the PVN can induce yawning [9], bilateral striatal lesions can abolish this response [11]. Additionally, high-dose injections of DA receptor agonists into the striatum or septum induced yawning in rats [12]. A subtype of rats, “high-yawning” rats, has the highest labeling of D1-like DA receptors in the caudate and putamen. This finding could possibly explain the increased yawning (and grooming) behaviors of these rats in comparison with the “low-yawning” rats [16]. In rhesus monkeys, it was shown that quinpirole, a DA agonist, induced yawning. Furthermore, through PET imaging, the researchers found that a D3R (D2-like receptor) preferring radioligand shows highest binding potential in the putamen, ventral pallidum, globus pallidus, and hippocampus [17]. Moreover, functional imaging studies have implicated the anterior dorsal insula in task-level control and attention [18]. It is possible that attention, such as that elicited by solving arithmetic questions and commands to carry out motor tasks, also activates the anterior dorsal insula which, in turn, inhibits the putaminal processing of yawning. This relationship between the insula and the putamen is supported by reports that patients with insular strokes present with pathological yawning [19]. But why do we yawn? Many speculations have been put forth, though no clear scientific evidence favors one over the other. It was initially believed that yawning functioned to increase oxygenation levels in the blood [2]. However, this was discredited since it was found that breathing high levels of either CO2 or O2 did not affect yawning frequency [20]. Some believe that yawning serves as an arousal mechanism, particularly during times of little external stimulation where lack of vigilance can prove harmful [2]. This idea has been extended to propose that yawning represents an interoceptive process, one that
S. Joshi et al. / Epilepsy & Behavior 66 (2017) 1–3
increases self-awareness and arousal [8]. The thermoregulatory theory of yawning posits that yawning serves to reduce brain and body temperature [5]. Indeed, there have been reported cases of pathological yawning in disorders of thermoregulation [21,22]. Furthermore, disappearance of yawning was reported in disorders with decreased DA neurons in the PVN, such as Parkinson's disease [23]. Lastly, yawning has been connected with increased blood cortisol levels and, therefore, is associated with stress and fatigue [6]. On the other hand, some argue that yawning serves a primarily communicative function. Contagious yawning was reported to be more common among kin and friends than strangers and was, therefore, interpreted as a representation of empathy [7]. This has been corroborated by studies revealing engagement in contagious yawning of the mirror neuron system (MNS), a system implicated in higher-level cognitive processing, such as empathy [24]. Functional MRI findings revealed activation of the right inferior frontal gyrus, a part of the MNS, when participants exhibited contagious yawning, thereby supporting the idea of empathetic yawning [25]. Furthermore, EEG findings have revealed that mu suppression on the EEG, an index utilized to represent MNS activation, was greater for participants viewing or hearing yawns than for controls [26]. These findings support the notion that contagious yawning is an expression of empathy and that the MNS may play a key role in this expression. In reference to the proposed theories, we hypothesize that the putamen's widespread connectivity with cortical and subcortical regions allows it to receive input regarding alterations in physiologic or social needs and initiate the motor execution of yawning, an action that can similarly be inhibited by other brain regions, possibly including the insula. 5. Conclusion Whether yawning has a social communicative function or a physiological significance, or both, is a question that remains to be answered. Here, we illustrate the role of the putamen through direct electrical stimulation and corroborate previous findings suggesting a role for the striatum in yawning. We hope that findings from this report contribute to future research investigating yawning. Conflict of interest The authors have no conflict of interest related to the current report. Acknowledgments This work was supported by a startup fund and departmental support from George Washington University to MZK.
3
References [1] Gallup AC. Why do we yawn? Primitive versus derived features. Neurosci Biobehav Rev 2011;35(3):765–9. [2] Baenninger R. On yawning and its functions. Psychon Bull Rev 1997;4(2):198–207. [3] Askenasy JJ. Is yawning an arousal defense reflex? J Psychol 1989;123(6):609–21. [4] Walusinski O. Yawning: unsuspected avenue for a better understanding of arousal and interoception. Med Hypotheses 2006;67(1):6–14. [5] Gallup AC, Gallup GG. Yawning and thermoregulation. Physiol Behav 2008;95(1–2): 10–6. [6] Thompson SBN. Born to yawn? Cortisol linked to yawning: a new hypothesis. Med Hypotheses 2011;77(5):861–2. [7] Norscia I, Palagi E. Yawn contagion and empathy in Homo sapiens. PLoS One 2011; 6(12), e28472. [8] Walusinski O. Yawning: unsuspected avenue for a better understanding of arousal and interoception. Med Hypotheses 2006;67(1):6–14. [9] Argiolas A, Melis MR. The neuropharmacology of yawning. Eur J Pharmacol 1998; 343(1):1–16. [10] Melis MR, Argiolas A, Gessa GL. Apomorphine-induced penile erection and yawning: site of action in brain. Brain Res 1987;415(1):98–104. [11] Dourish CT, Hutson PH. Bilateral lesions of the striatum induced with 6hydroxydopamine abolish apomorphine-induced yawning in rats. Neuropharmacology 1985;24(11):1051–5. [12] Yamada K, Tanaka M, Shibata K, Furukawa T. Involvement of septal and striatal dopamine D-2 receptors in yawning behavior in rats. Psychopharmacology (Berl) 1986;90(1):9–13. [13] Sato-Suzuki I, Kita I, Oguri M, Arita H. Stereotyped yawning responses induced by electrical and chemical stimulation of paraventricular nucleus of the rat. J Neurophysiol 1998;80(5):2765–75. [14] Van Erp AM, Kruk MR, Willekens-Bramer DC, Bressers WM, Roeling TA, Veening JG, et al. Grooming induced by intrahypothalamic injection of ACTH in the rat: comparison with grooming induced by intrahypothalamic electrical stimulation and i.c.v. injection of ACTH. Brain Res 1991;538(2):203–10. [15] Haber SN. Corticostriatal circuitry. Dialogues Clin Neurosci 2016;18(1):7–21. [16] Díaz-Romero M, Arias-Montaño JA, Eguibar JR, Flores G. Enhanced binding of dopamine D1 receptors in caudate-putamen subregions in high-yawning Sprague– Dawley rats. Synap N Y N 2005;56(2):69–73. [17] Martelle SE, Nader SH, Czoty PW, John WS, Duke AN, Garg PK, et al. Further characterization of quinpirole-elicited yawning as a model of dopamine D3 receptor activation in male and female monkeys. J Pharmacol Exp Ther 2014;350(2):205–11. [18] Nelson SM, Dosenbach NUF, Cohen AL, Wheeler ME, Schlaggar BL, Petersen SE. Role of the anterior insula in task-level control and focal attention. Brain Struct Funct 2010;214(5–6):669–80. [19] Krestel H, Weisstanner C, Hess CW, Bassetti CL, Nirkko A, Wiest R. Insular and caudate lesions release abnormal yawning in stroke patients. Brain Struct Funct 2015;220(2):803–12. [20] Provine RR, Tate BC, Geldmacher LL. Yawning: no effect of 3–5% CO2, 100% O2, and exercise. Behav Neural Biol 1987;48(3):382–93. [21] Gallup GG, Gallup AC. Excessive yawning and thermoregulation: two case histories of chronic, debilitating bouts of yawning. Sleep Breath Schlaf Atm 2010;14(2): 157–9. [22] Gallup AC. Excessive yawning and thermoregulatory dysfunction. Sleep Breath Schlaf Atm 2011;15(3):271–3. [23] Walusinski O. Yawning in diseases. Eur Neurol 2009;62(3):180–7. [24] Rizzolatti G. The mirror neuron system and its function in humans. Anat Embryol (Berl) 2005;210(5–6):419–21. [25] Haker H, Kawohl W, Herwig U, Rössler W. Mirror neuron activity during contagious yawning — an fMRI study. Brain Imaging Behav 2013;7(1):28–34. [26] Cooper NR, Puzzo I, Pawley AD, Bowes-Mulligan RA, Kirkpatrick EV, Antoniou PA, et al. Bridging a yawning chasm: EEG investigations into the debate concerning the role of the human mirror neuron system in contagious yawning. Cogn Affect Behav Neurosci 2012;12(2):393–405.
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Brief Communication
Yawning induced by focal electrical stimulation in the human brain Sweta Joshi a, Arezou Bayat a, Linda Gagnon a, Donald C. Shields b, Mohamad Z. Koubeissi a,⁎ a b
Department of Neurology, George Washington University, 2150 Pennsylvania Avenue, 9th Floor, Washington, D.C. 20037, USA Department of Neurological Surgery, George Washington University, 2150 Pennsylvania Avenue, Suite 7-420, Washington, D.C. 20037, USA
a r t i c l e
i n f o
Article history: Received 18 August 2016 Accepted 7 September 2016 Available online xxxx Keywords: Yawning Putamen Electrical stimulation Epilepsy Insula
a b s t r a c t The primary function of yawning is not fully understood. We report a case in which electrical stimulation of the putamen in the human brain consistently elicited yawning. A 46-year-old woman with intractable epilepsy had invasive depth electrode monitoring and cortical stimulation mapping as part of her presurgical epilepsy evaluation. The first two contacts of a depth electrode that was intended to sample the left insula were in contact with the putamen. Stimulation of these contacts at 6 mA and 8 mA consistently elicited yawning on two separate days. Engagement in arithmetic and motor tasks during stimulation did not result in yawning. When considering the role of the putamen in motor control and its extensive connectivity to cortical and brainstem regions, our findings suggest that it plays a key role in the execution of motor movements necessitated by yawning. Furthermore, given the role of the anterior insula in attention and focused tasks, activation of this area while engaged in arithmetic and motor tasks could inhibit the putaminal processing necessary for yawning. Many have hypothesized the function of yawning; however, it remains debatable whether yawning serves a primarily physiological or communicative function or perhaps both. © 2016 Elsevier Inc. All rights reserved.
1. Introduction The function of yawning is not clear. Physiological and communicative functions have been hypothesized [1]. Some authors have hypothesized it to be physiologically important in oxygenation [2], arousal and vigilance [3,4], thermoregulation [5], and stress [6]. Others argue that because of its contagious nature, yawning serves a communicative function, specifically that it is an expression of empathy [7]. A number of anatomical structures including the brainstem and hypothalamus have been implicated in yawning [3,8,9], whereas the role of the striatum remains controversial [10,11,12]. Most evidence for the neural substrates of yawning come from pharmacological investigations of the roles of such neurotransmitters as acetylcholine, serotonin, dopamine, oxytocin, and other excitatory neuropeptides [9]. To our knowledge, there have been no reports from humans in which electrical stimulation of a brain region induced yawning, and reports from animals are minimal [13,14]. Here, we report a unique case of electrical stimulation of the putamen consistently inducing yawning in a patient with depth electrodes implanted for evaluation of intractable epilepsy. 2. Methods A 46-year-old woman with pharmacoresistant seizures underwent implantation of depth electrodes for identification of the seizure focus. She had automotor seizures with alteration of awareness. Because her ⁎ Corresponding author at: 22nd & I Street NW, 9th Floor, Washington, D.C. 20037, USA. E-mail address: [email protected] (M.Z. Koubeissi).
http://dx.doi.org/10.1016/j.yebeh.2016.09.006 1525-5050/© 2016 Elsevier Inc. All rights reserved.
scalp-EEG monitoring had suggested bilateral temporal seizure foci, 8 multicontact intracerebral depth electrodes (Ad-Tech, Park Ridge, IL, USA, 10 contact electrodes; 0.5-cm interelectrode distance) were stereotactically implanted in bilateral hippocampi as well as extratemporal structures that are connected with the medial temporal lobes, including the insulae. Two contacts of one depth electrode that aimed at sampling the left insular cortex were in the putamen. Her invasive monitoring concluded bilateral independent hippocampal onsets. As part of the comprehensive intracranial EEG evaluation, electrocortical stimulation mapping was done on the third and the fourth day postimplantation. Electrode placement was determined by coregistering preoperative MRI with postoperative CT (Fig. 1). Stimulation current ranged from 2 to 10 mA, using 0.2-ms pulse width at a frequency of 50 Hz and 3- to 10-second train durations.
3. Results Stimulation of the two putamen contacts at intensities of 2 mA or 4 mA did not result in any discernible behavioral phenomena. At 6 or 8 mA, however, stimulation consistently elicited yawning. The patient was assigned a reading task during mapping, and, upon stimulation at 6 mA, her reading pace slowed, and she yawned 5.5 s following the onset of the train. She was stimulated on two other occasions at 6 mA and yawned within 4.5 and 5.5 s after stimulation onset. She was stimulated 6 times at 8 mA. During the first three stimulations, she exhibited the same behavioral changes noted at 6 mA, namely a decrease in her reading pace accompanied with yawning 4.5–6 s following
2
S. Joshi et al. / Epilepsy & Behavior 66 (2017) 1–3
Fig. 1. Electrode location. Preoperative MRI superimposed with postoperative CT shows placement of the electrode contacts whose stimulation elicited yawning. Coronal, sagittal, and axial cuts reveal the first (top) and second (bottom) contacts within the left putamen.
stimulation onset. Following the third stimulation, when asked whether she was sleepy, she affirmed. We then tested the hypothesis whether engagement in complex verbal and motor tasks could modify the elicited yawning response. Thus, attempts at 8 mA were done while engaging the patient in cognitive and motor tasks before stimulation onset. The tasks included following repetitive verbal commands (e.g., point to the window and touch your nose) and solving simple arithmetic problems. It appeared that these tasks abolished yawning. However, on two occasions, she would take a deep inspiration, suggestive of yawning onset, though without evolution into a complete yawn. She remained alert and followed all commands throughout the rest of the mapping session and did not yawn spontaneously. Stimulation of other electrodes that day did not elicit yawning. When the same putamen contacts were stimulated at 6 mA the following day, the patient again consistently yawned a few seconds after the onset of the stimulation train. No other motor or memory deficits were apparent during mapping, and the patient consistently returned to baseline upon cessation of stimulation. Again, stimulation of other electrodes including ones in the insula and the posterior cingulate gyrus did not elicit yawning. The EEG did not show any seizure activity or afterdischarges. 4. Discussion Although many have explored the neuroanatomical substrates of yawning, the direct involvement of the striatum has remained unconfirmed [10,11,12]. Here, we provide direct evidence, through electrical stimulation, of the involvement of the putamen in yawning. We found that putamen stimulation on two separate days consistently elicited yawning — a response that we found modifiable by paying full attention to cognitive and motor tasks. We, thus, propose that the putamen play a key role in the execution of motor movements of yawning. Among the basal ganglia, the putamen has been most associated with motor control, and it is possible that putaminal stimulation activates the motor network of yawning [15]. The 4.5- to 6-second latency between stimulation onset and yawning suggests further processing of an action that is encoded in the putamen across other motor execution networks. Whether putaminal stimulation is related to sleep itself is unlikely, although it cannot be totally ruled out based on this case.
While the patient reported that she was sleepy during stimulation, she did not fall asleep and maintained full attention to assigned tasks. The above considerations may be supported by the known extensive anatomical connectivity of the putamen to cortical and brainstem areas and its role in motor control. Animal studies have suggested roles for the paraventricular nucleus (PVN) of the hypothalamus, brainstem, and hippocampus, but not the putamen, in yawning [3,8,9] There are proposed roles for a number of neurotransmitters in yawning, including acetylcholine, serotonin, oxytocin, and dopamine (DA), among others. The primary site of action of these neurotransmitters has been hypothesized to be the PVN [9]. While injections of DA receptor agonists, such as apomorphine, in the PVN can induce yawning [9], bilateral striatal lesions can abolish this response [11]. Additionally, high-dose injections of DA receptor agonists into the striatum or septum induced yawning in rats [12]. A subtype of rats, “high-yawning” rats, has the highest labeling of D1-like DA receptors in the caudate and putamen. This finding could possibly explain the increased yawning (and grooming) behaviors of these rats in comparison with the “low-yawning” rats [16]. In rhesus monkeys, it was shown that quinpirole, a DA agonist, induced yawning. Furthermore, through PET imaging, the researchers found that a D3R (D2-like receptor) preferring radioligand shows highest binding potential in the putamen, ventral pallidum, globus pallidus, and hippocampus [17]. Moreover, functional imaging studies have implicated the anterior dorsal insula in task-level control and attention [18]. It is possible that attention, such as that elicited by solving arithmetic questions and commands to carry out motor tasks, also activates the anterior dorsal insula which, in turn, inhibits the putaminal processing of yawning. This relationship between the insula and the putamen is supported by reports that patients with insular strokes present with pathological yawning [19]. But why do we yawn? Many speculations have been put forth, though no clear scientific evidence favors one over the other. It was initially believed that yawning functioned to increase oxygenation levels in the blood [2]. However, this was discredited since it was found that breathing high levels of either CO2 or O2 did not affect yawning frequency [20]. Some believe that yawning serves as an arousal mechanism, particularly during times of little external stimulation where lack of vigilance can prove harmful [2]. This idea has been extended to propose that yawning represents an interoceptive process, one that
S. Joshi et al. / Epilepsy & Behavior 66 (2017) 1–3
increases self-awareness and arousal [8]. The thermoregulatory theory of yawning posits that yawning serves to reduce brain and body temperature [5]. Indeed, there have been reported cases of pathological yawning in disorders of thermoregulation [21,22]. Furthermore, disappearance of yawning was reported in disorders with decreased DA neurons in the PVN, such as Parkinson's disease [23]. Lastly, yawning has been connected with increased blood cortisol levels and, therefore, is associated with stress and fatigue [6]. On the other hand, some argue that yawning serves a primarily communicative function. Contagious yawning was reported to be more common among kin and friends than strangers and was, therefore, interpreted as a representation of empathy [7]. This has been corroborated by studies revealing engagement in contagious yawning of the mirror neuron system (MNS), a system implicated in higher-level cognitive processing, such as empathy [24]. Functional MRI findings revealed activation of the right inferior frontal gyrus, a part of the MNS, when participants exhibited contagious yawning, thereby supporting the idea of empathetic yawning [25]. Furthermore, EEG findings have revealed that mu suppression on the EEG, an index utilized to represent MNS activation, was greater for participants viewing or hearing yawns than for controls [26]. These findings support the notion that contagious yawning is an expression of empathy and that the MNS may play a key role in this expression. In reference to the proposed theories, we hypothesize that the putamen's widespread connectivity with cortical and subcortical regions allows it to receive input regarding alterations in physiologic or social needs and initiate the motor execution of yawning, an action that can similarly be inhibited by other brain regions, possibly including the insula. 5. Conclusion Whether yawning has a social communicative function or a physiological significance, or both, is a question that remains to be answered. Here, we illustrate the role of the putamen through direct electrical stimulation and corroborate previous findings suggesting a role for the striatum in yawning. We hope that findings from this report contribute to future research investigating yawning. Conflict of interest The authors have no conflict of interest related to the current report. Acknowledgments This work was supported by a startup fund and departmental support from George Washington University to MZK.
3
References [1] Gallup AC. Why do we yawn? Primitive versus derived features. Neurosci Biobehav Rev 2011;35(3):765–9. [2] Baenninger R. On yawning and its functions. Psychon Bull Rev 1997;4(2):198–207. [3] Askenasy JJ. Is yawning an arousal defense reflex? J Psychol 1989;123(6):609–21. [4] Walusinski O. Yawning: unsuspected avenue for a better understanding of arousal and interoception. Med Hypotheses 2006;67(1):6–14. [5] Gallup AC, Gallup GG. Yawning and thermoregulation. Physiol Behav 2008;95(1–2): 10–6. [6] Thompson SBN. Born to yawn? Cortisol linked to yawning: a new hypothesis. Med Hypotheses 2011;77(5):861–2. [7] Norscia I, Palagi E. Yawn contagion and empathy in Homo sapiens. PLoS One 2011; 6(12), e28472. [8] Walusinski O. Yawning: unsuspected avenue for a better understanding of arousal and interoception. Med Hypotheses 2006;67(1):6–14. [9] Argiolas A, Melis MR. The neuropharmacology of yawning. Eur J Pharmacol 1998; 343(1):1–16. [10] Melis MR, Argiolas A, Gessa GL. Apomorphine-induced penile erection and yawning: site of action in brain. Brain Res 1987;415(1):98–104. [11] Dourish CT, Hutson PH. Bilateral lesions of the striatum induced with 6hydroxydopamine abolish apomorphine-induced yawning in rats. Neuropharmacology 1985;24(11):1051–5. [12] Yamada K, Tanaka M, Shibata K, Furukawa T. Involvement of septal and striatal dopamine D-2 receptors in yawning behavior in rats. Psychopharmacology (Berl) 1986;90(1):9–13. [13] Sato-Suzuki I, Kita I, Oguri M, Arita H. Stereotyped yawning responses induced by electrical and chemical stimulation of paraventricular nucleus of the rat. J Neurophysiol 1998;80(5):2765–75. [14] Van Erp AM, Kruk MR, Willekens-Bramer DC, Bressers WM, Roeling TA, Veening JG, et al. Grooming induced by intrahypothalamic injection of ACTH in the rat: comparison with grooming induced by intrahypothalamic electrical stimulation and i.c.v. injection of ACTH. Brain Res 1991;538(2):203–10. [15] Haber SN. Corticostriatal circuitry. Dialogues Clin Neurosci 2016;18(1):7–21. [16] Díaz-Romero M, Arias-Montaño JA, Eguibar JR, Flores G. Enhanced binding of dopamine D1 receptors in caudate-putamen subregions in high-yawning Sprague– Dawley rats. Synap N Y N 2005;56(2):69–73. [17] Martelle SE, Nader SH, Czoty PW, John WS, Duke AN, Garg PK, et al. Further characterization of quinpirole-elicited yawning as a model of dopamine D3 receptor activation in male and female monkeys. J Pharmacol Exp Ther 2014;350(2):205–11. [18] Nelson SM, Dosenbach NUF, Cohen AL, Wheeler ME, Schlaggar BL, Petersen SE. Role of the anterior insula in task-level control and focal attention. Brain Struct Funct 2010;214(5–6):669–80. [19] Krestel H, Weisstanner C, Hess CW, Bassetti CL, Nirkko A, Wiest R. Insular and caudate lesions release abnormal yawning in stroke patients. Brain Struct Funct 2015;220(2):803–12. [20] Provine RR, Tate BC, Geldmacher LL. Yawning: no effect of 3–5% CO2, 100% O2, and exercise. Behav Neural Biol 1987;48(3):382–93. [21] Gallup GG, Gallup AC. Excessive yawning and thermoregulation: two case histories of chronic, debilitating bouts of yawning. Sleep Breath Schlaf Atm 2010;14(2): 157–9. [22] Gallup AC. Excessive yawning and thermoregulatory dysfunction. Sleep Breath Schlaf Atm 2011;15(3):271–3. [23] Walusinski O. Yawning in diseases. Eur Neurol 2009;62(3):180–7. [24] Rizzolatti G. The mirror neuron system and its function in humans. Anat Embryol (Berl) 2005;210(5–6):419–21. [25] Haker H, Kawohl W, Herwig U, Rössler W. Mirror neuron activity during contagious yawning — an fMRI study. Brain Imaging Behav 2013;7(1):28–34. [26] Cooper NR, Puzzo I, Pawley AD, Bowes-Mulligan RA, Kirkpatrick EV, Antoniou PA, et al. Bridging a yawning chasm: EEG investigations into the debate concerning the role of the human mirror neuron system in contagious yawning. Cogn Affect Behav Neurosci 2012;12(2):393–405.