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.

Coordination between respiration and swallowing during non-invasive positive pressure ventilation.

BACKGROUND AND OBJECTIVE: The purpose of this study was to test the hypothesis that the risk of silent aspiration is increased in non-invasive positive pressure ventilation. METHODS: We analysed the coordination between respiration and swallowing, in 12 young volunteers and 10 elder volunteers, by simultaneously monitoring respiratory flow, laryngeal movement and swallowing sound in three different conditions: control, continuous positive airway pressure (CPAP), and bi-level positive airway pressure (BiPAP). A step-wise multiple regression analysis was performed with the occurrence rate of inspiration after swallows as the dependent variable and various correlated variables as the independent variables. RESULTS: In both subject groups, the occurrence rate of inspiration after swallow was greater with BiPAP compared with control and CPAP conditions. Repetitive saliva swallowing test count and swallow non-inspiratory flow occurrence rate were extracted as predictor variables for risk of inspiration after swallows during BiPAP treatment. CONCLUSION: We found that the occurrence rate of inspiration after swallow is increased with BiPAP use irrespective of age. The results suggest that swallow non-inspiratory flow may trigger inspiratory support in the BiPAP mode, resulting in a risk of aspiration.

A knock-in mouse model of N-terminal R420W mutation of cardiac ryanodine receptor exhibits arrhythmogenesis with abnormal calcium dynamics in cardiomyocytes.

Cardiac ryanodine receptor gene (RyR2) mutations cause fatal arrhythmogenic diseases such as catecholaminergic polymorphic ventricular tachycardia and arrhythmogenic right ventricular cardiomyopathy. The N-terminal region of RyR2 is one of the hot spots for mutations. In this study, we investigated cardiac phenotypes of a knock-in mouse model carrying R420W mutation of RyR2. The N-terminal R420W mutation has already been found in juvenile sudden death cadavers of unrelated families. The depolarization-induced Ca(2+) transient amplitude was significantly lower in cardiomyocytes from RyR2(R420W/R420W) mice compared with wild-type mice. The time to peak of the Ca(2+) transient was significantly increased in RyR2(R420W/R420W) mice. Furthermore, the prolonged decay time from the peak of the Ca(2+) transient was detected in RyR2(R420W/R420W) mice. ECG telemetry revealed that various types of arrhythmias were induced in RyR2(R420W/R420W) mice in response to administration of caffeine and adrenaline. The mutant mice showed high occurrences of arrhythmias in response to heart stimulants compared with wild-type mice. These findings suggest that R420W mutation impairs depolarization-induced Ca(2+) oscillation in cardiomyocytes, which possibly results in sudden death due to stress-induced arrhythmias.

"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.

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.

Breathing-Swallowing discoordination after definitive chemoradiotherapy for head and neck cancers is associated with aspiration pneumonia.

PURPOSE: Swallowing dysfunction and the risk of aspiration pneumonia are frequent clinical problems in the treatment of head and neck squamous cell carcinomas (HNSCCs). Breathing-swallowing coordination is an important factor in evaluating the risk of aspiration pneumonia. To investigate breathing-swallowing discoordination after chemoradiotherapy (CRT), we monitored respiration and swallowing activity before and after CRT in patients with HNSCCs. METHODS: Non-invasive swallowing monitoring was prospectively performed in 25 patients with HNSCCs treated with CRT and grade 1 or lower radiation-induced dermatitis. Videoendoscopy, videofluoroscopy, Food Intake LEVEL Scale, and patient-reported swallowing difficulties were assessed. RESULTS: Of the 25 patients selected for this study, four dropped out due to radiation-induced dermatitis. The remaining 21 patients were analyzed using a monitoring system before and after CRT. For each of the 21 patients, 405 swallows were analyzed. Swallowing latency and pause duration after the CRT were significantly extended compared to those before the CRT. In the analysis of each swallowing pattern, swallowing immediately followed by inspiration (SW-I pattern), reflecting breathing-swallowing discoordination, was observed more frequently after CRT (p = 0.0001). In 11 patients, the SW-I pattern was observed more frequently compared to that before the CRT (p = 0.00139). One patient developed aspiration pneumonia at 12 and 23 months after the CRT. CONCLUSION: The results of this preliminary study indicate that breathing-swallowing discoordination tends to increase after CRT and could be involved in aspiration pneumonia. This non-invasive method may be useful for screening swallowing dysfunction and its potential risks.

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.

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.

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.

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.

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.

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.

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.

Preinspiratory calcium rise in putative pre-Botzinger complex astrocytes.

The neural inspiratory activity originates from a ventrolateral medullary region called the pre-Bötzinger complex (preBötC), yet the mechanism underlying respiratory rhythmogenesis is not completely understood. Recently, the role of not only neurons but astrocytes in the central respiratory control has attracted considerable attention. Here we report our discovery that an intracellular calcium rise in a subset of putative astrocytes precedes inspiratory neuronal firing in rhythmically active slices. Functional calcium imaging from hundreds of preBötC cells revealed that a subset of putative astrocytes exhibited rhythmic calcium elevations preceding inspiratory neuronal activity with a time lag of approximately 2 s. These preinspiratory putative astrocytes maintained their rhythmic activities even during the blockade of neuronal activity with tetrodotoxin, whereas the rhythm frequency was lowered and the intercellular phases of these rhythms were decoupled. In addition, optogenetic stimulation of preBötC putative astrocytes induced firing of inspiratory neurons. These findings raise the possibility that astrocytes in the preBötC are actively involved in respiratory rhythm generation in rhythmically active slices.

Interleukin-13 enhanced Ca2+ oscillations in airway smooth muscle cells.

Physiological mechanisms associated with interleukin-13 (IL-13), a key cytokine in asthma, in intracellular Ca(2+) signaling in airway smooth muscle cells (ASMCs) remain unclear. The aim of this study was to assess effects of IL-13 on Ca(2+) oscillations in response to leukotriene D4 (LTD4) in human cultured ASMCs. LTD4-induced Ca(2+) oscillations in ASMCs pretreated with IL-13 were imaged by confocal microscopy. mRNA expressions of cysteinyl leukotriene 1 receptors (CysLT1R), CD38, involved with the ryanodine receptors (RyR) system, and transient receptor potential canonical (TRPC), involved with store-operated Ca(2+) entry (SOCE), were determined by real-time PCR. In IL-13-pretreated ASMCs, frequency of LTD4-induced Ca(2+) oscillations and number of oscillating cells were significantly increased compared with untreated ASMCs. Both xestospongin C, a specific inhibitor of inositol 1,4,5-triphosphate receptors (IP(3)R), and ryanodine or ruthenium red, inhibitors of RyR, partially blocked LTD4-induced Ca(2+) oscillations. Ca(2+) oscillations were almost completely inhibited by 50 µM of 2-aminoethoxydiphenyl borate (2-APB), which dominantly blocks SOCE but not IP(3)R at this concentration. Pretreatment with IL-13 increased the mRNA expressions of CysLT1R and CD38, but not of TRPC1 and TRPC3. We conclude that IL-13 enhances frequency of LTD4-induced Ca(2+) oscillations in human ASMCs, which may be cooperatively modulated by IP(3)R, RyR systems and possibly by SOCE.

Interferential electric stimulation applied to the neck increases swallowing frequency.

Swallowing disorders are a common complaint among the elderly. Recently, surface electrical stimulation applied to the neck region has received increased attention as a new modality to treat pharyngeal dysphagia. Previous reports used pulsed current at a frequency range of 1-120 Hz. Kilohertz-frequency alternating currents (ACs) have not been tested for treating dysphagia. Therefore, we evaluated the effects of interferential currents (IFCs), the most popular modality of amplitude-modulated kilohertz-frequency ACs in clinical practice, on the swallowing reflex in healthy subjects. We found that IFC stimulation at the sensory threshold with 50-Hz modulation significantly increased the number of swallows without any discomfort, but pure AC stimulation at the carrier frequency did not have a significant effect. There was no statistically significant difference in the time course of the number of swallows among 1,000-, 2,000-, 4,000-, and 6,000-Hz carrier frequencies. The number of swallows remained increased during the 15-min IFC stimulation, suggesting that IFC stimulation facilitates the swallowing reflex without adaptation, at least during this stimulation period. We suggest that an IFC stimulation or a low-frequency, modulated kilohertz AC stimulation, which would be more comfortable than pulsed currents, is an alternative stimulation mode for treating pharyngeal dysphagia.

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.

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.

Dual oscillator model of the respiratory neuronal network generating quantal slowing of respiratory rhythm.

We developed a dual oscillator model to facilitate the understanding of dynamic interactions between the parafacial respiratory group (pFRG) and the preBötzinger complex (preBötC) neurons in the respiratory rhythm generation. Both neuronal groups were modeled as groups of 81 interconnected pacemaker neurons; the bursting cell model described by Butera and others [model 1 in Butera et al. (J Neurophysiol 81:382-397, 1999a)] were used to model the pacemaker neurons. We assumed (1) both pFRG and preBötC networks are rhythm generators, (2) preBötC receives excitatory inputs from pFRG, and pFRG receives inhibitory inputs from preBötC, and (3) persistent Na(+) current conductance and synaptic current conductances are randomly distributed within each population. Our model could reproduce 1:1 coupling of bursting rhythms between pFRG and preBötC with the characteristic biphasic firing pattern of pFRG neurons, i.e., firings during pre-inspiratory and post-inspiratory phases. Compatible with experimental results, the model predicted the changes in firing pattern of pFRG neurons from biphasic expiratory to monophasic inspiratory, synchronous with preBötC neurons. Quantal slowing, a phenomena of prolonged respiratory period that jumps non-deterministically to integer multiples of the control period, was observed when the excitability of preBötC network decreased while strengths of synaptic connections between the two groups remained unchanged, suggesting that, in contrast to the earlier suggestions (Mellen et al., Neuron 37:821-826, 2003; Wittmeier et al., Proc Natl Acad Sci USA 105(46):18000-18005, 2008), quantal slowing could occur without suppressed or stochastic excitatory synaptic transmission. With a reduced excitability of preBötC network, the breakdown of synchronous bursting of preBötC neurons was predicted by simulation. We suggest that quantal slowing could result from a breakdown of synchronized bursting within the preBötC.