Respiratory Pattern Generator Research Articles

Respiratory rhythm multistability during sleep-wake states

Respiratory period (RP) changes occurring during sleep-waking states were studied during 5- to 8-h recording sessions in chronic cats. RP distribution was clearly trimodal, the shortest mode occurring essentially during alert wakefulness, the largest mode during slow wave sleep and the intermediate mode during drowsy wakefulness. Immediate shifts were observed at instant awakening, whereas after an EEG arousal lasting a few seconds, the RP could remain short for several minutes. Results suggest that the respiratory pattern generator depends upon several attractors.

Correlated and uncorrelated high-frequency oscillations in phrenic and recurrent laryngeal neurograms.

1. Power spectral analysis of phrenic and recurrent laryngeal (or efferent vagal) inspiratory discharge activity from anesthetized cats revealed a peak within the 60- to 110-Hz range in all spectra, plus a peak within the 40- to 60-Hz range in the laryngeal (and efferent vagal) spectra, and a peak less than 40 Hz in the phrenic spectra. 2. A 60- to 110-Hz peak was present in coherence spectra between the left and right phrenic neurograms, the left and right recurrent laryngeal (and efferent vagal) neurograms, and all combinations of phrenic-laryngeal (and phrenic-efferent vagal) pairs. It is concluded that the nearly-periodic oscillations represented by these peaks arise from a single source that projects functionally in parallel to many respiratory motor outputs. This source may be part of, or interact with, respiratory central pattern generation. 3. The 40- to 60-Hz oscillations in left and right recurrent laryngeal (and efferent vagal) neurograms were uncorrelated or occasionally were very weakly correlated. Thus it is unlikely that these oscillations arise from a common source such as a second respiratory central pattern generator. 4. The oscillations less than 40 Hz were weakly correlated between left and right phrenic neurograms. This correlation may be due substantially to spinal crossed-phrenic pathways. 5. It is proposed that both the 40- to 60-Hz oscillations in recurrent laryngeal neurograms and the oscillations below 40 Hz in phrenic neurograms originate in neural circuits associated with individual left or right recurrent laryngeal or phrenic motor outputs. 6. Our results do not support the interpretation that multiple peaks in phrenic and recurrent laryngeal power spectra are due to two respiratory central pattern generators whose outputs have parallel pathways to respiratory motoneurons.

Power spectra of inspiratory nerve activity with lung inflations in cats.

To investigate the effect of lung inflations on the high-frequency synchrony (70-122 Hz) observed in the inspiratory activity of respiratory motor nerves of decerebrate cats, I applied a step increase in lung inflation pressure at fixed delays into the inspiratory phase and computed power spectra of phrenic neurograms before and during inflation. In 25 decerebrate paralyzed cats the frequency of the high spectral peak was 92.3 +/- 11.1 Hz before and 105.3 +/- 12.1 Hz during the step in inflation pressure, shifting upward by 13.0 +/- 6.0 Hz. For 8 of the 25 cats, the recurrent laryngeal and phrenic neurograms were recorded simultaneously. The high spectral peak was present during inspiration in the recurrent laryngeal power spectra and coherent with the high peak in the phrenic power spectra. In response to lung inflation, the high peak disappeared from the power spectra of the recurrent laryngeal nerve as the inspiratory activity was inhibited; a shift upward in frequency was not detectable. Comparing inspiratory times (TI, based on the phrenic neurograms) for breaths with no lung inflations to those for breaths with lung inflations, I found that lung inflations early in inspiration caused a decrease in TI, lung inflations at intermediates times had no effect on TI, and lung inflations late in inspiration caused an increase in TI. Despite lung inflation decreasing, not affecting, or increasing inspiratory duration and amplitude of the phrenic neurogram, lung inflation always caused a shift upward in the high-frequency peak of the phrenic power density. The fact that lung inflation, a powerful respiratory stimulus, affected the frequency of the high peak in a consistent manner suggests that the high-frequency synchrony is an important and robust feature of the central respiratory pattern generator.

Patterns of breathing in response to alternating patterns of alveolar carbon dioxide pressures in man.

The time profile of alveolar PCO2 within the respiratory cycle has been forced to follow contrasting patterns in alternate breaths, in two different ways. Within-breath changes (w.b.c., with a CO2-rich inspirate supplied early or late in alternate inspirations) involved minimal alternation of end-tidal PCO2. Between-breath changes (b.b.c., with whole inspirates of CO2-free or CO2-rich gas) involved large swings of end-tidal PCO2. As previously reported (Metias, Cunningham, Howson, Petersen & Wolff, 1981), both patterns of forcing were associated with alternation of ventilation, but only when hypoxia was present. The patterns of the alternating reflex responses in 118 runs on four human subjects in steady hypoxia are described in terms of alternation of inspiratory and expiratory tidal volume, time and mean flow. These patterns often disappeared, or changed unpredictably in mid-run. The inspiratory pattern of reflex alternation depended in part on the type of forcing, but alternation of inspiratory tidal volume was usually observed with both types. No single pattern of expiratory alternation emerged as predominant. The pattern of reflex expiratory alternation was surprisingly independent of the pattern of inspiratory alternation: indeed, in w.b.c., but not in b.b.c., alternation of mean expiratory flow and of mean inspiratory flow were mutually exclusive. It is concluded that in man, as in cats and dogs, the arterial chemoreceptor pathway has access to various parts of the respiratory pattern generator, the exact response depending to some extent on the timing within the respiratory cycle. In particular, expiratory variables may be influenced directly through the arterial chemoreceptor pathway, i.e. without any supposedly mediating inspiratory alternation being demonstrable. The results are discussed briefly in relation to some current views on the organization of respiratory control.

Stimulating fastigial nucleus pressor region elicits patterned respiratory responses.

Electrical stimulation of the ventromedial region of the rostral fastigial nucleus (FN) in the cat produced marked quantifiable changes in respiration that were highly correlated with the concurrently elicited cardiovascular responses. The threshold- and stimulus-response curves were very similar for the two responses. Stimulation at relatively low frequencies produced increases in respiratory rate at all active sites. At approximately half the sites biphasic responses were observed with increases in stimulus frequency. These were characterized by a transient period of apnea beginning with onset of the stimulus, followed by an increased respiratory rate. At the remaining sites respiratory rate increased at all stimulation frequencies tested. Inspiratory duration decreased, and mean inspiratory flow increased. Tidal volume was not significantly altered. Similar changes were also observed when the pressor response was blocked by phenoxybenzamine. These observations, together with the frequent demonstration of expiratory-to-inspiratory and inspiratory-to-expiratory phase switching with short-burst stimulation, suggest that the FN can influence a respiratory central pattern generator. Based on these findings, a possible role for the FN in integrating cardiovascular and respiratory responses is suggested.

Respiratory pattern generation in adult lampreys (Lampetra fluviatilis): interneurons and burst resetting.

The central pattern generator for the respiratory rhythm in adult lampreys was studied in isolated brain preparations. At least three different types of respiratory units were found in intra- and extracellular recordings near the trigeminal nucleus (Fig. 1), including: units that start firing before the motorneurons, recorded from the ventral surface (Figs. 2 and 3), follower cells near rostral nucleus V (Fig. 4), units bursting after the motorneurons, found in the sulcus limitans (Figs. 5 and 6). Transections of the medulla indicated that the rostral half of nucleus V could be removed without reducing the respiratory frequency (Fig. 8). The earliest respiratory events that could be recorded from the ependymal surface or the cranial nerves were observed near nuclei IX-VII-caudal V during quiet breathing. There was a rostrocaudal delay in the onset of bursts of more caudal motorneurons (Figs. 9, 10, and 12). The rostrocaudal delay became reversed, such that bursts started earlier in n.X than n.IX, during episodes of intense breathing that were accompanied by prolonged discharges in the medial reticular formation (Fig. 11). Stimulation of the medulla surface, near the base of nerve V, could trigger bursts prematurely and reset the timing of the respiratory rhythm, yielding a discontinuous phase response curve (Fig. 14). In sum, 6 types of respiratory interneurons can presently be distinguished (Fig. 15). The sulcus limitans near nucleus V is a candidate location for components of the pattern generator.

1732 RESPIRATORY DYSRHYTHMIA: A NEW CAUSE OF CENTRAL ALVEOLAR HYPOVENTILATION (CAH)

Normal mammalian breathing is characterized by the rhythmic, alternating activation of inspiratory and expiratory muscles. In previously described patients with CAH, neural output to respiratory muscles during sleep has been characterized by an inadequate rate or depth of breathing. In the present case, CAH appeared to result from a disorganization of neural output to inspiratory and expiratory muscles. SB was a normal infant until he developed aseptic meningitis at age five months. Persistent brainstem dysfunction at 16 months was indicated by inability to suck and swallow, diminished gag reflex and CAH requiring continuous mechanical ventilation. Polygraphic recordings during sleep demonstrated severe central hypoventilation (PACO2 > 76mmHg), writhing truncal movements, and marked though disorganized respiratory muscle activation with a tonic or right-left pattern rather than the normal inspiratory-expiratory phase switching. Marked respiratory muscle electromyographic activity indicated quantitatively adequate central neural output. Fluoroscopy confirmed dyssynchronous diaphragmatic movements; only rarely did the right and left hemidiaphragms contract simultaneously. Phrenic nerve stimulation ruled out diaphragmatic paralysis. We conclude that injury to the brainstem respiratory pattern generator can result in CAH when normal inspiratory-expiratory switching mechanisms are damaged.

Generation of respiratory activity by the lamprey brain exposed to picrotoxin and strychnine, and weak synaptic inhibition in motoneurons

The roles of Cl-dependent synaptic inhibition in the generation of fictive breathing were tested in isolated brains of adult lampreys, Ichthyomyzon unicuspis. Only a few inhibitory synaptic potentials were recorded in respiratory motoneurons between excitatory bursts. This was also true after Cl − injections inverted them to depolarizing potentials. A weak and variable phase of Cl-sensitive synaptic inhibition occurred at the ends of excitatory bursts. Respiratory motoneurons had a pronounced post-spike hyperpolarization, which was distinct from synaptic inhibition and appeared to be a more important mechanism for termination of firing. The production of the basic rhythm for respiration was tested in strychnine, picrotoxin, bicuculline and Cl-free fluid. Low concentrations of the blocking drugs prevented the inhibitory effects of bath-applied glycine and γ-aminobutyric acid, but essentially normal respiratory bursts still occurred. Equilibration of isolated brains in high concentrations of strychnine and picrotoxin did not prevent periodic activities, but burst durations were increased and inter-burst intervals were longer and less regular than normal. Similar bursts could also occur transiently in Cl-free fluid. Recordings from the IX and X motor nuclei indicated that respiratory neurons produced the periodic bursts in the presence of strychnine and picrotoxin. Hemisections of the brain behind the V motor nuclei eliminated the bursts ipsilaterally. This indicated that descending excitation was necessary during pattern generation both in normal fluid and in the presence of antagonists of synaptic inhibition. Conventional synaptic inhibition does not appear to be essential for respiratory pattern generation in the adult lamprey but may contribute to its modulation. The hypothetical neural oscillator may consist of excitatory bursting interneurons.

Abnormal respiratory pattern generation during sleep in patients with autonomic dysfunction.

We examined the control of breathing during wakefulness and sleep in 3 patients with autonomic nervous dysfunction who were free of respiratory and sleep-related symptoms. During wakefulness, the ability of the patients to voluntarily reproduce a breath of a given tidal volume did not differ from that of healthy control subjects, indicating normal function of the behavioral respiratory control system. Defects in the metabolic control system were indicated in all 3 patients by lack of a ventilatory response to acute hypoxia. During sleep, minute volume of ventilation in the patients with autonomic dysfunction was not significantly less than that in the healthy subjects, but their pattern of breathing was highly irregular, resulting in coefficients of variation of respiratory variables that were 2 to 3 times greater than normal (p < 0.05). This irregularity of breathing persisted during slow-wave sleep, when ventilatory pattern is normally highly regular. Three patients with Parkinson's disease were also st...

Evidence for respiratory and locomotor pattern generators in the rabbit cervico-thoracic cord and for their interactions.

In addition to the wellknown fictive locomotion, a fictive respiration can also be obtained in decorticate, unanaesthetized rabbit preparations after curarization and vagotomy. Both patterns were abolished after high spinal (C2 or C3) transection. Spinal rhythmic capabilities could be disclosed after administration of nialamide and DOPA: together with the earlier demonstrated locomotor-like bursting in hindlimb and forelimb muscle nerves, two different types of phrenic bursting patterns could be observed, depending on endtidal CO2 levels: (1) short lasting phrenic bursts (SLPBs), coordinated with locomotor bursts, result of a locomotor driving process; (2) when end-tidal CO2 was slightly increased (4.5 instead of 4.0%), long lasting phrenic bursts (LLPBs) developed: they have no causal link with the locomotor bursts. Intraspinal interactions were shown to operate between these rhythmic patterns: (1) the already mentioned caudo-rostral driving from hindlimb or posterior locomotion generators (pLGs) onto forelimb bursting and onto phrenic activity too (providing SLPBs in the latter case); (2) the rostro-caudal inhibition of fore- and hindlimb locomotor activity throughout each LLPB. Since forelimb locomotor-like bursting and LLPBs could still be obtained after functional isolation of the cervico-thoracic cord (through C2 and Th12 spinal transections) with comparable interactions as before Th12 transection, it is concluded that: two categories of generators, forelimb or anterior locomotion generators (aLGs), and chemosensitive respiration generators (RGs) are both present in this part of the cord, on the one hand; interactions between RGs and pLGs are likely to be achieved via aLGs on the other.

Power spectral analysis of inspiratory nerve activity in the decerebrate cat

To investigate the high frequency oscillations observed in the inspiratory activity of respiratory motor nerves of decerebrate cats, we applied a signal processing technique, power spectral analysis, to the electrical activity of the phrenic and recurrent laryngeal nerves. We found two peaks in the phrenic nerve power spectral densities, one at 88.1 ± 6.4 Hz (mean ± S.D.) and the other at 37.1 ± 9.7 Hz, and two peaks for the recurrent laryngeal nerve, at 87.4 ± 10.1 Hz and at 55.4 ± 5.1 Hz. We identified 3 factors affecting the peaks. Anesthetics reduced or eliminated the 88 Hz peak and produced new low frequency peaks in the phrenic and recurrent laryngeal nerves. Increasing end-tidal CO 2 decreased the bandwidth of the 88 Hz peak and increased its amplitude relative to that of the low frequency peak. Decreasing body temperature from 38 to 30°C reduced the frequency of the 88 Hz peak by 5.0 Hz/°C. The power spectral density of the phrenic nerve activity differed from that of the recurrent laryngeal nerve activity because the single fibers in each nerve had different power spectral densities. About 70% of the fibers recorded in a nerve had power spectral densities similar to that of the whole nerve. A minority of the phrenic nerve fibers had the same low spectral peak as the recurrent laryngeal fibers had the same low spectral peak as the a minority of the recurrent laryngeal fibers had the same low spectral peak as the phrenic nerve. Bilateral removal of the dorsal respiratory group eliminated the high frequency peak in the power spectral density of the phrenic nerve and the peripheral reflexes, but rhythmic bursts of inspiratory activity remained. From these findings we hypothesized that there are two central respiratory pattern generators in the brain stem with parallel pathways to the respiratory motoneurons.

Influence of the compound NA872 on cardiopulmonary maturation in the unanaesthetised fetal lamb.

15 fetal lambs were instrumented on approximately day 100 (term 147 days) with small catheters in their jugular veins, carotid arteries and tracheas and fine electrodes in their diaphragms and on the lateral surfaces of their thoraces. Measurements were made intermittently of carotid arterial pressure, jugular venous pressure, amniotic fluid pressure, ECG and electrical activity in the diaphragm for 2-hour periods up to day 120. From day 120, two hourly recordings were made daily and samples of lung liquid taken until day 130. On this day, studies of lung mechanics were made on selected fetuses. From day 120, 8 animals were treated with the compound NA872 and 7 animals were given a control infusion of normal saline. In comparison to control animals the lecithin-sphingomyelin (L:S) ratio increased in the test fetuses from days 125--130; respiratory activity (diaphragmatic EMG) was suppressed in the test animals suggesting a more mature respiratory system; but resting lung volume on the test animals was smaller. Heart rate decreased as rapidly in the test animals while changes in systemic vascular pressures were similar. These results indicate that while the lungs are more 'mature' in that L:S ratio is increased, resting lung volumes are smaller, and respiratory activity is decreased. They raise the interesting questions of the influence of fetal respiratory activity on lung and thoracic cage development and the possible direct action of the drug NA872 on the respiratory pattern generator and the lung.