In-vivo optogenetic identification and electrophysiology of glycinergic neurons in pre-Bötzinger complex of mice.

Breathing requires distinct patterns of neuronal activity in the brainstem. The most critical part of the neuronal network responsible for respiratory rhythm generation is the preBötzinger Complex (preBötC), located in the ventrolateral medulla. This area contains both rhythmogenic glutamatergic neurons and also a high number of inhibitory neurons. Here, we aimed to analyze the activity of glycinergic neurons in the preBötC in anesthetized mice. To identify inhibitory neurons, we used a transgenic mouse line that allows expression of Channelrhodopsin 2 in glycinergic neurons. Using juxtacellular recordings and optogenetic activation via a single recording electrode, we were able to identify neurons as inhibitory and define their activity pattern in relation to the breathing rhythm. We could show that the activity pattern of glycinergic respiratory neurons in the preBötC was heterogeneous. Interestingly, only a minority of the identified glycinergic neurons showed a clear phase-locked activity pattern in every respiratory cycle. Taken together, we could show that neuron identification is possible by a combination of juxtacellular recordings and optogenetic activation via a single recording electrode.

"Brain-breath" interactions: respiration-timing-dependent impact on functional brain networks and beyond.

Breathing is a natural daily action that one cannot do without, and it sensitively and intensely changes under various situations. What if this essential act of breathing can impact our overall well-being? Recent studies have demonstrated that breathing oscillations couple with higher brain functions, i.e., perception, motor actions, and cognition. Moreover, the timing of breathing, a phase transition from exhalation to inhalation, modulates specific cortical activity and accuracy in cognitive tasks. To determine possible respiratory roles in attentional and memory processes and functional neural networks, we discussed how breathing interacts with the brain that are measured by electrophysiology and functional neuroimaging: (i) respiration-dependent modulation of mental health and cognition; (ii) respiratory rhythm generation and respiratory pontomedullary networks in the brainstem; (iii) respiration-dependent effects on specific brainstem regions and functional neural networks (e.g., glutamatergic PreBötzinger complex neurons, GABAergic parafacial neurons, adrenergic C1 neurons, parabrachial nucleus, locus coeruleus, temporoparietal junction, default-mode network, ventral attention network, and cingulo-opercular salience network); and (iv) a potential application of breathing manipulation in mental health care. These outlines and considerations of "brain-breath" interactions lead to a better understanding of the interoceptive and cognitive mechanisms that underlie brain-body interactions in health conditions and in stress-related and neuropsychiatric disorders.

The lesion site of organophosphorus-induced central apnea and the effects of antidotes.

Organophosphorus poisoning kills individuals by causing central apnea; however, the underlying cause of death remains unclear. Following findings that the pre-Bötzinger complex impairment alone does not account for central apnea, we analyzed the effect of paraoxon on the brainstem-spinal cord preparation, spanning the lower medulla oblongata to phrenic nucleus. Respiratory bursts were recorded by connecting electrodes to the ventral 4th cervical nerve root of excised brainstem-spinal cord preparations obtained from 6-day-old Sprague-Dawley rats. We observed changes in respiratory bursts when paraoxon, neostigmine, atropine, and 2-pyridine aldoxime methiodide were administered via bath application. The percentage of burst extinction in the paraoxon-poisoning group was 50% compared with 0% and 18.2% in the atropine and 2-pyridine aldoxime methiodide treatment groups, respectively. Both treatments notably mitigated the paraoxon-induced reduction in respiratory bursts. In the neostigmine group, similar to paraoxon, bursts stopped in 66.7% of cases but were fully reversed by atropine. This indicates that the primary cause of central apnea is muscarinic receptor-mediated in response to acetylcholine excess. Paraoxon-induced central apnea is hypothesized to result from neural abnormalities within the inferior medulla oblongata to the phrenic nucleus, excluding pre-Bötzinger complex. These antidotes antagonize central apnea, suggesting that they may be beneficial therapeutic agents.

Electrical stimulation mitigates muscle degradation shift in gene expressions during 12-h mechanical ventilation.

Ventilator-induced diaphragm dysfunction (VIDD), a dysfunction of the diaphragm muscle caused by prolonged mechanical ventilation (MV), is an important factor that hinders successful weaning from ventilation. We evaluated the effects of electrical stimulation of the diaphragm muscle (pulsed current with off-time intervals) on genetic changes during 12 h of MV (E-V12). Rats were divided into four groups: control, 12-h MV, sham operation, and E-V12 groups. Transcriptome analysis using an RNA microarray revealed that 12-h MV caused upregulation of genes promoting muscle atrophy and downregulation of genes facilitating muscle synthesis, suggesting that 12-h MV is a reasonable method for establishing a VIDD rat model. Of the genes upregulated by 12-h MV, 18 genes were not affected by the sham operation but were downregulated by E-V12. These included genes related to catabolic processes, inflammatory cytokines, and skeletal muscle homeostasis. Of the genes downregulated by 12-h MV, 6 genes were not affected by the sham operation but were upregulated by E-V12. These included genes related to oxygen transport and mitochondrial respiration. These results suggested that 12-h MV shifted gene expression in the diaphragm muscle toward muscle degradation and that electrical stimulation counteracted this shift by suppressing catabolic processes and increasing mitochondrial respiration.

Transcutaneous cervical vagus nerve stimulation improved motor cortex excitability in healthy adults: a randomized, single-blind, self-crossover design study.

Purpose: To investigate the effect of transcutaneous cervical vagus nerve stimulation (tcVNS) on motor cortex excitability in healthy adults. Method: Twenty eight healthy subjects were assigned to receive real and sham tcVNS for 30 min. The interval between the real and sham conditions was more than 24 h, and the sequence was random. The central and peripheral motor-evoked potential (MEP) of the right first dorsal interosseous (FDI) muscle was measured by transcranial magnetic stimulation (TMS) before and after stimulation. MEP latency, MEP amplitude and rest motor threshold (rMT) were analyzed before and after stimulation. Results: MEP amplitude, MEP latency and rMT had significant interaction effect between time points and conditions (p < 0.05). After real stimulation, the MEP amplitude was significantly increased (p < 0.001). MEP latency (p < 0.001) and rMT (p = 0.006) was decreased than that of baseline. The MEP amplitude on real condition was higher than that of sham stimulation after stimulation (p = 0.027). The latency after the real stimulation was significantly shorter than that after sham stimulation (p = 0.005). No significantly difference was found in rMT after stimulation between real and sham conditions (p > 0.05). Conclusion: tcVNS could improve motor cortex excitability in healthy adults.

Hippocampal ensemble dynamics and memory performance are modulated by respiration during encoding.

During offline brain states, such as sleep and memory consolidation, respiration coordinates hippocampal activity. However, the role of breathing during online memory traces remains unclear. Here, we show that respiration can be recruited during online memory encoding. Optogenetic manipulation was used to control activation of the primary inspiratory rhythm generator PreBötzinger complex (PreBötC) in transgenic mice. When intermittent PreBötC-induced apnea covered the object exploration time during encoding, novel object detection was impaired. Moreover, the mice did not exhibit freezing behavior during presentation of fear-conditioned stimuli (CS+) when PreBötC-induced apnea occurred at the exact time of encoding. This apnea did not evoke changes in CA3 cell ensembles between presentations of CS+ and conditioned inhibition (CS-), whereas in normal breathing, CS+ presentations produced dynamic changes. Our findings demonstrate that components of central respiratory activity (e.g., frequency) during online encoding strongly contribute to shaping hippocampal ensemble dynamics and memory performance.

The Anterior Cingulate Cortex is Critical for Acute Stress-induced Hypersensitivity in Mice.

Stress can be categorized according to physical, psychological and social factors. Exposure to stress produces stress-induced hypersensitivity and forms negative emotions such as anxiety and depression. For example, acute physical stress induced by the elevated open platform (EOP) causes prolonged mechanical hypersensitivity. The anterior cingulate cortex (ACC) is a cortical region involved in pain and negative emotions. Recently, we showed that mice exposed to the EOP changed spontaneous excitatory, but not inhibitory transmission in layer II/III pyramidal neurons of the ACC. However, it is still unclear whether the ACC is involved in the EOP induced mechanical hypersensitivity, and how the EOP alters evoked synaptic transmission on excitatory and inhibitory synaptic transmission in the ACC. In this study, we injected ibotenic acid into the ACC to examine if it was involved in stress-induced mechanical hypersensitivity induced by EOP exposure. Next, by using whole-cell patch-clamp recording from brain slice preparation, we analyzed action potentials and evoked synaptic transmission from layer II/III pyramidal neurons within the ACC. Lesion of the ACC completely blocked the stress-induced mechanical hypersensitivity induced by EOP exposure. Mechanistically, EOP exposure mainly altered evoked excitatory postsynaptic currents such as input-output and paired pulse ratio. Intriguingly, the mice exposed in the EOP also produced low-frequency stimulation induced short-term depression on excitatory synapses in the ACC. These results suggest that the ACC plays a critical role in the modulation of stress-induced mechanical hypersensitivity, possibly through synaptic plasticity on excitatory transmission.

Swallowing disorder - A possible therapeutic target for preventing COPD exacerbations.

Dysphagia is a common comorbidity of chronic obstructive pulmonary disease (COPD). In this review article, we show that swallowing disorder can be detected at its early stage as a manifestation of breathing-swallowing discoordination. Furthermore, we provide evidence that low-pressure continuous airway pressure (CPAP) and transcutaneous electrical sensory stimulation using interferential current (IFC-TESS) counteract swallowing disorders and may reduce exacerbations in patients with COPD. Our first prospective study showed that inspiration immediately before or after swallowing is associated with COPD exacerbation. However, the inspiration before swallowing (I-SW) pattern could be interpreted as an airway-protecting behavior. Indeed, the second prospective study showed that the I-SW pattern is more frequently observed in patients who did not experience exacerbations. As potential therapeutic candidates, CPAP normalizes the timing of swallowing, and IFC-TESS applied to the neck acutely facilitates swallowing and chronically improves nutrition and airway protection. Further studies are necessary to elucidate whether such interventions reduce exacerbations in patients with COPD.

Cell types and synchronous-activity patterns of inspiratory neurons in the preBötzinger complex of mouse medullary slices during early postnatal development.

To examine whether and how the inspiratory neuronal network in the preBötzinger complex (preBötC) develops during the early postnatal period, we quantified the composition of the population of inspiratory neurons between postnatal day 1 (p1) and p10 by applying calcium imaging to medullary transverse slices in double-transgenic mice expressing fluorescent marker proteins. We found that putative excitatory and glycinergic neurons formed a majority of the population of inspiratory neurons, and the composition rates of these two inspiratory neurons inverted at p5-6. We also found that the activity patterns of these two types of inspiratory neurons became significantly well-synchronized with the inspiratory rhythmic bursting pattern in the preBötC within the first postnatal week. GABAergic and GABA-glycine cotransmitting inspiratory neurons formed only a small population just after birth, which almost disappeared until p10. In conclusion, the inspiratory neuronal network in the preBötC matures at the level of both neuronal population and neuronal activities during early postnatal development.

Respiration-timing-dependent changes in activation of neural substrates during cognitive processes.

We previously showed that cognitive performance declines when the retrieval process spans an expiratory-to-inspiratory (EI) phase transition (an onset of inspiration). To identify the neural underpinning of this phenomenon, we conducted functional magnetic resonance imaging (fMRI) while participants performed a delayed matching-to-sample (DMTS) recognition memory task with a short delay. Respiration during the task was monitored using a nasal cannula. Behavioral data replicated the decline in memory performance specific to the EI transition during the retrieval process, while an extensive array of frontoparietal regions were activated during the encoding, delay, and retrieval processes of the task. Within these regions, when the retrieval process spanned the EI transition, activation was reduced in the anterior cluster of the right temporoparietal junction (TPJa, compared to cases when the retrieval process spanned the inspiratory-to-expiratory phase transition) and the left and right middle frontal gyrus, dorsomedial prefrontal cortex, and somatosensory areas (compared to cases when the retrieval process did not span any phase transition). These results in task-related activity may represent respiratory interference specifically in information manipulation rather than memory storage. Our findings demonstrate a cortical-level effect of respiratory phases on cognitive processes and highlight the importance of the timing of breathing for successful performance.

Temporal variations in the pattern of breathing: techniques, sources, and applications to translational sciences.

The breathing process possesses a complex variability caused in part by the respiratory central pattern generator in the brainstem; however, it also arises from chemical and mechanical feedback control loops, network reorganization and network sharing with nonrespiratory motor acts, as well as inputs from cortical and subcortical systems. The notion that respiratory fluctuations contain hidden information has prompted scientists to decipher respiratory signals to better understand the fundamental mechanisms of respiratory pattern generation, interactions with emotion, influences on the cortical neuronal networks associated with cognition, and changes in variability in healthy and disease-carrying individuals. Respiration can be used to express and control emotion. Furthermore, respiration appears to organize brain-wide network oscillations via cross-frequency coupling, optimizing cognitive performance. With the aid of information theory-based techniques and machine learning, the hidden information can be translated into a form usable in clinical practice for diagnosis, emotion recognition, and mental conditioning.

Interferential Current Stimulation for Swallowing Disorders in Chronic Obstructive Pulmonary Disease: A Preliminary Study.

Objectives: Swallowing function is affected in patients with chronic obstructive pulmonary disease (COPD), putting them at risk of exacerbation of COPD. We previously reported the effectiveness of the repetitive saliva swallowing test (RSST) in screening for patients at risk of COPD exacerbation. However, evidence on how to improve swallowing function in this population is extremely limited. Interferential current transcutaneous electrical sensory stimulation (IFC-TESS) stimulates the larynx and pharynx, thereby improving their sensory function. IFC-TESS is an emerging tool to enhance airway protection and increase swallowing frequency; however, its safety and efficacy in patients with COPD is unknown. Therefore, we performed a preliminary prospective study focusing on stable COPD patients. Methods: Patients with stable COPD who were hospitalized for yearly evaluation were recruited. Patients were included if their RSST was 5 or less. Nurses carried out IFC-TESS twice daily for 10 days. Swallow screening results were compared before and after the 10-day intervention. Results: Ten patients were included in the study. The IFC-TESS intervention was performed safely. Patients and nurses reported no discomfort or concerns regarding the intervention. The EAT-10 and RSST scores improved significantly after the intervention, and tongue pressure also tended to improve. Conclusions: IFC-TESS may be a promising intervention to improve swallowing in patients with COPD who are easily fatigued and struggle to perform swallowing exercises.

Swallowing Dynamics and Breathing-Swallowing Coordination Are Altered in Patients with Mild Cognitive Impairment.

INTRODUCTION: Postinspiratory activity, which is essential for laryngeal closure during swallowing to prevent aspiration of food into the airways, is reduced in a mouse model of tauopathy. Therefore, we hypothesized that patients at the stage of mild cognitive impairment (MCI) exhibit alterations in swallowing dynamics and coordination between swallowing and breathing. METHODS: We examined breathing-swallowing coordination in patients with MCI. Patients who scored ≥24 on the Mini-Mental State Examination and <26 on the Japanese version of the Montreal Cognitive Assessment were recruited at Sumoto Itsuki Hospital. Parameters associated with breathing-swallowing coordination were assessed using a combination of two sensors: a respiratory flow sensor and a piezoelectric sensor attached to the skin surface of the anterior neck. RESULTS: Nineteen patients met the criteria for MCI; 16 of these patients (79.5 ± 9.1 years old) scored <3 on the 10-item Eating Assessment Tool and were enrolled in the study. Their data were compared with those of an age-matched elderly cohort (79.9 ± 2.9 years old). The frequencies of swallowing during inspiration and swallowing immediately followed by inspiration in patients with MCI were 6.9% and 9.6%, respectively; these frequencies were not significantly different from those of the age-matched elderly cohort. However, the timing of swallowing in the respiratory cycle was significantly delayed in the MCI patients, and both time from the onset to the peak of laryngeal elevation and the duration between the onset of rapid laryngeal elevation and the time when the larynx returned to the resting position were significantly lengthened in this group. CONCLUSION: At the stage of MCI, breathing-swallowing coordination has already started to decline.

Questionnaire survey on nurses and speech therapists regarding dysphagia rehabilitation in Japan.

OBJECTIVE: Current interventions of dysphagia are not generalizable, and treatments are commonly used in combination. We conducted a questionnaire survey on nurses and speech therapists regarding dysphagia rehabilitation to understand the current situation in Japan. METHODS: The questionnaire was sent to 616 certified nurses in dysphasia nursing and 254 certified speech-language-hearing therapists for dysphagia. Based on "Summaries of training methods in 2014" by JSDR, 24 local indirect exercises, 11 general indirect exercises, and 13 direct exercises were selected. The Likert scale "How do you feel about each method" was used as follows: A; Frequency, B; Ease, C; Adherence, D; Effectiveness (1-5))?". RESULTS: Two hundred fifty (40%) nurses and 145 (57%) speech-language-hearing therapists (ST) responded to the questionnaire. The direct exercise was associated with a significantly high score in every question. In indirect exercises, "Cervical range of motion exercise," "Orofacial myofunctional exercise," "Lip closure exercise." "Ice massage of pharynx" and "Huffing" were used relatively frequently. "Balloon dilatation therapy" and "Tube exercise" was associated with a relatively high discrepancy for two questions. Frequency" and the sum of "Ease," "Adherence," and "Effectiveness." was significantly correlated for local indirect exercises (r2 = 0.928, P < 0.01), general indirect exercises (r2 = 0.987, P < 0.01), and direct exercises (r2 = 0.996, P < 0.01) (Fig. 5). CONCLUSION: This study examined the current situation of dysphagia rehabilitation in Japan. Our results aid to increase understanding and selection of rehabilitative treatments for dysphagia patients in Japan.

Breathing-Swallowing Discoordination and Inefficiency of an Airway Protective Mechanism Puts Patients at Risk of COPD Exacerbation.

Introduction: Dysphagia is a newly acknowledged multifactorial risk factor for the exacerbation of chronic obstructive pulmonary disease (COPD). Effective screening methods are awaited. We performed a prospective study to evaluate the impact of musculature and breathing-swallowing discoordination on the exacerbation of COPD with a novel swallowing monitor using a piezoelectric sensor. Patients and Methods: This was the second part of a prospective study of patients with COPD from the Iizuka COPD cohort. Seventy patients with stable COPD underwent dysphagia screening, skeletal muscle mass index (SMI) and tongue pressure measurements, and swallowed 3 mL and 30 mL of water while wearing a swallowing monitor. Patients were followed for one year. Results: During the follow-up period, 28 patients experienced exacerbations (E group), and 42 had none (non-E group). There was no significant difference in tongue pressure measurements between the two groups. The SMI in the E group was significantly lower than that in the non-E group. Among the swallowing monitor measurements, the 3 mL I-SW% (the percentage of swallows in which inspiration preceded the swallow [out of ten 3 mL swallows]) was significantly lower in the E group than in the non-E group. Conclusion: Breathing-swallowing coordination is an independent factor related to the exacerbation of COPD. Not only the presence of discoordination but also the inability to produce an airway protection mechanism may contribute to more frequent aspiration and exacerbations.

Careful history taking detects initially unknown underlying causes of aspiration pneumonia.

AIM: The majority of pneumonia in the elderly is attributed to aspiration. Identifying the cause of aspiration is essential for efficient treatment and prevention. However, the methodology on how to investigate the causes is not established. Therefore, we studied cases that were initially admitted for pneumonia and were newly diagnosed with an underlying cause of aspiration. This is the first study to analyze such cases collectively. METHODS: This was a retrospective study. Patients aged 65 years or older admitted for pneumonia from October 2012 to November 2018 and were newly diagnosed with a cause of aspiration after admission was included. Patients were excluded if they had hospital-acquired pneumonia, interstitial lung disease, or obstructive pneumonia or were immunocompromised. RESULTS: In total, 4043 patients were admitted for pneumonia and 125 cases who were newly diagnosed with causes of aspiration after admission were included in the study. This constituted 30.7% of suspected aspiration pneumonia cases in which there was no known cause of aspiration on admission. The most common conditions newly identified were neurologic disorders, upper gastrointestinal disorders, drug-induced conditions, and head and neck disease. Some were lethal. The diagnosis enabled treatment of the underlying condition and prevention of aspiration in most cases. The most common sign that lead to the diagnosis was symptoms seen from admission, followed by chronic symptoms. CONCLUSION: In 30.7% of those with suspected aspiration pneumonia with an unknown cause, a cause of aspiration was newly diagnosed. Careful history taking concerning neurological, gastrointestinal and drug-induced disorders is essential in elderly patients with pneumonia. Geriatr Gerontol Int 2020; 20: 785-790.

Laryngeal afferent modulation of swallowing interneurons in the dorsal medulla in perfused rats.

OBJECTIVES: The purpose of this study was to investigate the influence of laryngeal afferent inputs on brainstem circuits that mediate and transmit swallowing activity to the orofacial musculature. METHODS: Experiments were performed on 19 arterially perfused juvenile rats. The activities of swallowing interneurons in relation to their respective motor outputs in the hypoglossal and vagus nerves were assessed during fictive swallowing with or without concurrent laryngeal sensory stimulation at intensities of 20, 40, and 60 µA. RESULTS: The hypoglossal nerve activity was gradually enhanced with increasing intensity of the sensory stimulation, while the vagus nerve activity was not altered. The activities of various interneurons were modulated by the laryngeal stimulation, but more than 50% of the recorded neurons were inhibited by the stimulation. Some interneurons demonstrated no obvious change in their discharge rates with laryngeal sensory stimulation during fictive swallowing. CONCLUSION: Laryngeal afferent inputs partially modulated the swallowing motor activity via enhanced or suppressed activities of the swallowing interneurons, while the essential motor pattern underlying the pharyngeal stage of swallowing remained basically unchanged. Thus, the output patterns of the complex sequential movements of swallowing could be basically predetermined and further adjusted according to sensory information related to the properties of the ingested food by a swallowing central pattern generator. LEVEL OF EVIDENCE: NA Laryngoscope, 130: 1885-1893, 2020.

Safety of transcutaneous electrical sensory stimulation of the neck in terms of vital parameters in dysphagia rehabilitation.

Transcutaneous electrical sensory stimulation (TESS) devices are approved for use in Japan, but their safety when used through the neck skin for dysphagia rehabilitation has not been reported. This study aimed to verify the safety of TESS use through the neck skin. Twenty patients (mean age 86.5 ± 5.1 years) with aspiration pneumonia undergoing dysphagia rehabilitation were included in this retrospective observational and matched control study. We compared vital signs in 10 subjects who underwent swallowing rehabilitation with the TESS device, and matched control patients over 7 days. The results were the following: tachycardia, 0.60 ± 1.07 vs. 0.70 ± 0.67 days; high blood pressure, 0.40 ± 0.70 vs. 0.50 ± 1.08 days; low blood pressure, 0.40 ± 0.70 vs. 0.10 ± 0.32 days; low oxygen saturation, 0.60 ± 1.58 vs. 0.50 ± 1.08 days, p = 0.870; oxygen administration, 0.80 ± 2.20 vs. 1.20 ± 2.15 days; tachypnea, 0.50 ± 0.71 vs. 0.50 ± 0.53 days; elevated body temperature, 2.00 ± 1.41 vs. 1.60 ± 1.96 days. There were no significant differences in clinical stability between the TESS and control groups of patients with aspiration pneumonia. TESS through the neck appears safe as an intervention in dysphagia rehabilitation.

Effects of noninvasive ventilation on the coordination between breathing and swallowing in patients with chronic obstructive pulmonary disease.

Purpose: As shown in our previous study, inspiration after swallowing (SW-I) increases during the bi-level positive airway pressure ventilation (BiPAP) in healthy subjects because swallowing-associated non-inspiratory flow (SNIF) triggers inspiratory support, while SW-I during continuous positive pressure ventilation (CPAP) is rare. In the present study, we evaluated the coordination between breathing and swallowing during spontaneous breathing, BiPAP, and CPAP in patients with chronic obstructive pulmonary disease (COPD). Patients and methods: This study is a prospective intervention study at the Hoshigaoka Medical Center (November 01, 2015-April 30, 2018). We simultaneously recorded the respiratory flow, laryngeal motion, and swallowing sounds during saliva swallowing in patients with COPD. We estimated the respiratory phase after swallowing, frequency of SNIF, the duration of the respiratory pause during swallowing, and timing of swallowing in the respiratory cycle and compared these parameters among control, CPAP, and BiPAP conditions. Results: The expiration after swallowing (SW-E) frequency was associated with the occurrence of SNIF (p<0.01), pause duration ≤0.8 s (p<0.01), and timing of swallowing at the intermediate respiratory phase (50-80% of the respiratory cycle from the onset of inspiration) (p<0.01). In particular, the occurrence of SNIF most substantially affected the SW-E frequency. The SW-I frequencies under the control, CPAP, and BiPAP conditions were 35.0%, 3.0%, and 37.7%, respectively. The pause durations were shorter during CPAP and BiPAP than under the control condition (p<0.01). During CPAP, the occurrence rates of SW-E. Residual denotes the percentage difference between observed and expected values (residual =10.8: p<0.01) and SNIF (residual =9.1: p<0.01) were significantly increased, and timing of swallowing shifted toward the intermediate respiratory phase (residual=3.5: p<0.01). Conclusion: CPAP decreases the SW-I frequency, increases the SNIF occurrence, and normalizes the timing of swallowing, all of which suggest that CPAP alleviates the risk of aspiration in patients with COPD.

TRPM8 channel is involved in the ventilatory response to CO2 mediating hypercapnic Ca2+ responses.

The role of TRP channels in the ventilatory response to CO2 was investigated in vivo. To this end, the respiration of unrestrained adult TRPM8-, TRPV1- and TRPV4-channel knockout mice was measured using whole-body plethysmography. Under control conditions and hyperoxic hypercapnia, no difference in respiratory parameters was observed between adult wild-type mice and TRPV1- and TRPV4-channel knockout mice. However, TRPM8-channel knockout mice showed decreased tidal volume under both hypercapnia and resting conditions. In addition, the expression of TRPM8, TRPV1 and TRPV4 mRNAs was detected in EGFP-positive glial cells in the medulla of GFAP promoter-EGFP transgenic mice by real-time PCR. Furthermore, we measured intracellular Ca2+ responses of TRPM8-overexpressing HEK-293 cells to hypercapnic acidosis. Subpopulations of cells that exhibited hypercapnic acidosis-induced Ca2+ response also responded to the application of menthol. These results suggest that TRPM8 partially mediates the ventilatory response to CO2 via changes in intracellular Ca2+ and is a chemosensing protein that may be involved in detecting endogenous CO2 production.