The primary hypothesis of this study was that the cough motor pattern is produced, at least in part, by the medullary respiratory neuronal network in response to inputs from "cough" and pulmonary stretch receptor relay neurons in the nucleus tractus solitarii. Computer simulations of a distributed network model with proposed connections from the nucleus tractus solitarii to ventrolateral medullary respiratory neurons produced coughlike inspiratory and expiratory motor patterns. Predicted responses of various "types" of neurons (I-DRIVER, I-AUG, I-DEC, E-AUG, and E-DEC) derived from the simulations were tested in vivo. Parallel and sequential responses of functionally characterized respiratory-modulated neurons were monitored during fictive cough in decerebrate, paralyzed, ventilated cats. Coughlike patterns in phrenic and lumbar nerves were elicited by mechanical stimulation of the intrathoracic trachea. Altered discharge patterns were measured in most types of respiratory neurons during fictive cough. The results supported many of the specific predictions of our cough generation model and suggested several revisions. The two main conclusions were as follows: 1) The Bötzinger/rostral ventral respiratory group neurons implicated in the generation of the eupneic pattern of breathing also participate in the configuration of the cough motor pattern. 2) This altered activity of Bötzinger/rostral ventral respiratory group neurons is transmitted to phrenic, intercostal, and abdominal motoneurons via the same bulbospinal neurons that provide descending drive during eupnea.

A large body of data suggests that the pontine respiratory group (PRG) is involved in respiratory phase-switching and the reconfiguration of the brain stem respiratory network. However, connectivity between the PRG and ventral respiratory column (VRC) in computational models has been largely ad hoc. We developed a network model with PRG-VRC connectivity inferred from coordinated in vivo experiments. Neurons were modeled in the "integrate-and-fire" style; some neurons had pacemaker properties derived from the model of Breen et al. We recapitulated earlier modeling results, including reproduction of activity profiles of different respiratory neurons and motor outputs, and their changes under different conditions (vagotomy, pontine lesions, etc.). The model also reproduced characteristic changes in neuronal and motor patterns observed in vivo during fictive cough and during hypoxia in non-rapid eye movement sleep. Our simulations suggested possible mechanisms for respiratory pattern reorganization during these behaviors. The model predicted that network- and pacemaker-generated rhythms could be co-expressed during the transition from gasping to eupnea, producing a combined "burst-ramp" pattern of phrenic discharges. To test this prediction, phrenic activity and multiple single neuron spike trains were monitored in vagotomized, decerebrate, immobilized, thoracotomized, and artificially ventilated cats during hypoxia and recovery. In most experiments, phrenic discharge patterns during recovery from hypoxia were similar to those predicted by the model. We conclude that under certain conditions, e.g., during recovery from severe brain hypoxia, components of a distributed network activity present during eupnea can be co-expressed with gasp patterns generated by a distinct, functionally "simplified" mechanism.

This study tested predictions from a network model of ventrolateral medullary respiratory neurone interactions for the generation of the cough motor pattern observed in inspiratory and expiratory pump muscles. Data were from 34 mid‐collicularly decerebrated, paralysed, artificially ventilated cats. Cough‐like patterns (fictive cough) in efferent phrenic and lumbar nerve activities were elicited by mechanical stimulation of the intrathoracic trachea. Neurones in the ventral respiratory group, including the Bötzinger and pre‐Bötzinger complexes, were monitored simultaneously with microelectrode arrays. Spike trains were analysed for evidence of functional connectivity and responses during fictive cough with cycle‐triggered histograms, autocorrelograms, cross‐correlograms, and spike‐triggered averages of phrenic and recurrent laryngeal nerve activities. Significant cross‐correlogram features were detected in 151 of 1988 pairs of respiratory modulated neurones. There were 59 central peaks, 5 central troughs, 11 offset peaks and 2 offset troughs among inspiratory neurone pairs. Among expiratory neurones there were 23 central peaks, 8 offset peaks and 4 offset troughs. Correlations between inspiratory and expiratory neurones included 20 central peaks, 10 central troughs and 9 offset troughs. Spike‐triggered averages of phrenic motoneurone activity had 51 offset peaks and 5 offset troughs. The concurrent responses and multiple short time scale correlations support parallel and serial network interactions proposed in our model for the generation of the cough motor pattern in the respiratory pump muscles. Inferred associations included the following. (a) Excitation of augmenting inspiratory (I‐Aug) neurones and phrenic motoneurones by I‐Aug neurones. (b) Inhibition of augmenting expiratory (E‐Aug) neurones by decrementing inspiratory (I‐Dec) neurones. (c) Inhibition of I‐Aug, I‐Dec and E‐Aug neurones by E‐Dec neurones. (d) Inhibition of I‐Aug and I‐Dec neurones and phrenic motoneurones by E‐Aug neurones. The data also confirm previous results and support hypotheses in current network models for the generation of the eupnoeic pattern.

Current models propose that a neuronal network in the ventrolateral medulla generates the basic respiratory rhythm and that this ventrolateral respiratory column (VRC) is profoundly influenced by the neurons of the pontine respiratory group (PRG). However, functional connectivity among PRG and VRC neurons is poorly understood. This study addressed four model-based hypotheses: 1) the respiratory modulation of PRG neuron populations reflects paucisynaptic actions of multiple VRC populations; 2) functional connections among PRG neurons shape and coordinate their respiratory-modulated activities; 3) the PRG acts on multiple VRC populations, contributing to phase-switching; and 4) neurons with no respiratory modulation located in close proximity to the VRC and PRG have widely distributed actions on respiratory-modulated cells. Two arrays of microelectrodes with individual depth adjustment were used to record sets of spike trains from a total of 145 PRG and 282 VRC neurons in 10 decerebrate, vagotomized, neuromuscularly blocked, ventilated cats. Data were evaluated for respiratory modulation with respect to efferent phrenic motoneuron activity and short-timescale correlations indicative of paucisynaptic functional connectivity using cross-correlation analysis and the "gravity" method. Correlogram features were found for 109 (3%) of the 3,218 pairs composed of a PRG and a VRC neuron, 126 (12%) of the 1,043 PRG-PRG pairs, and 319 (7%) of the 4,340 VRC-VRC neuron pairs evaluated. Correlation linkage maps generated for the data support our four motivating hypotheses and suggest network mechanisms for proposed modulatory functions of the PRG.

Airway protection is the prevention and/or removal of material by behaviors, such as cough and swallow. We tested the hypothesis that cough and swallow, in response to aspiration, are a “meta-behavior” and thus are coordinated and have alterations in excitability to respond to aspiration risk and maintain homeostasis. Anesthetized animals were challenged with a protocol that simulated ongoing aspiration and induced both coughing and swallowing. Electromyograms of the mylohyoid, geniohyoid, thyrohyoid, thyroarytenoid, thyropharyngeus, cricopharyngeus, parasternal, rectus abdominis muscles together with esophageal pressure were recorded to identify and evaluate cough and swallow. During simulated aspiration, both cough and swallow intensity increased and swallow duration decreased consistent with a more rapid pharyngeal clearance. A phase restriction between cough and swallow was also observed; swallow was restricted to the E2 phase of cough during chest wall and abdominal motor quiescence. These results support the conclusion that the cough and swallow pattern generators are an airway protective meta-behavior. The resulting alterations in swallow drive during the simulated aspiration protocol also supports the conclusion that the trachea provides feedback on swallow quality, informing the brainstem about aspiration incidences. The overall coordination of cough and swallow led to the additional conclusion that mechanically the larynx and upper esophageal sphincter act as two separate valves controlling the direction of positive and negative pressures from the upper airway into the thorax.