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Optogenetic stimulation of pre–Bötzinger complex reveals novel circuit interactions in swallowing–breathing coordination
Abstract
The coordination of swallowing with breathing, in particular inspiration, is essential for homeostasis in most organisms. While much has been learned about the neuronal network critical for inspiration in mammals, the pre–Bötzinger complex (preBötC), little is known about how this network interacts with swallowing. Here we activate within the preBötC excitatory neurons (defined as Vglut2 and Sst neurons) and inhibitory neurons (defined as Vgat neurons) and inhibit and activate neurons defined by the transcription factor Dbx1 to gain an understanding of the coordination between the preBötC and swallow behavior. We found that stimulating inhibitory preBötC neurons did not mimic the premature shutdown of inspiratory activity caused by water swallows, suggesting that swallow-induced suppression of inspiratory activity is not directly mediated by the inhibitory neurons in the preBötC. By contrast, stimulation of preBötC Dbx1 neurons delayed laryngeal closure of the swallow sequence. Inhibition of Dbx1 neurons increased laryngeal closure duration and stimulation of Sst neurons pushed swallow occurrence to later in the respiratory cycle, suggesting that excitatory neurons from the preBötC connect to the laryngeal motoneurons and contribute to the timing of swallowing. Interestingly, the delayed swallow sequence was also caused by chronic intermittent hypoxia (CIH), a model for sleep apnea, which is 1) known to destabilize inspiratory activity and 2) associated with dysphagia. This delay was not present when inhibiting Dbx1 neurons. We propose that a stable preBötC is essential for normal swallow pattern generation and disruption may contribute to the dysphagia seen in obstructive sleep apnea.
Supplementary resource (1)
... The lack of extensive dendritic lengths at eighth and beyond branch orders is also consistent with this premise. This oesophageal activation in swallow is likely highly stereotyped in action [i.e., a reflex binary, initiated synchronously by distension or by the initiation of the swallow pattern (Andrew, 1956b;Meyer and Castell, 1982;Paterson, 1999;Broussard and Altschuler, 2000)], similar to the laryngeal functions in ventilation and swallow (Andrew, 1955;Fregosi and Ludlow, 2014;Huff et al., 2022;Pitts and Iceman, 2023). By contrast, laryngeal muscles operate over a wider range of behaviours (notably changes in pitch during vocalisation) (Wetzel et al., 1980;Bartlett and Knuth, 1984;Jurgens, 2009;Riede et al., 2020) and emotional states McIntosh et al., 1978;Barfield et al., 1979;Vanderhorst et al., 2000;Holstege, 2014), particularly in humans (Levin, 2006;Pisanski et al., 2022). ...
... What remains evolutionarily peculiar is the observation that these oesophageal-innervating MNs are rostral to both pharyngeal MNs and the disparate brainstem swallow centres within the nucleus of the solitary tract and the dorsal and ventral swallow groups (Holstege et al., 1983;Kessler and Jean, 1985a,b;Zheng et al., 1997;Jean, 2001;Huff et al., 2022;Pitts and Iceman, 2023). Second, these neurons are activated last in the swallow phase-first oral, then pharyngeal, then oesophageal (Pitts and Iceman, 2023). ...
... Indeed, interactions between emotional processing centres of the brainstem and the muscles of speech/vocalisation are becoming increasingly studied (Vanderhorst et al., 2000;Holstege, 2014;Subramanian et al., 2018Subramanian et al., , 2021. Similarly to oesophageal MNs, these MNs must coordinate their activation with the control of breathing as well as vomiting, cough, and a host of other behaviours (Kessler and Jean, 1985b;Car and Amri, 1987;Tomomune and Takata, 1988;Amri et al., 1991;Nishino and Hiraga, 1991;Dick et al., 1993;Umezaki et al., 1998;Jean, 2001;Sawczuk and Mosier, 2001;Roda et al., 2002;Pitts et al., 2012;Fregosi and Ludlow, 2014;Huff et al., 2022). Thus, compared to oesophageal MNs, palate and laryngeal MNs must integrate their activities across a wider range of behavioural states. ...
Introduction
Motor neurons (MNs) within the nucleus ambiguus innervate the skeletal muscles of the larynx, pharynx, and oesophagus. These muscles are activated during vocalisation and swallowing and must be coordinated with several respiratory and other behaviours. Despite many studies evaluating the projections and orientation of MNs within the nucleus ambiguus, there is no quantitative information regarding the dendritic arbours of MNs residing in the compact, and semicompact/loose formations of the nucleus ambiguus..
Methods
In female and male Fischer 344 rats, we evaluated MN number using Nissl staining, and MN and non-MN dendritic morphology using Golgi–Cox impregnation Brightfield imaging of transverse Nissl sections (15 μm) were taken to stereologically assess the number of nucleus ambiguus MNs within the compact and semicompact/loose formations. Pseudo-confocal imaging of Golgi-impregnated neurons within the nucleus ambiguus (sectioned transversely at 180 μm) was traced in 3D to determine dendritic arbourisation.
Results
We found a greater abundance of MNs within the compact than the semicompact/loose formations. Dendritic lengths, complexity, and convex hull surface areas were greatest in MNs of the semicompact/loose formation, with compact formation MNs being smaller. MNs from both regions were larger than non-MNs reconstructed within the nucleus ambiguus.
Conclusion
Adding HBLS to the diet could be a potentially effective strategy to improve horses’ health.
... Obstructive sleep apnea (OSA) represents a significant public health burden and is increasing in prevalence (Franklin and Lindberg, 2015). Cardiopulmonary sequelae of OSA include arterial hypertension, increased ventilatory response to hypercapnia, endothelial dysfunction, atherosclerosis, and disordered swallowbreathing coordination (Fletcher, 2001;Prabhakar et al., 2005;Schulz et al., 2005;Nanduri et al., 2012;Dumitrascu et al., 2013;Huff et al., 2022). Chronic intermittent hypoxia (CIH) is used as an experimental paradigm to model the pathophysiological changes associated with OSA. ...
... Heterozygous Dbx1creERT2 mice were donated by Dr. Christopher Del Negro (College of William and Mary, VA) and a homozygous breeder line was generated at SCRI. Homozygous Dbx1creERT2 dams were plug checked and injected intraperitoneally (IP) at E10.5 with tamoxifen (24 mg/kg) to target preBötC Dbx1 neurons (Baertsch et al., 2019;Huff et al., 2022). ChAT-IRES-cre(Δneo), technically known as 129S-Chat tm1(cre)Lowl /MwarJ strain, and Vglut2-IRES2-FlpO-D, technically known as 129S-Slc17a6 tm1.1(flpo)Hze /J were obtained from Jackson Laboratories (stock numbers 031661 and 030212, respectively). ...
... Offspring from optogenetic lines were randomly assigned to CIH or normoxia (control) protocols. The CIH protocol used in the present study has been previously described (Huff et al., 2022). Briefly, mouse cages were kept inside a custom-built dual oxygen/nitrogen cycling chamber (Oxycycler, Huff Technologies Inc., Morganfield, KY). ...
The sympathetic nervous system modulates arterial blood pressure. Individuals with obstructive sleep apnea (OSA) experience numerous nightly hypoxic episodes and exhibit elevated sympathetic activity to the cardiovascular system leading to hypertension. This suggests that OSA disrupts normal respiratory-sympathetic coupling. This study investigates the role of the postinspiratory complex (PiCo) and preBötzinger complex (preBötC) in respiratory-sympathetic coupling under control conditions and following exposure to chronic intermittent hypoxia (CIH) for 21 days (5% O2–80 bouts/day). The surface of the ventral brainstem was exposed in urethane (1.5 g/kg) anesthetized, spontaneously breathing adult mice. Cholinergic (ChAT), glutamatergic (Vglut2), and neurons that co-express ChAT and Vglut2 at PiCo, as well as Dbx1 and Vglut2 neurons at preBötC, were optogenetically stimulated while recording activity from the diaphragm (DIA), vagus nerve (cVN), and cervical sympathetic nerve (cSN). Following CIH exposure, baseline cSN activity increased, breathing frequency increased, and expiratory time decreased. In control mice, stimulating PiCo specific cholinergic-glutamatergic neurons caused a sympathetic burst during all phases of the respiratory cycle, whereas optogenetic activation of cholinergic-glutamatergic PiCo neurons in CIH mice increased sympathetic activity only during postinspiration and late expiration. Stimulation of glutamatergic PiCo neurons increased cSN activity during the postinspiratory phase in control and CIH mice. Optogenetic stimulation of ChAT containing neurons in the PiCo area did not affect sympathetic activity under control or CIH conditions. Stimulating Dbx1 or Vglut2 neurons in preBötC evoked an inspiration and a concomitant cSN burst under control and CIH conditions. Taken together, these results suggest that PiCo and preBötC contribute to respiratory-sympathetic coupling, which is altered by CIH, and may contribute to the hypertension observed in patients with OSA.
... While we are unable to evaluate the functional significance of the variable swallow motor patterns triggered by PiCo in this study, we previously reported CIH causes a disruption in swallow motor pattern with a delay in swallow-related laryngeal activation. This same delay was also generated when preBötC Dbx1 neurons were stimulated (Huff et al., 2022). ...
... OSA-related dysphagia has been characterized as a delayed swallow reflex, decreased time between swallow and initiation of the next inspiration, and disruption of the pharyngeal phase of swallow (Levring Jäghagen et al., 2003;Teramoto et al., 1999;Valbuza et al., 2011). Using an in vivo mouse model, we recently described that CIH delays swallow-related laryngeal activation that increases the risk for foreign materials to enter into the airway (aspiration) instead of the esophagus (Huff et al., 2022). Here we show that PiCo, a neuronal network that is critical for the generation of postinspiratory activity (Anderson et al., 2016) and implicated in the coordination of swallowing and breathing (Huff et al., 2023), is severely affected by CIH. ...
... Continuing in the supine position, the occipital bone was removed, followed by continuous perfusion of the ventral medullary surface with warmed (~36°C) artificial cerebral spinal fluid (aCSF; in mM: 118 NaCl, 3 KCl, 25 NaHCO 3 , 1 NaH 2 PO 4 , 1 MgCl 2 , 1.5 CaCl 2 , 30 d-glucose) equilibrated with carbogen (95% O 2 , 5% CO 2 ) by a peristaltic pump (Dynamax RP-1, Rainin Instrument Co, Emeryville, CA). As previously published (Figure 6a in Huff et al., 2022), the XII and X nerves were isolated unilaterally, cut distally, and their activity was recorded from a fire-polished pulled borosilicate glass tip (B150-86-15, Sutter Instrument, Novato, CA) filled with aCSF connected to the monopolar suction electrode (A-M Systems, Sequim, WA) and held in a 3D micromanipulator (Narishige, Tokyo, Japan). Multiple bipolar EMGs, using 0.002″ and 0.003″ coated stainless steel wires (A-M Systems, part nos. ...
Obstructive sleep apnea (OSA) is a prevalent sleep-related breathing disorder that results in multiple bouts of intermittent hypoxia. OSA has many neurological and systemic comorbidities, including dysphagia, or disordered swallow, and discoordination with breathing. However, the mechanism in which chronic intermittent hypoxia (CIH) causes dysphagia is unknown. Recently, we showed the postinspiratory complex (PiCo) acts as an interface between the swallow pattern generator (SPG) and the inspiratory rhythm generator, the preBötzinger complex, to regulate proper swallow-breathing coordination (Huff et al., 2023). PiCo is characterized by interneurons co-expressing transporters for glutamate (Vglut2) and acetylcholine (ChAT). Here we show that optogenetic stimulation of ChATcre:Ai32, Vglut2cre:Ai32, and ChATcre:Vglut2FlpO:ChR2 mice exposed to CIH does not alter swallow-breathing coordination, but unexpectedly disrupts swallow behavior via triggering variable swallow motor patterns. This suggests that glutamatergic–cholinergic neurons in PiCo are not only critical for the regulation of swallow-breathing coordination, but also play an important role in the modulation of swallow motor patterning. Our study also suggests that swallow disruption, as seen in OSA, involves central nervous mechanisms interfering with swallow motor patterning and laryngeal activation. These findings are crucial for understanding the mechanisms underlying dysphagia, both in OSA and other breathing and neurological disorders.
... During waking, central apnea can be triggered by emotional stress in both physiological (e.g., sighing, crying, or laughter) or pathological states (Azab et al., 2015, Klingbeil et al., 2021. Swallowing is a vital behavior that must be coordinated with breathing (Anderson et al., 2016;Huff et al., 2022Huff et al., , 2023Cedborg et al., 2009). Coordinating swallowing and breathing is intricate due to significant functional overlap. ...
... Coordinating swallowing and breathing is intricate due to significant functional overlap. Certain muscles have a competing drive with respiratory activity, playing multifunctional roles in both swallowing and breathing processes (Huff et al., 2022). Ensuring the secure passage of a bolus through the pharynx requires a temporary pause in respiration, a phenomenon recognized as swallow-related apnea (Cedborg et al., 2009;Huff et al., 2022;Huff et al., 2023). ...
... Certain muscles have a competing drive with respiratory activity, playing multifunctional roles in both swallowing and breathing processes (Huff et al., 2022). Ensuring the secure passage of a bolus through the pharynx requires a temporary pause in respiration, a phenomenon recognized as swallow-related apnea (Cedborg et al., 2009;Huff et al., 2022;Huff et al., 2023). Patients with PD may have abnormal respiratory-swallow coordination (Pinnington et al., 2000;, increasing their risk of serious conditions such as dehydration, malnutrition, and aspiration pneumonia (Bloem et al., 2021). ...
This study aimed to evaluate the timing and frequency of spontaneous apneas during breathing and swallowing by using cineradiography on mouse models of early/initial or late/advanced Parkinson’s disease (PD). C57BL/6J mice received either 6-OHDA or vehicle injections into their right striatum, followed by respiratory movement recordings during spontaneous breathing and swallowing, and a stress challenge, two weeks later. Experimental group animals showed a significantly lower respiratory rate (158.66 ± 32.88 breaths/minute in late PD, 173.16 ± 25.19 in early PD versus 185.27 ± 25.36 in controls; p<0.001) and a significantly higher frequency of apneas (median 1 apnea/minute in both groups versus 0 in controls; p<0.001). Other changes included reduced food intake and the absence of swallow apneas in experimental mice. 6-OHDA-induced nigrostriatal degeneration in mice disrupted respiratory control, swallowing, stress responsiveness, and feeding behaviors, potentially hindering airway protection and elevating the risk of aspiration.
... While we are unable to evaluate the functional significance of the variable swallow motor patterns triggered by PiCo in this study, we previously reported CIH causes a disruption in swallow motor pattern with a delay in swallow-related laryngeal activation. This same delay was also generated when preBötC Dbx1 neurons were stimulated (Huff et al., 2022). ...
... OSA-related dysphagia has been characterized as a delayed swallow reflex, decreased time between swallow and initiation of the next inspiration, and disruption of the pharyngeal phase of swallow (Levring Jäghagen et al., 2003;Teramoto et al., 1999;Valbuza et al., 2011). Using an in vivo mouse model, we recently described that CIH delays swallow-related laryngeal activation that increases the risk for foreign materials to enter into the airway (aspiration) instead of the esophagus (Huff et al., 2022). Here we show that PiCo, a neuronal network that is critical for the generation of postinspiratory activity (Anderson et al., 2016) and implicated in the coordination of swallowing and breathing (Huff et al., 2023), is severely affected by CIH. ...
... Continuing in the supine position, the occipital bone was removed, followed by continuous perfusion of the ventral medullary surface with warmed (~36°C) artificial cerebral spinal fluid (aCSF; in mM: 118 NaCl, 3 KCl, 25 NaHCO 3 , 1 NaH 2 PO 4 , 1 MgCl 2 , 1.5 CaCl 2 , 30 d-glucose) equilibrated with carbogen (95% O 2 , 5% CO 2 ) by a peristaltic pump (Dynamax RP-1, Rainin Instrument Co, Emeryville, CA). As previously published (Figure 6a in Huff et al., 2022), the XII and X nerves were isolated unilaterally, cut distally, and their activity was recorded from a fire-polished pulled borosilicate glass tip (B150-86-15, Sutter Instrument, Novato, CA) filled with aCSF connected to the monopolar suction electrode (A-M Systems, Sequim, WA) and held in a 3D micromanipulator (Narishige, Tokyo, Japan). Multiple bipolar EMGs, using 0.002″ and 0.003″ coated stainless steel wires (A-M Systems, part nos. ...
Obstructive sleep apnea (OSA) is a prevalent sleep-related breathing disorder that results in multiple bouts of intermittent hypoxia. OSA has many neurologic and systemic comorbidities including dysphagia, or disordered swallow and discoordination with breathing. However, the mechanism in which chronic intermittent hypoxia (CIH) causes dysphagia is unknown. Recently we showed the Postinspiratory complex (PiCo) acts as an interface between the swallow pattern generator (SPG) and the inspiratory rhythm generator, the preBötzinger Complex, to regulate proper swallow-breathing coordination (A. D. Huff et al., 2023). PiCo is characterized by interneurons co-expressing transporters for glutamate (Vglut2) and acetylcholine (ChAT). Here we show that optogenetic stimulation of ChATcre:Ai32, Vglut2cre:Ai32, and ChATcre:Vglut2FlpO:ChR2 mice exposed to CIH does not alter swallow-breathing coordination, but unexpectedly the generation of swallow motor pattern was significantly disturbed. This suggests, glutamatergic-cholinergic neurons in PiCo are not only critical for the gating of postinspiratory and swallow activity, but also play important roles in the generation of swallow motor pattern. Our study also suggests that swallow disruption, as seen in OSA involves central nervous mechanisms interfering with the generation of the swallow pattern and laryngeal activation. These findings are crucial for understanding the mechanisms underlying dysphagia in OSA and other breathing and neurological disorders.
... We confirmed that optogenetic stimulation of PiCo neurons triggers swallow and laryngeal activation similar to the control mice exposed to room air (A. D. Huff et al., 2023). ...
... Looking back to the control mice exposed to room air, only 1 out of 7 mice had a burst of submental complex activity, 4 mice had a low tonic submental complex activity and 2 mice had no submental activity (A. D. Huff et al., 2023). ...
... Whereas under control conditions, when mice were exposed to room air, we found no significant difference in the probability of triggering a swallow between ChATcre:Ai32, Vglut2:Ai32, and ChATcre:Vglut2FlpO:ChR2 mice (A. D. Huff et al., 2023). ...
Obstructive sleep apnea (OSA) is a prevalent sleep-related breathing disorder that results in multiple bouts of intermittent hypoxia. OSA has many neurologic and systemic comorbidities including dysphagia, or disordered swallow and discoordination with breathing. However, the mechanism in which chronic intermittent hypoxia (CIH) causes dysphagia is unknown. Recently we showed the Postinspiratory complex (PiCo) acts as an interface between the swallow pattern generator (SPG) and the inspiratory rhythm generator, the preBotzinger Complex, to regulate proper swallow-breathing coordination (A. D. Huff et al., 2023). PiCo is characterized by interneurons co-expressing transporters for glutamate (Vglut2) and acetylcholine (ChAT). Here we show that optogenetic stimulation of ChATcre:Ai32, Vglut2cre:Ai32, and ChATcre:Vglut2FlpO:ChR2 mice exposed to CIH does not alter swallow-breathing coordination, but unexpectedly the generation of swallow motor pattern was significantly disturbed. This suggests, glutamatergic-cholinergic neurons in PiCo are not only critical for the gating of postinspiratory and swallow activity, but also play important roles in the generation of swallow motor pattern. Our study also suggests that swallow disruption, as seen in OSA involves central nervous mechanisms interfering with the generation of the swallow pattern and laryngeal activation. These findings are crucial for understanding the mechanisms underlying dysphagia in OSA and other breathing and neurological disorders.
... Kleinfeld and colleagues introduce the concept of pre-premotor regions 'pre 2 motor' to describe that respiratory oscillators can modulate other orofacial premotor oscillators such as whisking and sniffing (McElvain et al., 2018;Moore et al., 2013;Moore et al., 2014) and recently described swallow (Huff et al., 2022;Pitts et al., 2021). By modulating the preBötzinger complex, swallow can be shifted to different times of the respiratory cycle as well as changing swallow-related amplitude, laryngeal duration, and motor pattern sequence (Huff et al., 2022). ...
... Kleinfeld and colleagues introduce the concept of pre-premotor regions 'pre 2 motor' to describe that respiratory oscillators can modulate other orofacial premotor oscillators such as whisking and sniffing (McElvain et al., 2018;Moore et al., 2013;Moore et al., 2014) and recently described swallow (Huff et al., 2022;Pitts et al., 2021). By modulating the preBötzinger complex, swallow can be shifted to different times of the respiratory cycle as well as changing swallow-related amplitude, laryngeal duration, and motor pattern sequence (Huff et al., 2022). Triggering swallow via PiCo activation results in a phase delay of the respiratory cycle, resetting the rhythm, whereas laryngeal activation (non-swallow) has a weaker effect on respiration phase (Figure 2). ...
... Triggering swallow via PiCo activation results in a phase delay of the respiratory cycle, resetting the rhythm, whereas laryngeal activation (non-swallow) has a weaker effect on respiration phase (Figure 2). Activation of PiCo-specific neurons arrested or abrogate inspiration triggering swallow, further indicating swallow's hierarchical control over breathing ( Figure 2C; Dick et al., 1993;Huff et al., 2022;Miller and Sherrington, 1915;Pitts et al., 2018). ...
Breathing needs to be tightly coordinated with upper airway behaviors, such as swallowing. Discoordination leads to aspiration pneumonia, the leading cause of death in neurodegenerative disease. Here, we study the role of the postinspiratory complex (PiCo) in coordinating breathing and swallowing. Using optogenetic approaches in freely breathing anesthetized ChATcre:Ai32, Vglut2cre:Ai32 and intersectional recombination of ChATcre:Vglut2FlpO:ChR2 mice reveals PiCo mediates airway protective behaviors. Activation of PiCo during inspiration or the beginning of postinspiration triggers swallow behavior in an all-or-nothing manner, while there is a higher probability for stimulating only laryngeal activation when activated further into expiration. Laryngeal activation is dependent on stimulation duration. Sufficient bilateral PiCo activation is necessary for preserving the physiological swallow motor sequence since activation of only a few PiCo neurons or unilateral activation leads to blurred upper airway behavioral responses. We believe PiCo acts as an interface between the swallow pattern generator and the preBötzinger complex to coordinate swallow and breathing. Investigating PiCo’s role in swallow and laryngeal coordination will aid in understanding discoordination with breathing in neurological diseases.
... Kleinfeld and colleagues introduce the concept of pre-premotor regions 'pre 2 motor' to describe that respiratory oscillators can modulate other orofacial premotor oscillators such as whisking and sniffing (McElvain et al., 2018;Moore et al., 2013;Moore et al., 2014) and recently described swallow (Huff et al., 2022;Pitts et al., 2021). By modulating the preBötzinger complex, swallow can be shifted to different times of the respiratory cycle as well as changing swallow-related amplitude, laryngeal duration, and motor pattern sequence (Huff et al., 2022). ...
... Kleinfeld and colleagues introduce the concept of pre-premotor regions 'pre 2 motor' to describe that respiratory oscillators can modulate other orofacial premotor oscillators such as whisking and sniffing (McElvain et al., 2018;Moore et al., 2013;Moore et al., 2014) and recently described swallow (Huff et al., 2022;Pitts et al., 2021). By modulating the preBötzinger complex, swallow can be shifted to different times of the respiratory cycle as well as changing swallow-related amplitude, laryngeal duration, and motor pattern sequence (Huff et al., 2022). Triggering swallow via PiCo activation results in a phase delay of the respiratory cycle, resetting the rhythm, whereas laryngeal activation (non-swallow) has a weaker effect on respiration phase (Figure 2). ...
... Triggering swallow via PiCo activation results in a phase delay of the respiratory cycle, resetting the rhythm, whereas laryngeal activation (non-swallow) has a weaker effect on respiration phase (Figure 2). Activation of PiCo-specific neurons arrested or abrogate inspiration triggering swallow, further indicating swallow's hierarchical control over breathing ( Figure 2C; Dick et al., 1993;Huff et al., 2022;Miller and Sherrington, 1915;Pitts et al., 2018). ...
Breathing needs to be tightly coordinated with upper airway behaviors, such as swallowing. Discoordination leads to aspiration pneumonia, the leading cause of death in neurodegenerative disease. Here, we study the role of the postinspiratory complex (PiCo) in coordinating breathing and swallowing. Using optogenetic approaches in freely breathing anesthetized ChATcre:Ai32, Vglut2cre:Ai32 and intersectional recombination of ChATcre:Vglut2FlpO:ChR2 mice reveals PiCo mediates airway protective behaviors. Activation of PiCo during inspiration or the beginning of postinspiration triggers swallow behavior in an all-or-nothing manner, while there is a higher probability for stimulating only laryngeal activation when activated further into expiration. Laryngeal activation is dependent on stimulation duration. Sufficient bilateral PiCo activation is necessary for preserving the physiological swallow motor sequence since activation of only a few PiCo neurons or unilateral activation leads to blurred upper airway behavioral responses. We believe PiCo acts as an interface between the swallow pattern generator and the preBötzinger complex to coordinate swallow and breathing. Investigating PiCo’s role in swallow and laryngeal coordination will aid in understanding discoordination with breathing in neurological diseases.
... Within the realm of optogenetics applied to transgenic rodent models, this review identified eight pivotal publications that harness this technique (Kottick and Del Negro, 2015;Cui et al., 2016;Koizumi et al., 2016;Vann et al., 2016;Ausborn et al., 2018;Vann et al., 2018;Ikeda et al., 2019;Huff et al., 2022). These investigations predominantly utilized transcription factors, namely, Phox2b, Dbx1, and Sst, as distinctive markers for the formulation of these models. ...
... This revelation underscored that these neurons, in their collective capacity, form a singular excitatory population instrumental in the respiratory rhythm generation. Augmenting this body of knowledge, Huff et al. (2022) posited that the preBötC, beyond its foundational role in respiratory rhythm generation, also plays an integral part in orchestrating the nuances of breathing and its shallowing dynamics. ...
The pre-Bötzinger complex, situated in the ventrolateral medulla, serves as the central generator for the inspiratory phase of the respiratory rhythm. Evidence strongly supports its pivotal role in generating, and, in conjunction with the post-inspiratory complex and the lateral parafacial nucleus, in shaping the respiratory rhythm. While there remains an ongoing debate concerning the mechanisms underlying these nuclei’s ability to generate and modulate breathing, transgenic rodent models have significantly contributed to our understanding of these processes. However, there is a significant knowledge gap regarding the spectrum of transgenic rodent lines developed for studying respiratory rhythm, and the methodologies employed in these models. In this study, we conducted a scoping review to identify commonly used transgenic rodent lines and techniques for studying respiratory rhythm generation and modulation. Following PRISMA guidelines, we identified relevant papers in PubMed and EBSCO on 29 March 2023, and transgenic lines in Mouse Genome Informatics and the International Mouse Phenotyping Consortium. With strict inclusion and exclusion criteria, we identified 80 publications spanning 1997–2022 using 107 rodent lines. Our findings revealed 30 lines focusing on rhythm generation, 61 on modulation, and 16 on both. The primary in vivo method was whole-body plethysmography. The main in vitro method was hypoglossal/phrenic nerve recordings using the en bloc preparation. Additionally, we identified 119 transgenic lines with the potential for investigating the intricate mechanisms underlying respiratory rhythm. Through this review, we provide insights needed to design more effective experiments with transgenic animals to unravel the mechanisms governing respiratory rhythm. The identified transgenic rodent lines and methodological approaches compile current knowledge and guide future research towards filling knowledge gaps in respiratory rhythm generation and modulation.
... Swallow preferentially occurs in the expiratory phase of breathing. While swallow occurs during post-inspiration in rats and mice (25,26), it is most likely to occur later in expiration in cats and humans (27)(28)(29). While swallow is mediated by cranial nerves, it is impaired by spinal cord injury (18), and is influenced by afferent feedback from pulmonary stretch receptors that are activated during inspiration (16,25). ...
Introduction
Aspiration pneumonia, a leading cause of mortality, poses an urgent challenge in contemporary society. Neuromuscular electrical stimulation (NMES) has been commonly used in dysphagia rehabilitation. However, given that NMES at motor threshold targets only specific muscles, it carries a potential risk of further compromising functions related to swallowing, respiration, and airway protection. Considering that the swallow motor pattern is orchestrated by the entire swallow pattern generator (the neural mechanism governing a sequence of swallow actions), a rehabilitation approach that centrally facilitates the entire circuit through sensory nerve stimulation is desirable. In this context, we propose a novel stimulation method using surface electrodes placed on the back to promote swallowing.
Methods
The efficacy of the proposed method in promoting swallowing was evaluated by electrically stimulating sensory nerves in the back or neck. Probabilistic stimulus was applied to either the back or neck of male and female rats. Swallows were evoked by an oral water stimulus, and electromyographic (EMG) activity of the mylohyoid, thyroarytenoid, and thyropharyngeus muscles served as the primary outcome measure.
Results
Gaussian frequency stimulation applied to the skin surface of the thoracic back elicited significant increases in EMG amplitude of all three swallow-related muscles. Neck stimulation elicited a significant increase in EMG amplitude of the thyroarytenoid during swallow, but not the mylohyoid or thyropharyngeus muscles.
Discussion
While the targeted thoracic spinal segments T9-T10 have been investigated for enhancing respiration, the promotion of swallowing through back stimulation has not been previously studied. Furthermore, this study introduces a new probabilistic stimulus based on Gaussian distribution. Probabilistic stimuli have been reported to excel in nerve stimulation in previous research. The results demonstrate that back stimulation effectively facilitated swallow more than neck stimulation and suggest potential applications for swallowing rehabilitation.
... Swallowing is a complex behavior that involves the sequential contraction of many swallowing-related muscles (5,6). It is controlled by neural pathways called the swallowing central pattern generators (CPG) in the brainstem (6)(7)(8)(9). Because of this complexity, it is essential to comprehend the pathophysiology of dysphagia. ...
Introduction
Swallowing impairment is a crucial issue that can lead to aspiration, pneumonia, and malnutrition. Animal models are useful to reveal pathophysiology and to facilitate development of new treatments for dysphagia caused by many diseases. The present study aimed to develop a new dysphagia model with reduced pharyngeal constriction during pharyngeal swallowing.
Methods
We analyzed the dynamics of pharyngeal swallowing over time with the pharyngeal branches of the vagus nerve (Ph-X) bilaterally or unilaterally transected, using videofluoroscopic assessment of swallowing in guinea pigs. We also evaluated the detailed anatomy of the pharyngeal constrictor muscles after the denervation.
Results
Videofluoroscopic examination of swallowing showed a significant increase in the pharyngeal area during swallowing after bilateral and unilateral sectioning of the Ph-X. The videofluoroscopy also showed significantly higher pharyngeal transit duration for bilateral and unilateral section groups. The thyropharyngeal muscle on the sectioned side was significantly thinner than that on the intact side. In contrast, the thickness of the cricopharyngeal muscles on the sectioned and intact sides were not significantly different. The mean thickness of the bilateral thyropharyngeal muscles showed a linear correlation to the pharyngeal area and pharyngeal transit duration.
Discussion
Data obtained in this study suggest that denervation of the Ph-X could influence the strength of pharyngeal contraction during pharyngeal swallowing in relation to thickness of the pharyngeal constrictor muscles, resulting in a decrease in bolus speed. This experimental model may provide essential information (1) for the development of treatments for pharyngeal dysphagia and (2) on the mechanisms related to the recovery process, reinnervation, and nerve regeneration following injury and swallowing impairment possibly caused by medullary stroke, neuromuscular disease, or surgical damage from head and neck cancer.
... While the pre-BötC is traditionally referred to as the inspiratory rhythm generating circuit of the respiratory network, recent data showed that this area of the rostroventral medullary reticular formation is also part of the distributed network that generates and controls the laryngeal adduction during the postinspiratory phase (Dhingra et al., 2019a, b;. Further, recent papers have now also shown that pre-BötC neurons have a role in the modulation of swallowing-breathing coordination (Huff et al., 2022) and in cough (Shen et al., 2022). Both reflex behaviors require laryngeal adduction and are upper-airway reflex motor behaviors. ...
... The potent influence of inhibitory neurotransmission underlies many aspects of the rhythmic nature of breathing [72,99,[233][234][235][236] and the coordination of breathing with other activities [2,10,237]. Considerable attention has been paid to respiratory neuromotor dysfunction in Rett syndrome, with breathing disturbances, alongside coordination of breathing problems (i.e., swallowing, speech, etcetera) common across patients and MECP2 models [37, 203,[238][239][240][241][242][243][244][245][246]. ...
During development, GABA and glycine play major trophic and synaptic roles in the establishment of the neuromotor system. In this review, we summarise the formation, function and maturation of GABAergic and glycinergic synapses within neuromotor circuits during development. We take special care to discuss the differences in limb and respiratory neuromotor control. We then investigate the influences that GABAergic and glycinergic neurotransmission has on two major developmental neuromotor disorders: Rett syndrome and spastic cerebral palsy. We present these two syndromes in order to contrast the approaches to disease mechanism and therapy. While both conditions have motor dysfunctions at their core, one condition Rett syndrome, despite having myriad symptoms, has scientists focused on the breathing abnormalities and their alleviation—to great clinical advances. By contrast, cerebral palsy remains a scientific quagmire or poor definitions, no widely adopted model and a lack of therapeutic focus. We conclude that the sheer abundance of diversity of inhibitory neurotransmitter targets should provide hope for intractable conditions, particularly those that exhibit broad spectra of dysfunction—such as spastic cerebral palsy and Rett syndrome.
... Namely, it suggests that the reafferent signal generated following each breath-and propagated from olfactory areas (OB) to nonolfactory areas (FC)-evokes a dynamic reorganization of local network activity, increasing not only gamma oscillations (as inferred by phase-amplitude coupling analysis) but also gamma synchrony. Consequently, it seems unlikely that the enhancement of gamma synchronization is strongly affected by an efferent copy signal sent from respiratory brainstem nuclei during the generation of rhythmical breathing [35], notwithstanding their participation in brain-wide network synchronization [40,49]. If this signal was decisive for gamma synchronization, we would expect the efferent copy to change along with different respiratory patterns and modify the gamma synchronization window accordingly, which was not observed here. ...
Nasal respiration influences brain dynamics by phase-entraining neural oscillations at the same frequency as the breathing rate and by phase-modulating the activity of faster gamma rhythms. Despite being widely reported, we still do not understand the functional roles of respiration-entrained oscillations. A common hypothesis is that these rhythms aid long-range communication and provide a privileged window for synchronization. Here we tested this hypothesis by analyzing electrocor-ticographic (ECoG) recordings in mice, rats, and cats during the different sleep-wake states. We found that the respiration phase modulates the amplitude of cortical gamma oscillations in the three species, although the modulated gamma frequency bands differed with faster oscillations (90-130 Hz) in mice, intermediate frequencies (60-100 Hz) in rats, and slower activity (30-60 Hz) in cats. In addition, our results also show that respiration modulates olfactory bulb-frontal cortex synchronization in the gamma range, in which each breathing cycle evokes (following a delay) a transient time window of increased gamma synchrony. Long-range gamma synchrony modulation occurs during quiet and active wake states but decreases during sleep. Thus, our results suggest that respiration-entrained brain rhythms orchestrate communication in awake mammals.
The control of the respiratory rhythm and airway motor activity is essential for life. Accumulating evidence indicates that the postinspiratory complex (PiCo) is crucial for generating behaviors that occur during the postinspiratory phase, including expiratory laryngeal activity and swallowing. Located in the ventromedial medulla, PiCo is defined by neurons co‐expressing two neurotransmitter markers (ChAT and Vglut2/Slc17a6). Here, we mapped the input–output connections of these neurons using viral tracers and intersectional viral‐genetic tools. PiCo neurons were specifically targeted by focal injection of a doubly conditional Cre‐ and FlpO‐dependent AAV8 viral marker (AAV8‐Con/Fon‐TVA‐mCherry) into the left PiCo of adult Chat Cre/wt : Vglut2 FlpO/wt mice, for anterograde axonal tracing. These experiments revealed projections to various brain regions, including the Cu, nucleus of the solitary tract (NTS), Amb, X, XII, Sp5, RMg, intermediate reticular nucleus (IRt), lateral reticular nucleus (LRt), pre‐Bötzinger complex (preBötC), contralateral PiCo, laterodorsal tegmental nucleus (LDTg), pedunculopontine tegmental nucleus (PPTg), periaqueductal gray matter (PAG), Kölliker–Fuse (KF), PB, and external cortex of the inferior colliculus (ECIC). A rabies virus (RV) retrograde transsynaptic approach was taken with EnvA‐pseudotyped G‐deleted (RV‐SAD‐G‐GFP) to similarly target PiCo neurons in Chat Cre/wt : Vglut2 FlpO/wt mice, following prior injections of helper AAVs (a mixture of AAV‐Ef1a‐Con/Fon oG and viral vector AAV8‐Con/Fon‐TVA‐mCherry). This combined approach revealed prominent synaptic inputs to PiCo neurons from NTS, IRt, and A1/C1. Although PiCo neurons project axons to the contralateral PiCo area, this approach did not detect direct contralateral connections. We suggest that PiCo serves as a critical integration site, projecting and receiving neuronal connections implicated in breathing, arousal, swallowing, and autonomic regulation.
Swallowing, both nutritive and non-nutritive, is highly dysfunctional in children with Leigh Syndrome (LS) and contributes to the need for both gastrostomy and tracheostomy tube placement. Without these interventions aspiration of food, liquid, and mucus occur resulting in repeated bouts of respiratory infection. No study has investigated whether mouse models of LS, a neurometabolic disorder, exhibit dysfunctions in neuromuscular activity of swallow and breathing integration. We used a genetic mouse model of LS in which the NDUFS4 gene is knocked out (KO) specifically in Vglut2 or Gad2 neurons. We found increased variability of the swallow motor pattern, disruption in breathing regeneration post swallow, and water-induced apneas only in Vglut2 KO mice. These physiological changes likely contribute to weight loss and premature death seen in this mouse model. Following chronic hypoxia (CH) exposure, swallow motor pattern, breathing regeneration, weight, and life expectancy were not changed in the Vglut2-Ndufs4-KO CH mice compared to control, indicating a rescue of phenotypes. These findings show that like patients with LS, Ndufs4 mouse models of LS exhibit swallow impairments as well as swallow-breathing dyscoordination alongside the other phenotypic traits described in previous studies. Understanding this aspect of LS will open roads for the development of future more efficacious therapeutic intervention for this illness.
In 1996 we published a review article (182) describing the state of knowledge about the structure and function of the central pattern generating circuits important for producing rhythmic behaviors. Although many of the core questions persist, much has changed since 1996. Here, we focus on newer studies that reveal ambiguities that complicate understanding circuit dynamics, despite the enormous technical advances of the recent past. In particular, we highlight recent studies of animal-to-animal variability, our understanding that circuit rhythmicity may be supported by multiple state-dependent mechanisms within the same animal, and that robustness and resilience in the face of perturbation may depend critically on the presence of modulators and degenerate circuit mechanisms. Additionally, we highlight the use of computational models to ask whether there are generalizable principles about circuit motifs that can be found across rhythmic motor systems in different animal species.
Chronic intermittent hypoxia (CIH) is a prevalent condition characterized by recurrent episodes of oxygen deprivation, linked to respiratory and neurological disorders. Prolonged CIH is known to have adverse effects, including endothelial dysfunction, chronic inflammation, oxidative stress, and impaired neuronal function. These factors can contribute to serious comorbidities, including metabolic disorders and cardiovascular diseases. To investigate the molecular impact of CIH, we examined male C57BL/6J mice exposed to CIH for 21 days, comparing to normoxic controls. We employed single-nucleus RNA sequencing to comprehensively examine the transcriptomic impact of CIH on key cell classes within the brainstem, specifically excitatory neurons, inhibitory neurons, and oligodendrocytes. These cell classes regulate essential physiological functions, including autonomic tone, cardiovascular control, and respiration. Through analysis of 10,995 nuclei isolated from pontine-medullary tissue, we identified seven major cell classes, further subdivided into 24 clusters. Our findings among these cell classes, revealed significant differential gene expression, underscoring their distinct responses to CIH. Notably, neurons exhibited transcriptional dysregulation of genes associated with synaptic transmission, and structural remodeling. In addition, we find dysregulated genes encoding ion channels, and inflammatory response. Concurrently, oligodendrocytes exhibited dysregulated genes associated with oxidative phosphorylation and oxidative stress. Utilizing CellChat network analysis, we uncovered CIH-dependent altered patterns of diffusible inter-cellular signaling. These insights offer a comprehensive transcriptomic cellular atlas of the pons-medulla and provide a fundamental resource for the analysis of molecular adaptations triggered by CIH.
Phonation critically depends on precise controls of laryngeal muscles in coordination with ongoing respiration. However, the neural mechanisms governing these processes remain unclear. We identified excitatory vocalization-specific laryngeal premotor neurons located in the retroambiguus nucleus (RAm VOC ) in adult mice as being both necessary and sufficient for driving vocal cord closure and eliciting mouse ultrasonic vocalizations (USVs). The duration of RAm VOC activation can determine the lengths of both USV syllables and concurrent expiration periods, with the impact of RAm VOC activation depending on respiration phases. RAm VOC neurons receive inhibition from the preBötzinger complex, and inspiration needs override RAm VOC -mediated vocal cord closure. Ablating inhibitory synapses in RAm VOC neurons compromised this inspiration gating of laryngeal adduction, resulting in discoordination of vocalization with respiration. Our study reveals the circuits for vocal production and vocal-respiratory coordination.
Obstructive sleep apnea (OSA) is a prevalent sleep-related breathing disorder that results in multiple bouts of intermittent hypoxia. OSA has many neurologic and systemic comorbidities including dysphagia, or disordered swallow and discoordination with breathing. However, the mechanism in which chronic intermittent hypoxia (CIH) causes dysphagia is unknown. Recently we showed the Postinspiratory complex (PiCo) acts as an interface between the swallow pattern generator (SPG) and the inspiratory rhythm generator, the preBötzinger Complex, to regulate proper swallow-breathing coordination (A. D. Huff et al., 2023). PiCo is characterized by interneurons co-expressing transporters for glutamate (Vglut2) and acetylcholine (ChAT). Here we show that optogenetic stimulation of ChATcre:Ai32, Vglut2cre:Ai32, and ChATcre:Vglut2FlpO:ChR2 mice exposed to CIH does not alter swallow-breathing coordination, but unexpectedly the generation of swallow motor pattern was significantly disturbed. This suggests, glutamatergic-cholinergic neurons in PiCo are not only critical for the gating of postinspiratory and swallow activity, but also play important roles in the generation of swallow motor pattern. Our study also suggests that swallow disruption, as seen in OSA involves central nervous mechanisms interfering with the generation of the swallow pattern and laryngeal activation. These findings are crucial for understanding the mechanisms underlying dysphagia in OSA and other breathing and neurological disorders.
The preBötzinger Complex (preBötC), a key primary generator of the inspiratory breathing rhythm, contains neurons that project directly to facial nucleus (7n) motoneurons to coordinate orofacial and nasofacial activity. To further understand the identity of 7n-projecting preBötC neurons, we used a combination of optogenetic viral transgenic approaches to demonstrate that selective photoinhibition of these neurons affects mystacial pad activity, with minimal effects on breathing. These effects are altered by the type of anesthetic employed and also between anesthetised and conscious states. The population of 7n-projecting preBötC neurons we transduced consisted of both excitatory and inhibitory neurons that also send collaterals to multiple brainstem nuclei involved with the regulation of autonomic activity. We show that modulation of subgroups of preBötC neurons, based on their axonal projections, is a useful strategy to improve our understanding of the mechanisms that coordinate and integrate breathing with different motor and physiological behaviours. This is of fundamental importance, given that abnormal respiratory modulation of autonomic activity and orofacial behaviours have been associated with the development and progression of diseases.
Breathing needs to be tightly coordinated with upper airway behaviors, such as swallowing. Discoordination leads to aspiration pneumonia, the leading cause of death in neurodegenerative disease. Here, we study the role of the postinspiratory complex (PiCo) in coordinating breathing and swallowing. Using optogenetic approaches in freely breathing anesthetized ChATcre:Ai32, Vglut2cre:Ai32 and intersectional recombination of ChATcre:Vglut2FlpO:ChR2 mice reveals PiCo mediates airway protective behaviors. Activation of PiCo during inspiration or the beginning of postinspiration triggers swallow behavior in an all-or-nothing manner, while there is a higher probability for stimulating only laryngeal activation when activated further into expiration. Laryngeal activation is dependent on stimulation duration. Sufficient bilateral PiCo activation is necessary for preserving the physiological swallow motor sequence since activation of only a few PiCo neurons or unilateral activation leads to blurred upper airway behavioral responses. We believe PiCo acts as an interface between the swallow pattern generator and the preBötzinger complex to coordinate swallow and breathing. Investigating PiCo’s role in swallow and laryngeal coordination will aid in understanding discoordination with breathing in neurological diseases.
Breathing needs to be tightly coordinated with upper airway behaviors, such as swallowing. Discoordination leads to aspiration pneumonia, the leading cause of death in neurodegenerative disease. Here we study the role of the Postinspiratory Complex (PiCo) in coordinating breathing and swallowing. Using optogenetic approaches in freely breathing- anesthetized ChATcre:Ai32, Vglut2cre:Ai32 and intersectional recombination of ChATcre:Vglut2FlpO:ChR2 mice reveals PiCo mediates airway protective behaviors. Activation of PiCo during inspiration or the beginning of postinspiration triggers swallow behavior in an all-or-nothing manner, while there is a higher probability for stimulating only laryngeal activation when activated further into expiration. Laryngeal activation is dependent on stimulation duration. Sufficient bilateral PiCo activation is necessary for preserving the physiologic swallow motor sequence, since activation of only a few PiCo neurons or unilateral activation leads to blurred upper airway behavioral responses. We believe PiCo acts as an interface between the swallow pattern generator and the preBötzinger complex to coordinate swallow and breathing. Investigating PiCo's role in swallow and laryngeal coordination will aid in understanding discoordination with breathing in neurological diseases.
Morphological studies have demonstrated that the lateral reticular nucleus (LRt) receives fibers projected from sites that are related to control of the swallowing reflex. Although the LRt may therefore be related to control of the swallowing reflex, the functional role of the LRt in the swallowing reflex remains unknown. The present study examined whether the swallowing reflex is modulated by stimulation of the LRt. These experiments were performed on rats anesthetized by urethane. The swallowing reflex was evoked by repetitive electrical stimulation of the superior laryngeal nerve (SLN) and was identified by electromyographic activities from the mylohyoid muscle. Electrical stimulation was applied to the LRt or glutamate was injected into the LRt. The number of swallows was reduced, and the latency of the onset of the first swallow was increased during electrical stimulation near the middle of the rostrocaudal direction of the LRt. The number of swallows was reduced, and the latency of onset of the first swallow increased after microinjection of glutamate near the rostrocaudal center of the LRt. The present study suggests that the LRt is involved in control of the swallowing reflex.
As neuronal subtypes are increasingly categorized, delineating their functional role is paramount. The preBötzinger complex (preBötC) subpopulation expressing the neuropeptide somatostatin (SST) is classified as mostly excitatory, inspiratory‐modulated and not rhythmogenic. We further characterized their phenotypic identity: 87% were glutamatergic and the balance were glycinergic and/or GABAergic. We then used optogenetics to investigate their modulatory role in both anaesthetized and freely moving mice. In anaesthetized mice, short photostimulation (100 ms) of preBötC SST⁺ neurons modulated breathing‐related variables in a combinatory phase‐ and state‐dependent manner; changes in inspiratory duration, inspiratory peak amplitude (Amp), and phase were different at higher (≥2.5 Hz) vs. lower (<2.5 Hz) breathing frequency (f). Moreover, we observed a biphasic effect of photostimulation during expiration that is probabilistic, that is photostimulation given at the same phase in consecutive cycles can evoke opposite responses (lengthening vs. shortening of the phase). These unexpected probabilistic state‐ and phase‐dependent responses to photostimulation exposed properties of the preBötC that were not predicted and cannot be readily accounted for in current models of preBötC pattern generation. In freely moving mice, prolonged photostimulation decreased f in normoxia, hypoxia or hypercapnia, and increased Amp and produced a phase advance, which was similar to the results in anaesthetized mice when f ≥ 2.5 Hz. We conclude that preBötC SST⁺ neurons are a key mediator of the extraordinary and essential lability of breathing pattern.
Key points
PreBötzinger complex (preBötC) SST⁺ neurons, which modulate respiratory pattern but are not rhythmogenic, were transfected with channelrhodopsin to investigate phase‐ and state‐dependent modulation of breathing pattern in anaesthetized and freely behaving mice in normoxia, hypoxia and hypercapnia.
In anaesthetized mice, photostimulation during inspiration increased inspiratory duration and amplitude regardless of baseline f, yet the effects were more robust at higher f.
In anaesthetized mice with low f (<2.5 Hz), photostimulation during expiration evoked either phase advance or phase delay, whereas in anaesthetized mice with high f (≥2.5 Hz) and in freely behaving mice in normoxia, hypoxia or hypercapnia, photostimulation always evoked phase advance.
Phase‐ and state‐dependency is a function of overall breathing network excitability.
The f‐dependent probabilistic modulation of breathing pattern by preBötC SST⁺ neurons was unexpected, requiring reconsideration of current models of preBötC function, which neither predict nor can readily account for such responses.
Introduction
Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder characterised by repeated narrowing and closure of the upper airway during sleep. Despite growing evidence that dysphagia is a frequent sequela of OSA, the role of speech-language pathologists (SLPs) in managing OSA remains unclear. The aim of this international study was to evaluate SLPs knowledge, attitudes, and experience of OSA.
Methods
A validated questionnaire, OSA Knowledge and Attitudes (OSAKA), was distributed to SLPs internationally via an online survey. Additional information on demographics, educational history, and clinical practices was ascertained.
Results
From a total of 1647 respondents, 822 clinicians from twenty-four countries were included in the final analysis. Knowledge of OSA among SLPs was limited; the mean (SD) rate of correct answers was 55% (22%). Over half of SLPs reported patients with OSA on their caseload, with the majority of patients referred for dysphagia services. Yet, only half of SLPs reported confidence in their ability to assess or manage dysphagia in patients with OSA. SLPs’ experience of OSA had an effect on their knowledge and attitudes [F (2, 817) = 17.279, p < 0.001].
Conclusions
SLPs are involved in the management of patients with OSA but are practising with limited knowledge and confidence. The findings highlight the need to increase OSA education and training for SLPs. In addition, there is a need for targeted research to increase the evidence base for development of clinical practice guidelines for dysphagia management in patients with OSA.
Purpose
The study of air pressure in the vocal tract is essential to understanding vocal function. Changes in vocal tract shape during different phonatory gestures are hypothesized to produce nonuniform air pressure across lower vocal tract locations. Current methods of air pressure measurement, however, are limited to a single location in the anterior oral cavity. The purposes of this study were (a) to assess the feasibility of a novel method of simultaneously measuring phonatory air pressure at multiple locations across the lower vocal tract using high-resolution pharyngeal manometry (HRM) and (b) to compare pressure across locations and among phonatory tasks.
Method
Two subjects underwent HRM while performing phonatory tasks. A catheter was passed transnasally and air pressure was measured simultaneously at five locations between the velopharyngeal port and the upper esophageal sphincter. Descriptive statistics were calculated for each location by task, and for each task averaged across locations.
Results
HRM was well tolerated, and air pressures from multiple locations in the lower vocal tract were able to be obtained simultaneously. During vocal tract semi-occlusion tasks, air pressures differed by location. Pressures averaged across locations demonstrated a pattern of increasing pressure with increasing semi-occlusion.
Conclusions
HRM is feasible for measuring air pressure simultaneously at multiple locations in the lower vocal tract during phonation with high spatial and temporal resolution, providing rich data to augment understanding of vocal function. The high spatial and temporal resolution yielded by this new method, paired with preliminary evidence that pressures change by location as a function of phonatory task, may be useful in future assays exploring differences in lower vocal tract air pressures between normal and disordered populations.
Quantitative functional anatomy of amniote thoracic and abdominal regions is crucial to understanding constraints on and adaptations for facilitating simultaneous breathing and locomotion. Crocodilians have diverse locomotor modes and variable breathing mechanics facilitated by basal and derived (accessory) muscles. However, the inherent flexibility of these systems is not well studied, and the functional specialisation of the crocodilian trunk is yet to be investigated. Increases in body size and trunk stiffness would be expected to cause a disproportionate increase in muscle force demands and therefore constrain the basal costal aspiration mechanism, necessitating changes in respiratory mechanics. Here, we describe the anatomy of the trunk muscles, their properties that determine muscle performance (mass, length and physiological cross‐sectional area [PCSA]) and investigate their scaling in juvenile Alligator mississippiensis spanning an order of magnitude in body mass (359 g–5.5 kg). Comparatively, the expiratory muscles (transversus abdominis, rectus abdominis, iliocostalis), which compress the trunk, have greater relative PCSA being specialised for greater force‐generating capacity, while the inspiratory muscles (diaphragmaticus, truncocaudalis ischiotruncus, ischiopubis), which create negative internal pressure, have greater relative fascicle lengths, being adapted for greater working range and contraction velocity. Fascicle lengths of the accessory diaphragmaticus scaled with positive allometry in the alligators examined, enhancing contractile capacity, in line with this muscle's ability to modulate both tidal volume and breathing frequency in response to energetic demand during terrestrial locomotion. The iliocostalis, an accessory expiratory muscle, also demonstrated positive allometry in fascicle lengths and mass. All accessory muscles of the infrapubic abdominal wall demonstrated positive allometry in PCSA, which would enhance their force‐generating capacity. Conversely, the basal tetrapod expiratory pump (transversus abdominis) scaled isometrically, which may indicate a decreased reliance on this muscle with ontogeny. Collectively, these findings would support existing anecdotal evidence that crocodilians shift their breathing mechanics as they increase in size. Furthermore, the functional specialisation of the diaphragmaticus and compliance of the body wall in the lumbar region against which it works may contribute to low‐cost breathing in crocodilians. The figure shows the head and upper torso of an American alligator.
Background
Epidemiology of dysphagia and its drivers in obstructive sleep apnea (OSA) are poorly understood. The study aims to investigate the prevalence of dysphagia symptoms and their association with demographic and clinical factors in patients with OSA.
Methods
Patients with OSA referring to an Academic Sleep Outpatient Clinic were enrolled in a prospective study. Demographic, clinical characteristics, and OSA symptoms were collected. All patients underwent home sleep cardiorespiratory polygraphy and the Eating-Assessment Tool questionnaire (EAT-10) to investigate dysphagia symptoms. Patients with a positive EAT-10 were offered to undergo a fiberoptic endoscopic evaluation of swallowing (FEES) to confirm the presence of dysphagia. FEES findings were compared with a healthy control group. Univariate and multivariate analyses were performed to assess predictors of dysphagia.
Results
951 patients with OSA (70% males, age 62 IQR51-71) completed the EAT-10, and 141 (15%) reported symptoms of dysphagia. Female gender (OR = 2.31), excessive daily sleepiness (OR = 2.24), number of OSA symptoms (OR = 1.25), anxiety/depression (OR = 1.89), and symptoms of gastroesophageal reflux (OR = 2.75) were significantly (p < 0.05) associated with dysphagia symptoms. Dysphagia was confirmed in 34 out of 35 symptomatic patients that accepted to undergo FEES. Patients with OSA exhibited lower bolus location at swallow onset, greater pharyngeal residue, and higher frequency and severity of penetration and aspiration events than healthy subjects (p < 0.05).
Conclusion
A consistent number of patients with OSA show symptoms of dysphagia, which are increased in females and patients with a greater OSA symptomatology, anxiety and depression, and gastroesophageal reflux. The EAT-10 appears a useful tool to guide the selection of patients at high risk of dysphagia. In clinical practice, the integration of screening for dysphagia in patients with OSA appears advisable.
Swallow is a primitive behavior regulated by medullary networks, responsible for movement of food/liquid from the oral cavity to the esophagus. To investigate how functionally heterogeneous networks along the medullary intermediate reticular formation (IRt) and ventral respiratory column (VRC) control swallow, we electrically stimulated the nucleus tractus solitarius to induce fictive swallow between inspiratory bursts, with concurrent optical recordings using a synthetic Ca ²⁺ indicator in the sagittally-sectioned rat hindbrain preparation (SSRH). Simultaneous recordings from hypoglossal nerve rootlet (XIIn) and ventral cervical spinal root C1-C2 enabled identification of the system-level correlates of A) swallow (identified as activation of the XIIn but not the cervical root), and B) Breuer-Hering expiratory reflex (BHE: lengthened E in response to stimuli during E). Optical recording revealed reconfiguration of respiration-modulated networks in the ventrolateral medulla during swallow and the BHE reflex. Recordings identified novel spatially compact networks in the IRt near the facial nucleus (VIIn) that were active during fictive swallow, suggesting that the swallow network is not restricted to the caudal medulla. These findings also establish the utility of using this in vitro preparation to investigate how functionally heterogeneous medullary networks interact and reconfigure to enable a repertoire of orofacial behaviors.
The mammalian vocal pattern generator is situated in the brainstem but its exact structure is debated. We mapped these circuits in rats by cooling and microstimulation. Local cooling disrupted call production above an anterior and a posterior brainstem position. Anterior cooling affected predominantly high frequency calls, whereas posterior cooling affected low frequency calls. Electrical microstimulation of the anterior part led to modulated high frequency calls, whereas microstimulation of the posterior part led to flat, low frequency calls. At intermediate positions cooling did not affect calls and stimulation did not elicit calls. The anterior region corresponds to a subsection of the parvicellular reticular formation that we term the vocalization parvicellular reticular formation (VoPaRt). The posterior vocalization sites coincide with the nucleus retroambiguus (NRA). VoPaRt and NRA neurons were very small and the VoPaRt was highly myelinated, suggestive of high-speed processing. Our data suggest an anatomically and functionally bipartite vocal pattern generator.
Afferent feedback can appreciably alter the pharyngeal phase of swallow. In order to measure the stability of the swallow motor pattern during several types of alterations in afferent feedback, we assessed swallow during a conventional water challenge in four anesthetized cats, and compared that to swallows induced by fixed (20 Hz) and stochastic (1-20Hz) electrical stimulation applied to the superior laryngeal nerve. The swallow motor patterns were evaluated by electromyographic activity (EMG) of eight muscles, based on their functional significance: laryngeal elevators (mylohyoid, geniohyoid, and thyrohyoid); laryngeal adductor (thyroarytenoid); inferior pharyngeal constrictor (thyropharyngeus); upper esophageal sphincter (cricopharyngeus); and inspiratory activity (parasternal and costal diaphragm). Both the fixed and stochastic electrical stimulation paradigms increased activity of the laryngeal elevators, produced short-term facilitation evidenced by increasing swallow durations over the stimulus period, and conversely inhibited swallow-related diaphragm activity. Both the fixed and stochastic stimulus conditions also increased specific EMG amplitudes, which never occurred with the water challenges. Stochastic stimulation increased swallow excitability, as measured by an increase in the number of swallows produced. Consistent with our previous results, changes in the swallow motor pattern for pairs of muscles were only sometimes correlated with each other. We conclude that alterations in afferent feedback produced particular variations of the swallow motor pattern. We hypothesize that specific SLN feedback might modulate the swallow central pattern generator during aberrant feeding conditions (food/liquid entering the airway), which may protect the airway and serve as potentially important clinical diagnostic indicators.
Objectives
The purpose of this systematic review was to summarize and qualitatively analyze published evidence elucidating the prevalence of dysphagia and detail alterations in swallowing function in patients with OSAS.
Methods
Computerized literature searches were performed from four search engines. The studies were selected based on the inclusion and exclusion criteria. The studies were screened using Covidence (Cochrane tool) and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement standards (PRISMA-2009). A total 2645 studies were initially retrieved, of which a total of 17 studies met inclusion criteria. Two reviewers, blinded to each other, evaluated level and strength of evidence using the Oxford Centre for Evidence-based Medicine Levels of Evidence and QualSyst, respectively.
Results
Dysphagia prevalence ranged from 16 to 78% among the eligible studies. Studies varied in operational definitions defining swallowing dysfunction (dysphagia) and method used to assess swallowing function. Approximately 70% of eligible studies demonstrated strong methodological quality. The majority of studies (n = 11; 65%) reported pharyngeal swallowing impairments in patients with OSAS, including delayed initiation of pharyngeal swallow and penetration/aspiration.
Conclusion
This systematic review describes swallowing function in patients with OSAS. However, due to the variability in defining OSAS and dysphagia, in the assessment method used to determine dysphagia, and heterogeneity of study designs, true prevalence is difficult to determine. Clinicians involved in the management of OSAS patients should employ validated assessment measures to determine if swallow dysfunction is present.
Introduction:
There is evidence that trauma caused by snoring in the pharynx could result in dysphagia in patients with obstructive sleep apnea, but the literature is still scarce to define the factors associated with the presence of dysphagia in these patients.
Aim:
To analyze the occurrence of dysphagia and its clinical and polysomnographic features in patients with moderate and severe obstructive sleep apnea, in addition to verifying the impact of dysphagia on the quality of life of these patients.
Methods:
Seventy patients with moderate or severe apnea (apnea and hypopnea index - AHI>15/hour) were selected. The patients underwent a sleep questionnaire, a quality of life in dysphagia questionnaire and a fiberoptic endoscopic evaluation of swallowing.
Results:
A total of 70 patients were included in the study, of which 49 were men (70 %), with a mean age of 48.9 years. The fiberoptic endoscopic evaluation of swallowing was altered in 27.3 % and the most frequent alteration was the premature oral leakage with fluid. Comparing the groups with and without dysphagia, the female gender was the only clinical parameter that showed a trend of statistical significance in the group with dysphagia (p=0.069). There was no statistical difference regarding the polysomnographic features and in the global quality of life score in dysphagia in the comparison between the groups.
Conclusions:
The presence of dysphagia in patients with moderate to severe apnea is frequent and subclinical, reinforcing the need to investigate this symptom in this group of patients. However, the presence of dysphagia did not result in worsening in patients' quality of life, suggesting that, although frequent, its effect is mild. There was no relevance regarding the association of clinical and polysomnographic parameters with the presence of dysphagia.
Background
Swallowing impairment (dysphagia) has been associated with COPD and may contribute to exacerbations of this chronic and progressive disease. Further, risk of mortality increases with concomitant presence of cachexia in the COPD population. The purpose of this prospective study was to depict oropharyngeal swallowing physiology in underweight patients with stable but advanced-stage COPD.
Patients and methods
Ten underweight patients with stable but advanced COPD underwent a modified barium swallow study. Analysis of oropharyngeal swallowing function was completed using the standardized Modified Barium Swallow Impairment Profile and the Penetration–Aspiration Scale. Scores from the Dysphagia Handicap Index and 10-item Eating Assessment Tool were collected to assess patient perception of swallowing difficulty. Findings were compared to age- and sex-matched healthy controls.
Results
Significantly higher MBSImP oral total scores (P=0.007) were observed in COPD patients compared to matched controls, but no difference was observed in pharyngeal total scores (P=0.105). Patients with COPD had significantly higher maximum PAS scores compared with controls (P=0.030). There was no significant difference in EAT-10 or DHI scores between patients with COPD and controls (P=0.41 and P=0.08, respectively).
Conclusion
Underweight patients with severe but stable COPD present with dysphagia that may not be recognized by the patient. Further investigation is needed to elucidate the interaction between the respiratory–swallowing systems, how muscular weakness may contribute to swallowing impairment, and responsiveness to swallowing treatment.
The brainstem pre-Bötzinger complex (preBötC) generates inspiratory breathing rhythms, but which neurons comprise its rhythmogenic core? Dbx1-derived neurons may play the preeminent role in rhythm generation, an idea well founded at perinatal stages of development but incompletely evaluated in adulthood. We expressed archaerhodopsin or channelrhodopsin in Dbx1 preBötC neurons in intact adult mice to interrogate their function. Prolonged photoinhibition slowed down or stopped breathing, whereas prolonged photostimulation sped up breathing. Brief inspiratory-phase photoinhibition evoked the next breath earlier than expected, whereas brief expiratory-phase photoinhibition delayed the subsequent breath. Conversely, brief inspiratory-phase photostimulation increased inspiratory duration and delayed the subsequent breath, whereas brief expiratory-phase photostimulation evoked the next breath earlier than expected. Because they govern the frequency and precise timing of breaths in awake adult mice with sensorimotor feedback intact, Dbx1 preBötC neurons constitute an essential core component of the inspiratory oscillator, knowledge directly relevant to human health and physiology.
Cardiac cycle phase is known to modulate processing of simple sensory information. This effect of the heartbeat on brain function is likely exerted via baroreceptors, the neurons sensitive for changes in blood pressure. From baroreceptors, the signal is conveyed all the way to the forebrain and the medial prefrontal cortex. In the two experiments reported, we examined whether learning, as a more complex form of cognition, can be modulated by the cardiac cycle phase. Human participants ( experiment 1) and rabbits ( experiment 2) were trained in trace eyeblink conditioning while neural activity was recorded. The conditioned stimulus was presented contingently with either the systolic or diastolic phase of the cycle. The tone used as the conditioned stimulus evoked amplified responses in both humans (electroencephalogram from “vertex,” Cz) and rabbits (hippocampal CA1 local field potential) when its onset was timed at systole. In humans, the cardiac cycle phase did not affect learning, but rabbits trained at diastole learned significantly better than those trained at a random phase of the cardiac cycle. In summary, our results suggest that neural processing of external stimuli and also learning can be affected by targeting stimuli on the basis of cardiac cycle phase. These findings might be useful in applications aimed at maximizing or minimizing the effects of external stimulation.
NEW & NOTEWORTHY It has been shown that rapid changes in bodily states modulate neural processing of external stimulus in brain. In this study, we show that modulation of neural processing of external stimulus and learning about it depends on the phase of the cardiac cycle. This is a novel finding that can be applied to optimize associative learning.
Breathing is a well-described, vital and surprisingly complex behaviour, with behavioural and physiological outputs that are easy to directly measure. Key neural elements for generating breathing pattern are distinct, compact and form a network amenable to detailed interrogation, promising the imminent discovery of molecular, cellular, synaptic and network mechanisms that give rise to the behaviour. Coupled oscillatory microcircuits make up the rhythmic core of the breathing network. Primary among these is the preBötzinger Complex (preBötC), which is composed of excitatory rhythmogenic interneurons and excitatory and inhibitory pattern-forming interneurons that together produce the essential periodic drive for inspiration. The preBötC coordinates all phases of the breathing cycle, coordinates breathing with orofacial behaviours and strongly influences, and is influenced by, emotion and cognition. Here, we review progress towards cracking the inner workings of this vital core.
The preBötzinger Complex (preBötC), a medullary network critical for breathing, relies on excitatory interneurons to generate the inspiratory rhythm. Yet, half of preBötC neurons are inhibitory, and the role of inhibition in rhythmogenesis remains controversial. Using optogenetics and electrophysiology in vitro and in vivo, we demonstrate that the intrinsic excitability of excitatory neurons is reduced following large depolarizing inspiratory bursts. This refractory period limits the preBötC to very slow breathing frequencies. Inhibition integrated within the network is required to prevent overexcitation of preBötC neurons, thereby regulating the refractory period and allowing rapid breathing. In vivo, sensory feedback inhibition also regulates the refractory period, and in slowly breathing mice with sensory feedback removed, activity of inhibitory, but not excitatory, neurons restores breathing to physiological frequencies. We conclude that excitation and inhibition are interdependent for the breathing rhythm, because inhibition permits physiological preBötC bursting by controlling refractory properties of excitatory neurons.
Breathing is vital for survival but also interesting from the perspective of rhythm generation. This rhythmic behavior is generated within the brainstem and is thought to emerge through the interaction between independent oscillatory neuronal networks. In mammals, breathing is composed of three phases – inspiration, post-inspiration, and active expiration – and this article discusses the concept that each phase is generated by anatomically distinct rhythm-generating networks: the preBötzinger complex (preBötC), the post-inspiratory complex (PiCo), and the lateral parafacial nucleus (pF L), respectively. The preBötC was first discovered 25 years ago and was shown to be both necessary and sufficient for the generation of inspiration. More recently, networks have been described that are responsible for post-inspiration and active expiration. Here, we attempt to collate the current knowledge and hypotheses regarding how respiratory rhythms are generated, the role that inhibition plays, and the interactions between the medullary networks. Our considerations may have implications for rhythm generation in general.
The objectives of this study are to investigate swallowing and its coordination with respiration in patients with obstructive sleep apnea (OSA). This is a prospective cohort study conducted in a tertiary referred Medical Center. A non-invasive method of assessing swallowing was used to detect the oropharyngeal swallowing parameters and the coordination with respiration during swallowing. The system used to assess swallowing detected: (1) movement of the larynx using a force-sensing resistor; (2) submental muscle activity using surface electromyography; and (3) coordination with respiration by measuring nasal airflow. Five sizes of water boluses (maximum 20 mL) were swallowed three times, and the data recorded and analyzed for each participant. Thirty-nine normal controls and 35 patients with OSA who fulfilled the inclusion criteria were recruited. The oropharyngeal swallowing parameters of the patients differed from the controls, including longer total excursion duration and shorter duration of submental muscles contraction. A longer swallowing respiratory pause (SRP), temporary coordination with respiration during swallowing, was demonstrated in the patients compared with the controls. The frequency of non-expiratory/expiratory pre- and postswallowing respiratory phase patterns of the patients was similar with the controls. There was significantly more piecemeal deglutition in OSA patients when clumping 10- and 20-mL water boluses swallowing together (p = 0.048). Oropharyngeal swallowing and coordination with respiration affected patients with OSA, and it could be detected using a non-invasive method. The results of this study may serve as a baseline for further research and help advance research methods in obstructive sleep apnea swallowing studies.
Background:
We hypothesized that obstructive sleep apnea (OSA) can predispose individuals to lower airway infections and community-acquired pneumonia (CAP) due to upper airway microaspiration. This study evaluated the association between OSA and CAP.
Methods:
We performed a case-control study that included 82 patients with CAP and 41 patients with other infections (control group). The controls were matched according to age, sex and body mass index (BMI). A respiratory polygraph (RP) was performed upon admission for patients in both groups. The severity of pneumonia was assessed according to the Pneumonia Severity Index (PSI). The associations between CAP and the Epworth Sleepiness Scale (ESS), OSA, OSA severity and other sleep-related variables were evaluated using logistic regression models. The associations between OSA, OSA severity with CAP severity were evaluated with linear regression models and non-parametric tests.
Findings:
No significant differences were found between CAP and control patients regarding anthropometric variables, toxic habits and risk factors for CAP. Patients with OSA, defined as individuals with an Apnea-Hypopnea Index (AHI) ≥10, showed an increased risk of CAP (OR = 2·86, 95%CI 1·29-6·44, p = 0·01). Patients with severe OSA (AHI≥30) also had a higher risk of CAP (OR = 3·18, 95%CI 1·11-11·56, p = 0·047). In addition, OSA severity, defined according to the AHI quartile, was also significantly associated with CAP (p = 0·007). Furthermore, OSA was significantly associated with CAP severity (p = 0·0002), and OSA severity was also associated with CAP severity (p = 0·0006).
Conclusions:
OSA and OSA severity are associated with CAP when compared to patients admitted to the hospital for non-respiratory infections. In addition, OSA and OSA severity are associated with CAP severity. These results support the potential role of OSA in the pathogenesis of CAP and could have clinical implications. This link between OSA and infection risk should be explored to investigate the relationships among gastroesophageal reflux, silent aspiration, laryngeal sensory dysfunction and CAP.
Trial registration:
ClinicalTrials.gov NCT01071421.
Chronic intermittent hypoxia (CIH) is a common state experienced in several breathing disorders, including obstructive sleep apnea (OSA) and apneas of prematurity. Unraveling how CIH affects the CNS, and in turn how the CNS contributes to apneas is perhaps the most challenging task. The preBötzinger complex (preBötC) is a pre-motor respiratory network critical for inspiratory rhythm generation. Here, we test the hypothesis that CIH increases irregular output from the isolated preBötC, which can be mitigated by antioxidant treatment. Electrophysiological recordings from brainstem slices revealed that CIH enhanced burst-to-burst irregularity in period and/or amplitude. Irregularities represented a change in individual fidelity among preBötC neurons, and changed transmission from preBötC to the hypoglossal motor nucleus (XIIn), which resulted in increased transmission failure to XIIn. CIH increased the degree of lipid peroxidation in the preBötC and treatment with the antioxidant, 5,10,15,20-Tetrakis (1-methylpyridinium-4-yl)-21H,23H-porphyrin manganese(III) pentachloride (MnTMPyP), reduced CIH-mediated irregularities on the network rhythm and improved transmission of preBötC to the XIIn. These findings suggest that CIH promotes a pro-oxidant state that destabilizes rhythmogenesis originating from the preBötC and changes the local rhythm generating circuit which in turn, can lead to intermittent transmission failure to the XIIn. We propose that these CIH-mediated effects represent a part of the central mechanism that may perpetuate apneas and respiratory instability, which are hallmark traits in several dysautonomic conditions.
Vocalizations as mews and cries in cats or crying and laughter in humans are examples of expression of emotions. These vocalizations are generated by the emotional motor system, in which the mesencephalic periaqueductal gray (PAG) plays a central role as demonstrated by the fact that lesions in the PAG lead to complete mutism in cats, monkeys as well as in humans. The PAG receives strong projections from higher limbic regions and from the anterior cingulate, insula and orbitofrontal cortical areas. In turn, the PAG has strong access to the caudal medullary nucleus retroambiguus (Schadt et al.). The NRA is the only cell group that has direct access to the motoneurons involved in vocalization, i.e. the motoneuronal cell groups innervating soft palate, pharynx and larynx as well as diaphragm, intercostal, abdominal and pelvic floor muscles. Together they determine the intra-abdominal, intra-thoracic and subglottic pressure, control of which is necessary for generating vocalization. Only humans can speak, because, via the lateral component of the volitional or somatic motor system, they are able to modulate vocalization into words and sentences. For this modulation they use their motor cortex, which, via its cortico-bulbar fibers, has direct access to the motoneurons innervating the muscles of face, mouth, tongue, larynx and pharynx. In conclusion, humans generate speech by activating two motor systems. They generate vocalization by activating the prefrontal-PAG-NRA-motoneuronal pathway, and, at the same time, they modulate this vocalization into words and sentences by activating the cortico-bulbar fibers to the face, mouth, tongue, larynx and pharynx motoneurons. This article is protected by copyright. All rights reserved.
Although previous studies demonstrated that patients with obstructive sleep apnea syndrome (OSAS) may present subclinical manifestations of dysphagia, in not one were different textures and volumes systematically studied. The aim of this study was to analyze the signs and symptoms of oropharyngeal dysphagia using fiberoptic endoscopic evaluation of swallowing (FEES) with boluses of different textures and volumes in a large cohort of patients with OSAS. A total of 72 OSAS patients without symptoms of dysphagia were enrolled. The cohort was divided in two groups: 30 patients with moderate OSAS and 42 patients with severe OSAS. Each patient underwent a FEES examination using 5, 10 and 20 ml of liquids and semisolids, and solids. Spillage, penetration, aspiration, retention, and piecemeal deglutition were considered. The penetration-aspiration scale (PAS), pooling score (PS), and dysphagia outcome and severity scale (DOSS) were used for quantitative analysis. Each patient completed the SWAL-QOL questionnaire. Forty-six patients (64 %) presented spillage, 20 (28 %) piecemeal deglutition, 26 (36 %) penetration, and 30 (44 %) retention. No differences were found in the PAS, PS, and DOSS scores between patients with moderate and severe OSAS. Patients with severe OSAS scored higher General Burden and Food selection subscales of the SWAL-QOL. Depending on the DOSS score, the cohort of patients was divided into those with and those without signs of dysphagia. Patients with signs of dysphagia scored lower in the General Burden and Symptoms subscales of the SWAL-QOL. OSAS patients show signs of swallowing impairment in about half of the population; clinicians involved in the management of these patients should include questions on swallowing when taking the medical history.
In the mammalian respiratory central pattern generator, the preBötzinger complex (preBötC) produces rhythmic bursts that drive inspiratory motor output. Cellular mechanisms initiated by each burst are hypothesized to be necessary to determine the timing of the subsequent burst, playing a critical role in rhythmogenesis. To explore mechanisms relating inspiratory burst generation to rhythmogenesis, we compared preBötC and hypoglossal (XII) nerve motor activity in medullary slices from neonatal mice in conditions where periods between successive inspiratory XII bursts were highly variable and distributed multimodally. This pattern resulted from rhythmic preBötC neural population activity that consisted of bursts, concurrent with XII bursts, intermingled with significantly smaller "burstlets". Burstlets occurred at regular intervals during significantly longer XII interburst intervals, at times when a XII burst was expected. When a preBötC burst occurred, its high amplitude inspiratory component (I-burst) was preceded by a preinspiratory component that closely resembled the rising phase of burstlets. Cadmium (8 μm) eliminated preBötC and XII bursts, but rhythmic preBötC burstlets persisted. Burstlets and preinspiratory activity were observed in ∼90% of preBötC neurons that were active during I-bursts. When preBötC excitability was raised significantly, burstlets could leak through to motor output in medullary slices and in vivo in adult anesthetized rats. Thus, rhythmic bursting, a fundamental mode of nervous system activity and an essential element of breathing, can be deconstructed into a rhythmogenic process producing low amplitude burstlets and preinspiratory activity that determine timing, and a pattern-generating process producing suprathreshold I-bursts essential for motor output.
The medullary reticular formation contains large populations of inadequately described, excitatory interneurons that have been implicated in multiple homeostatic behaviors including breathing, viserosensory processing, vascular tone, and pain. Many hindbrain nuclei show a highly stereotyped pattern of localization across vertebrates suggesting a strong underlying genetic organization. Whether this is true for neurons within the reticular regions of hindbrain is unknown. Hindbrain neurons are derived from distinct developmental progenitor domains each of which expresses distinct patterns of transcription factors (TFs). These neuronal populations have distinct characteristics such as transmitter identity, migration, and connectivity suggesting developmentally expressed TFs might identify unique subpopulations of neurons within the reticular formation. A fate-mapping strategy using perinatal expression of reporter genes within Atoh1, Dbx1, Lmx1b, and Ptf1a transgenic mice coupled with immunohistochemistry (IHC) and in situ hybridization (ISH) were used to address the developmental organization of a large subset of reticular formation glutamatergic neurons. All hindbrain lineages have relatively large populations that extend the entire length of the hindbrain. Importantly, the location of neurons within each lineage was highly constrained. Lmx1b- and Dbx1- derived populations were both present in partially overlapping stripes within the reticular formation extending from dorsal to ventral brain. Within each lineage, distinct patterns of gene expression and organization were localized to specific hindbrain regions. Rostro-caudally sub-populations differ sequentially corresponding to proposed pseudo-rhombomereic boundaries. Dorsal-ventrally, sub-populations correspond to specific migratory positions. Together these data suggests the reticular formation is organized by a highly stereotyped developmental logic.
Key points
The transcription factor Dbx1 gives rise to putatively respiratory rhythm‐generating neurons in the pre‐Bötzinger complex. Comparative analysis of Dbx1 ‐derived ( Dbx1 ⁺ ) and non‐ Dbx1 ‐ derived ( Dbx1 ⁻ ) neurons can help elucidate the cellular bases of respiratory rhythm generation.
In vitro , Dbx1 ⁺ neurons activate earlier in the respiratory cycle, discharge larger magnitude inspiratory bursts and exhibit a lower rheobase compared with Dbx1 ⁻ neurons.
The Dbx1 ⁺ neurons tend to express the intrinsic currents I A (transient outward A‐current) and I h (hyperpolarization‐activated current) in diametric opposition, which may facilitate temporal summation of excitatory synaptic inputs, whereas the Dbx1 ⁻ neurons show no significant pattern of expression regarding I A and I h .
The Dbx1 ⁺ neurons exhibit smooth, spineless dendrites that project in the transverse plane, whereas the Dbx1 ⁻ neurons are confined to the transverse plane to a lesser extent and sometimes exhibit spines.
The properties of Dbx1 ⁺ neurons that may contribute to respiratory rhythmogenesis include a high level of excitability linked to ongoing network activity and dendritic properties that may facilitate synaptic integration.
Abstract Breathing in mammals depends on an inspiratory‐related rhythm that is generated by glutamatergic neurons in the pre‐Bötzinger complex (preBötC) of the lower brainstem. A substantial subset of putative rhythm‐generating preBötC neurons derive from a single genetic line that expresses the transcription factor Dbx1 , but the cellular mechanisms of rhythmogenesis remain incompletely understood. To elucidate these mechanisms, we carried out a comparative analysis of Dbx1 ‐expressing neurons ( Dbx1 ⁺ ) and non‐ Dbx1 ‐derived ( Dbx1 ⁻ ) neurons in the preBötC. Whole‐cell recordings in rhythmically active newborn mouse slice preparations showed that Dbx1 ⁺ neurons activate earlier in the respiratory cycle and discharge greater magnitude inspiratory bursts compared with Dbx1 ⁻ neurons. Furthermore, Dbx1 ⁺ neurons required less input current to discharge spikes (rheobase) in the context of network activity. The expression of intrinsic membrane properties indicative of A‐current ( I A ) and hyperpolarization‐activated current ( I h ) tended to be mutually exclusive in Dbx1 ⁺ neurons. In contrast, there was no such relationship in the expression of currents I A and I h in Dbx1 ⁻ neurons. Confocal imaging and digital morphological reconstruction of recorded neurons revealed dendritic spines on Dbx1 ⁻ neurons, but Dbx1 ⁺ neurons were spineless. The morphology of Dbx1 ⁺ neurons was largely confined to the transverse plane, whereas Dbx1 ⁻ neurons projected dendrites to a greater extent in the parasagittal plane. The putative rhythmogenic nature of Dbx1 ⁺ neurons may be attributable, in part, to a higher level of intrinsic excitability in the context of network synaptic activity. Furthermore, Dbx1 ⁺ neuronal morphology may facilitate temporal summation and integration of local synaptic inputs from other Dbx1 ⁺ neurons, taking place largely in the dendrites, which could be important for initiating and maintaining bursts and synchronizing activity during the inspiratory phase.
Cell type-specific expression of optogenetic molecules allows temporally precise manipulation of targeted neuronal activity. Here we present a toolbox of four knock-in mouse lines engineered for strong, Cre-dependent expression of channelrhodopsins ChR2-tdTomato and ChR2-EYFP, halorhodopsin eNpHR3.0 and archaerhodopsin Arch-ER2. All four transgenes mediated Cre-dependent, robust activation or silencing of cortical pyramidal neurons in vitro and in vivo upon light stimulation, with ChR2-EYFP and Arch-ER2 demonstrating light sensitivity approaching that of in utero or virally transduced neurons. We further show specific photoactivation of parvalbumin-positive interneurons in behaving ChR2-EYFP reporter mice. The robust, consistent and inducible nature of our ChR2 mice represents a significant advance over previous lines, and the Arch-ER2 and eNpHR3.0 mice are to our knowledge the first demonstration of successful conditional transgenic optogenetic silencing. When combined with the hundreds of available Cre driver lines, this optimized toolbox of reporter mice will enable widespread investigations of neural circuit function with unprecedented reliability and accuracy.
Huntington's disease (HD) is a progressive neurodegenerative autosomal dominant disease characterized by choreatic and hypokinetic movements, disturbed behaviour, and cognitive decline. Pneumonia is the most common cause of death, followed by cardiovasculair diseases. It has been suggested that choking is the causative underlying factor for pneumonia in HD. As a detailed specification of the type of pneumonia has never been performed, we analyzed the records of our Brain Bank containing 224 cases to determine the exact cause of death and type of pneumonia. The conclusion is that the majority (86.8%) of our HD patients where the cause of death could be identified died from aspiration pneumonia.
A subset of preBötzinger Complex (preBötC) neurokinin 1 receptor (NK1R) and somatostatin peptide (SST)-expressing neurons are necessary for breathing in adult rats, in vivo. Their developmental origins and relationship to other preBötC glutamatergic neurons are unknown. Here we show, in mice, that the "core" of preBötC SST(+)/NK1R(+)/SST 2a receptor(+) (SST2aR) neurons, are derived from Dbx1-expressing progenitors. We also show that Dbx1-derived neurons heterogeneously coexpress NK1R and SST2aR within and beyond the borders of preBötC. More striking, we find that nearly all non-catecholaminergic glutamatergic neurons of the ventrolateral medulla (VLM) are also Dbx1 derived. PreBötC SST(+) neurons are born between E9.5 and E11.5 in the same proportion as non-SST-expressing neurons. Additionally, preBötC Dbx1 neurons are respiratory modulated and show an early inspiratory phase of firing in rhythmically active slice preparations. Loss of Dbx1 eliminates all glutamatergic neurons from the respiratory VLM including preBötC NK1R(+)/SST(+) neurons. Dbx1 mutant mice do not express any spontaneous respiratory behaviors in vivo. Moreover, they do not generate rhythmic inspiratory activity in isolated en bloc preparations even after acidic or serotonergic stimulation. These data indicate that preBötC core neurons represent a subset of a larger, more heterogeneous population of VLM Dbx1-derived neurons. These data indicate that Dbx1-derived neurons are essential for the expression and, we hypothesize, are responsible for the generation of respiratory behavior both in vitro and in vivo.
Breathing is a bilaterally synchronous behavior that relies on a respiratory rhythm generator located in the brainstem. An essential component of this generator is the preBötzinger complex (preBötC), which paces inspirations. Little is known about the developmental origin of the interneuronal populations forming the preBötC oscillator network. We found that the homeobox gene Dbx1 controls the fate of glutamatergic interneurons required for preBötC rhythm generation in the mouse embryo. We also found that a conditional inactivation in Dbx1-derived cells of the roundabout homolog 3 (Robo3) gene, which is necessary for axonal midline crossing, resulted in left-right de-synchronization of the preBötC oscillator. Together, these findings identify Dbx1-derived interneurons as the core rhythmogenic elements of the preBötC oscillator and indicate that Robo3-dependent guidance signaling in these cells is required for bilaterally synchronous activity.
Neuronal activity in the respiratory network is functionally dependent on inhibitory synaptic transmission. Using two-photon excitation microscopy, we analyzed the integration of glycinergic neurons in the isolated inspiratory pre-Bötzinger complex-driven network of the rhythmic slice preparation. Inspiratory (96%) and ‘tonic’ expiratory neurons (4%) were identified via an increase or decrease, respectively, of the cytosolic free calcium concentration during the inspiratory-related respiratory burst. Furthermore, in BAC-transgenic mice expressing EGFP under the control of the GlyT2-promoter, 50% of calcium-imaged inspiratory neurons were glycinergic. Inspiratory bursting of glycinergic neurons in the slice was confirmed by whole-cell recording. We also found glycinergic neurons that receive phasic inhibition from other glycinergic neurons. Our calcium imaging data show that glycinergic neurons comprise a large population of inspiratory neurons in the pre-Bötzinger complex-driven network of the rhythmic slice preparation.
Electronic supplementary material
The online version of this article (doi:10.1007/s00424-009-0647-1) contains supplementary material, which is available to authorized users.
Temporal coupling between theta and gamma oscillations is a hallmark activity pattern of several cortical networks and becomes especially prominent during REM sleep. In a parallel approach, nasal breathing has been recently shown to generate phase-entrained network oscillations which also modulate gamma. Both slow rhythms (theta and respiration-entrained oscillations) have been suggested to aid large-scale integration but they differ in frequency, display low coherence, and modulate different gamma sub-bands. Respiration and theta are therefore believed to be largely independent. In the present work, however, we report an unexpected but robust relation between theta-gamma coupling and respiration in mice. Interestingly, this relation takes place not through the phase of individual respiration cycles, but through respiration rate: the strength of theta-gamma coupling exhibits an inverted V-shaped dependence on breathing rate, leading to maximal coupling at breathing frequencies of 4-6 Hz. Noteworthy, when subdividing sleep epochs into phasic and tonic REM patterns, we find that breathing differentially relates to theta-gamma coupling in each state, providing new evidence for their physiological distinctiveness. Altogether, our results reveal that breathing correlates with brain activity not only through phase-entrainment but also through rate-dependent relations with theta-gamma coupling. Thus, the link between respiration and other patterns of cortical network activity is more complex than previously assumed.
Nasal breathing generates a rhythmic signal which entrains cortical network oscillations in widespread brain regions on a cycle-to-cycle time scale. It is unknown, however, how respiration and neuronal network activity interact on a larger time scale: are breathing frequency and typical neuronal oscillation patterns correlated? Is there any directionality or temporal relationship? To address these questions, we recorded field potentials from the posterior parietal cortex of mice together with respiration during REM sleep. In this state, the parietal cortex exhibits prominent θ and γ oscillations while behavioral activity is minimal, reducing confounding signals. We found that the instantaneous breathing frequency strongly correlates with the instantaneous frequency and amplitude of both θ and γ oscillations. Cross-correlograms and Granger causality revealed specific directionalities for different rhythms: changes in θ activity precede and Granger-cause changes in breathing frequency, suggesting control by the functional state of the brain. On the other hand, the instantaneous breathing frequency Granger causes changes in γ frequency, suggesting that γ is influenced by a peripheral reafference signal. These findings show that changes in breathing frequency temporally relate to changes in different patterns of rhythmic brain activity. We hypothesize that such temporal relations are mediated by a common central drive likely to be located in the brainstem.
We assessed the mechanism of mammalian breathing rhythmogenesis in the preBötzinger complex (preBötC) in vitro, where experimental tests remain inconsistent with hypotheses of canonical rhythmogenic cellular or synaptic mechanisms, i.e., pacemaker neurons or inhibition. Under rhythmic conditions, in each cycle, an inspiratory burst emerges as (presumptive) preBötC rhythmogenic neurons transition from aperiodic uncorrelated population spike activity to become increasingly synchronized during preinspiration (for ∼50–500 ms), which can trigger inspiratory bursts that propagate to motoneurons. In nonrhythmic conditions, antagonizing GABAA receptors can initiate this synchronization while inducing a higher conductance state in nonrhythmogenic preBötC output neurons. Our analyses uncover salient features of preBötC network dynamics where inspiratory bursts arise when and only when the preBötC rhythmogenic subpopulation strongly synchronizes to drive output neurons. Furthermore, downstream propagation of preBötC network activity, ultimately to motoneurons, is dependent on the strength of input synchrony onto preBötC output neurons exemplifying synchronous propagation of network activity.
Rhythmic variation in heart rate and respiratory pattern are coupled in a way that optimizes the level of oxygen in the blood stream of the lungs and the body as well as saves energy in pulmonary gas exchange. It has been suggested that the cardiac cycle and respiratory pattern are coupled to neural oscillations of the brain. Yet, studies on how this rhythmic coupling is related to behavior are scarce. There is some evidence that, for example, the phase of respiration affects memory retrieval and the electrophysiological oscillatory state of the limbic system. It is also known that the phase of the cardiac cycle and hippocampal electrophysiological oscillations alone affect learning. Here, we studied whether the timing of training trials to different phases of respiration affects learning trace eyeblink conditioning in healthy adult humans. Trials consisting of a neutral conditioned stimulus (200‐ms tone) and a slightly aversive unconditioned stimulus (100‐ms air puff toward the eye), presented with a 600‐ms trace interval, were timed to either inspiration or expiration. A control group was trained regardless of respiratory phase. We found that, at the end of training, the rate of conditioned responses was higher in the group trained at expiration than it was in the other two groups. That is, brain state seems to fluctuate as a function of respiratory rhythm, and this fluctuation is also behaviorally relevant, exerting its effect on, at the least, a simple form of associative learning.
Rhythmicity is a universal timing mechanism in the brain, and the rhythmogenic mechanisms are generally dynamic. This is illustrated for the neuronal control of breathing, a behavior that occurs as a one-, two-, or three-phase rhythm. Each breath is assembled stochastically, and increasing evidence suggests that each phase can be generated independently by a dedicated excitatory microcircuit. Within each microcircuit, rhythmicity emerges through three entangled mechanisms: (a) glutamatergic transmission, which is amplified by (b) intrinsic bursting and opposed by (c) concurrent inhibition. This rhythmogenic triangle is dynamically tuned by neuromodulators and other network interactions. The ability of coupled oscillators to reconfigure and recombine may allow breathing to remain robust yet plastic enough to conform to nonventilatory behaviors such as vocalization, swallowing, and coughing. Lessons learned from the respiratory network may translate to other highly dynamic and integrated rhythmic systems, if approached one breath at a time. Expected final online publication date for the Annual Review of Neuroscience Volume 41 is July 8, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
GABA, muscimol, and baclofen were microinjected into the rostral (rNTS) and caudal solitary tract nucleus (cNTS) in 24 anesthetized cats. Electromyograms (EMGs) of diaphragm (DIA) and abdominal muscles (ABD), blood pressure and esophageal pressure (EP) were recorded and analysed. Bilateral microinjections of 1 mM GABA (total 66 ± 4 nl), 1 mM baclofen (64 ± 4 nl) and unilateral microinjections of 0.5 mM muscimol (33 ± 1 nl) in the rNTS significantly reduced cough number (CN), amplitudes of ABD EMGs, expiratory EP, and prolonged the duration of the cough inspiratory phase. GABA microinjections decreased the amplitudes of cough-related DIA EMGs and inspiratory EP; muscimol microinjections decreased the cough DIA EMG on the contralateral side. Only microinjections of GABA into the cNTS suppressed CN. In some cases, microinjections prolonged the inspiratory phase, lowered respiratory rate, changed the depth of breathing, and increased blood pressure and heart rate. Our results confirm that GABA-ergic inhibitory mechanisms in the rNTS can regulate coughing in the anesthetized cat.
Objectives: This study aimed to investigate the prevalence of clinical symptoms related to abnormal swallowing in a large sample of obstructive sleep apnea syndrome (OSAS) patients. Methods:Oropharyngeal symptoms for abnormal swallowing were assessed by a self-administered questionnaire in 507 consecutive patients (females: 65, males: 442; mean age: 49.6 ± 12.6 years old) with clinical symptoms of OSAS, enrolled for cardiorespiratory evaluation. Results:Overall, 16.2% of patients (82/507) had at least one symptom for abnormal swallowing and 6.3% (32/507) had two or more symptoms. The most frequent symptom was difficulty with coughing up phlegm during or after a meal (8.3%). Demographic, sleep, and clinical variables did not differ between the patients with and without abnormal symptoms. Conclusions:The results of the current study showed that 16% of middle-aged OSAS patients reported pharyngeal symptoms related to abnormal swallowing, regardless of the severity of OSAS.
Normal breathing in rodents requires activity of glutamatergic Dbx1-derived (Dbx1+) preBötzinger Complex (preBötC) neurons expressing somatostatin (SST). We combined in vivo optogenetic and pharmacological perturbations to elucidate the functional roles of these neurons in breathing. In transgenic adult mice expressing channelrhodopsin (ChR2) in Dbx1+ neurons, photoresponsive preBötC neurons had preinspiratory or inspiratory firing patterns associated with excitatory effects on burst timing and pattern. In transgenic adult mice expressing ChR2 in SST+ neurons, photoresponsive preBötC neurons had inspiratory or postinspiratory firing patterns associated with excitatory responses on pattern or inhibitory responses that were largely eliminated by blocking synaptic inhibition within preBötC or by local viral infection limiting ChR2 expression to preBötC SST+ neurons. We conclude that: (1) preinspiratory preBötC Dbx1+ neurons are rhythmogenic, (2) inspiratory preBötC Dbx1+ and SST+ neurons primarily act to pattern respiratory motor output, and (3) SST+-neuron-mediated pathways and postsynaptic inhibition within preBötC modulate breathing pattern.
Objective
The aim of this study was to investigate the objective and subjective effectiveness of multilevel surgery, i.e. combined lingualplasty with new technique of partial posterior glossectomy (PPG) and uvulopalatopharyngoplasty in moderate to severe obstructive sleep apnea (OSA) patients.
Study design and setting
Retrospective study of 60 OSA patients undergoing multilevel surgery for the treatment of moderate to severe OSA.
Results
Preoperative mean apnea hypopnea index (AHI) was 57.5 events/h and preoperative mean lowest SpO2 was 79.1%. After multilevel surgery, postoperative mean AHI significantly decreased to 29.7 events/h (p < 0.001) and postoperative mean lowest SpO2 increased to 84.4% (p < 0.001). Patients had postoperative followup assessments for 1 to 3 years. Results of surgery was classified as curative in 35/60 (58.3%) of patients, and as effective, i.e. postoperative AHI less than preoperative AHI in 52/60 patients (86.7 %). Surgery was ineffective in 8/60 (13.3%) patients. Early postoperative complications comprised early velopharyngeal insufficiency (VPI) 20% (12/60), dysarthria 20% (12/60) and wound dehiscence 3.33% (2/60) but without serious complications after 1 year.
Conclusion
Combined lingualplasty (with new PPG) and uvulopalatopharyngoplasty (UPPP) as multilevel surgery can be an effective treatment of choice for patients with moderate to severe OSA. No mediumterm serious complication was found.
Keywords
Apnea hypopnea index, Glossectomy, Lateral pharyngoplasty, Multilevel surgery in obstructive sleep apnea, Obstructive sleep apnea, Uvulopalatoplasty.
How to cite this article
Tungkeeratichai J, Apirakkittikul N, Kunachak S. Multilevel Surgery in Moderate to Severe Obstructive Sleep Apnea Patients. Int J Otorhinolaryngol Clin 2014;6(3):8791.
Key points
Laryngeal adduction is a major mechanism in sealing off entry to the trachea to prevent aspiration during swallowing.
An experimental protocol to reliably elicit sequential swallowing by oral injection of small volumes of water was developed in the in situ perfused brainstem preparation of juvenile rats.
The sequential swallowing motor pattern consists of two distinct components: (i) phasic swallowing, indicated by rhythmic sequential vagal nerve bursting, and (ii) protective laryngeal adduction, indicated by background tonic vagal discharge.
Pharmacological manipulation of the Kölliker–Fuse nucleus revealed that it specifically mediates the protective tonic laryngeal adduction, while GABAergic neurotransmission is needed in the nucleus of the solitary tract for the generation of the sequential swallowing motor pattern.
We conclude that sequential swallow motor patterning, including effective airway protection, requires balanced excitatory–inhibitory synaptic interaction within the nucleus of the solitary tract and the Kölliker–Fuse nucleus, as well as between the two nuclei.
Abstract
Both swallowing and respiration involve postinspiratory laryngeal adduction. Swallowing‐related postinspiratory neurons are likely to be located in the nucleus of the solitary tract (NTS) and those involved in respiration are found in the Kölliker–Fuse nucleus (KF). The function of KF and NTS in the generation of swallowing and its coordination with respiration was investigated in perfused brainstem preparations of juvenile rats ( n = 41). Orally injected water evoked sequential pharyngeal swallowing (s‐PSW) seen as phasic, spindle‐shaped bursting of vagal nerve activity (VNA) against tonic postinspiratory discharge. KF inhibition by microinjecting isoguvacine (GABA A receptor agonist) selectively attenuated tonic postinspiratory VNA ( n = 10, P < 0.001) but had no effect on frequency or timing of s‐PSW. KF disinhibition after bicuculline (GABA A receptor antagonist) microinjections caused an increase of the tonic VNA ( n = 8, P < 0.01) resulting in obscured and delayed phasic s‐PSW. Occurrence of spontaneous PSW significantly increased after KF inhibition ( P < 0.0001) but not after KF disinhibition ( P = 0.14). NTS isoguvacine microinjections attenuated the occurrence of all PSW ( n = 5, P < 0.01). NTS bicuculline microinjections ( n = 6) resulted in spontaneous activation of a disordered PSW pattern and long‐lasting suppression of respiratory activity. Pharmacological manipulation of either KF or NTS also triggered profound changes in respiratory postinspiratory VNA. Our results indicate that the s‐PSW comprises two functionally distinct components. While the primary s‐PSW is generated within the NTS, a KF‐mediated laryngeal adductor reflex safeguards the lower airways from aspiration. Synaptic interaction between KF and NTS is required for s‐PSW coordination with respiration as well as for proper gating and timing of s‐PSW.
Therapy for Parkinson's disease (PD) has been progressing. However, the prognosis for patients with PD is still unclear. We studied the course of PD in patients in the San-in Area of Japan over a long time period. The main purpose of this study was to see whether there was a difference in survival between PD patients and the general population. Information on 114 deceased PD patients, who died between 1989 and 1996, was collected from hospitals belonging to the Tottori University Parkinson's Disease Epidemiology Study Group. Although the duration of illness was prolonged, the survival of PD patients was still poorer than that of the general population. The most common cause of death was pneumonia. The main cause of death in young PD patients was also pneumonia. In order to improve the survival of PD patients, PD-related conditions should be treated more extensively, especially pneumonia.Copyright � 1997 S. Karger AG, Basel
Background:
Reporting of cause of death in patients with Alzheimer's disease (AD) has changed over the past few decades but concerns persist over the accuracy of death certificate completion in this setting.
Objectives:
To examine the causes of death in AD and examine how this compares with those affecting the normal population.
Methods:
Death certificates were obtained for 85 AD patients and 52 control subjects from a cohort of 396 participants. Underlying causes of death and other conditions mentioned on the death certificates of the AD patients were analysed and compared with the Northern Ireland population age-and-sex adjusted mortality rates and subsequently to the death certificates of control subjects.
Results:
AD and pneumonia were causes of significant excess mortality and the most common underlying causes of death in the AD patient group (23.53 and 17.65%, respectively). When compared with the control subjects, AD and gastrointestinal diseases were found to be more prevalent. AD was recorded on 63.5% of death certificates of AD subjects who died during follow-up.
Conclusion:
The cause of death documented for AD patients may be affected by the physician's knowledge of the patient or reflects the approach to management of patients with end-stage dementia.
Swallow is defined as the coordinated neuromuscular activity of the mouth, pharynx, larynx, and esophagus. Movement of a bolus and air must be coordinated by swallow remodeling of the respiratory pattern. The brainstem contains respiratory and swallow neural control networks that generate the pattern for breathing and swallow. Swallow control of respiration is proposed to be through recruitment of swallow neural elements that retask existing respiratory neural network elements. Swallow reconfiguration of the respiratory neural network is fundamental to airway protection and integrated with other airway protective reflexes. Thus, swallow, breathing, cough, and other airway defensive behaviors are produced by a central neural motor system that shares elements. It is hypothesized that swallow and airway defensive behaviors are controlled by a recruited behavioral control assembly system that is organized in a fashion that allows for precise coordination of the expression of these behaviors to maintain airway protection.
Patients with obstructive sleep apnea (OSA) may have subclinical swallowing abnormalities due to progressive mechanical trauma of the pharyngeal tissues caused by snoring. There are few trials on swallowing among OSA patients, and most of them used videoradiography. The aim of this trial was to show swallowing function in OSA patients by nasal fibroscopy.
Eleven patients with OSA diagnosed by polysomnography, with a mean age of 48 ± 14 years, without spontaneous complaints of swallowing, and 14 non-snoring volunteers, with a mean age of 47 ± 12 years, without spontaneous complaints of swallowing, participated in the study. The participants were evaluated using nasal fibroscopy. Each participant was offered diet boluses (5 and 10 ml) such as thin liquids, purée, and solids, and their swallowing function was determined according to the following criteria: (1) premature oral leakage to the pharynx; (2) laryngeal penetration; (3) tracheal aspiration; and (4) pharyngeal stasis.
Sixty-four percent of the OSA patients presented premature oral leakage, 55% presented pharyngeal stasis of the bolus after swallowing, and we did not observe laryngeal penetration or tracheal aspiration. There were no subclinical manifestations in the control group.
OSA patients presented subclinical manifestations of abnormal swallowing, when analyzed using nasal fibroscopy, possibly associated with neuromuscular injury caused by snoring.
The purpose of this retrospective study was to gain insight into the contribution of the dorsolateral pons to the coordination of swallowing and breathing in awake goats. In 4 goats, cannulas were chronically implanted bilaterally through the lateral (LPBN) and medial (MPBN) parabrachial nuclei just dorsal to the Kölliker-Fuse nucleus (KFN). After >2weeks recovery from this surgery, the goats were studied for 5½h on a control day, and on separate days after receiving 1 and 10μl injections of ibotenic acid (IA) separated by 1week. The frequency of swallows did not change during the control and 1μl IA studies, but after injection of 10μl IA, there was a transient 65% increase in frequency of swallows (P<0.05). Under control conditions swallows occurred throughout the respiratory cycle, where late-E swallows accounted for 67.6% of swallows. The distribution of swallow occurrence throughout the respiratory cycle was unaffected by IA injections. Consistent with the concept that swallowing is dominant over breathing, we found that swallows increased inspiratory (T(I)) and expiratory (T(E)) time and decreased tidal volume (V(T)) of the breath of the swallow (n) and/or the subsequent (n+1) breath. Injections of 10μl IA attenuated the normal increases in T(I) and T(E) and further attenuated V(T) of the n breath. Additionally, E and I swallows reset respiratory rhythm, but injection of 1 or 10μl IA progressively attenuated this resetting, suggesting a decreased dominance over respiratory motor output with increasing IA injections. Post mortem histological analysis revealed about 50% fewer (P<0.05) neurons remained in the KFN, LPBN, and MPBN in lesioned compared to control goats. We conclude that dorsolateral pontine nuclei have a modulatory role in a hypothesized holarchical neural network regulating swallowing and breathing particularly contributing to the normal dominance of swallowing over breathing in both rhythm and motor pattern generation.
Drinking and eating are essential skills for survival and benefit from the coordination of several pattern generating networks and their musculoskeletal effectors to achieve safe swallows. Oralpharyngoesophageal motility develops during infancy and early childhood, and is influenced by various factors, including neuromuscular maturation, dietary and postural habits, arousal state, ongoing illnesses, congenital anomalies, and the effects of medical or surgical interventions. Gastroesophageal reflux is frequent in neonates and infants, and its role in neonatal morbidity including dysphagia, chronic lung disease, or apparent life-threatening events is not well understood. This review highlights recent studies aimed at understanding the development of oral feeding skills, and cross-system interactions among the brainstem, spinal, and cerebral networks involved in feeding.
Functional linkages between suck-swallow and swallow-respiration manifest transitional forms during late gestation through the first year of life, which can be delayed or modified by sensory experience or disease processes, or both. Relevant central pattern generator (CPG) networks and their neuromuscular targets attain functional status at different rates, which ultimately influences cross-system CPG interactions. Entrainment of trigeminal primary afferents accelerates pattern genesis for the suck CPG and transition-to-oral feed in the RDS preterm infant.
The genesis of within-system CPG control for rate and amplitude scaling matures differentially for suck, mastication, swallow, and respiration. Cross-system interactions among these CPGs represent targets of opportunity for new interventions, which optimize experience-dependent mechanisms to promote safe swallows among newborn and pediatric patients.