Respiratory Nerve Research Articles

Most inspiratory neurons in the pre-Bötzinger complex are suppressed during vomiting in dogs

Pulmonary ventilation is almost completely suppressed during actual retching. Correspondingly, respiratory activity either disappears or changes to retching activity in peripheral respiratory nerves and respiratory neurons of the Bötzinger complex and the caudal part of the ventral respiratory group. These results suggest the possibility that the respiratory rhythm generator is suppressed during retching. Recently, the pre-Bötzinger complex (pre-BÖT) has been postulated to generate respiratory rhythm. To evaluate this possibility, the activities of pre-BÖT neurons were observed during fictive retching and exoulsion in decerebrate paralyzed dogs. Inspiratory (I) neurons in the pre-BÖT consisted of pre-, early-, late-, post- and throughout-subtypes, as in cats and rats. Inspiratory firing almost completely disappeared during fictive retching in about 70% of the 158 pre-BÖT I neurons examined, and changed to weak bursts produced either with retches or between retches in most of the remaining 30%. Similarly, all but one of the 21 I neurons examined did not produce any discharge with fictive expulsion. In contrast, all of the pre-BÖT expiratory and inspiratory-expiratory neurons examined produced vigorous bursts either with retches or between retches, and with expulsion. These results suggest that inspiratory outputs from the respiratory rhythm generator are almost completely suppressed during retching and expulsion, and that expiratory outputs change to retching and expulsion activities.

Changes in outflow to respiratory pump muscles produced by natural vestibular stimulation.

1. Activity was recorded from abdominal (expiratory) and phrenic (inspiratory) nerves during natural vestibular stimulation in multiple vertical planes and the horizontal plane in decerebrate cats. Vestibular stimulation was produced by rotating the head in animals whose upper cervical dorsal roots were transected to remove inputs from neck receptors; the upper airway and carotid sinus were denervated, and the vagus nerves were transected to assure that the head rotations did not elicit visceral or pulmonary inputs. 2. The plane of head rotation that produced maximal modulation of respiratory nerve activity (response vector orientation) was measured at one or more frequencies between 0.05 and 0.5 Hz. The dynamics of the response were then studied with sinusoidal (0.05-2 Hz) stimuli aligned with this orientation. In some animals, sinusoidal horizontal rotations of the head at 0.5 and 1 Hz or static head tilts in the pitch and roll planes were also delivered. 3. Typically, maximal modulation of abdominal nerve outflow was elicited by head rotations in a plane near pitch; nose-up rotations produced increased outflow, and nose-down rotations reduced nerve discharges. The gains of the responses (relative to stimulus position) remained relatively constant across stimulus frequencies, and the phases were consistently near stimulus position, like regularly firing otolith afferents. Static nose-up tilt produced elevated abdominal nerve activity throughout the stimulus period, providing further evidence that pitch-sensitive otolith receptors contribute to the response. Horizontal head rotations had little influence on abdominal nerve discharges. 4. The abdominal nerve responses to head rotation were abolished by chemical or aspiration lesions of the medial and inferior vestibular nuclei, which is concordant with the responses resulting from activation of vestibular receptors. Transections of axons arising from bulbospinal neurons in the ventral respiratory group, which are known to be the predominant source of expiratory signals to the spinal cord, reduced but did not abolish the vestibuloabdominal reflex. Thus it is likely that nonrespiratory neurons also participate in generating this response. 5. Nose-up pitch of the head; and in particular large (50 degrees) static tilts, produced small increases in phrenic nerve activity. Ear-down tilt and horizontal rotation of the head produced no responses in the phrenic nerve. 6. The existence of vestibular inputs to some respiratory motoneurons suggests that the vestibular system has influences on muscles in addition to those typically considered to have antigravity roles, and participates globally in adjusting muscle activity during movement and changes in posture.

Effects of sevoflurane on respiratory activities in the phrenic nerve of decerebrate cats.

Although the depressive effect of sevoflurane on ventilation has been reported, its potency and mode of action on the neural respiratory activity is still unclear. Therefore, the effects of sevoflurane on the phrenic nerve discharge and the respiratory timing were compared with those of halothane. The efferent activity of the phrenic nerve was recorded from decerebrate, un-anesthetized and artificially ventilated cats, and its power spectrum was calculated. The inspiratory and expiratory periods were measured. Sevoflurane and halothane of the doses of 0.5-1.5 MAC were inhaled for 15 min. With 0.5 MAC, sevoflurane decreased the total power and two dominant spectral components of the high-frequency oscillation and medium-frequency oscillation in the power spectrum. With the same MAC dose, halothane had a greater depressive effect in a normocapnic condition with the vagus nerves being intact. In a state of hypercapnia or after vagotomy, the effect of halothane was considerably attenuated whereas that of sevoflurane remained unaltered. Halothane increased the neural respiratory rate much more than sevoflurane in both normocapnic and hypercapnic states. Vagotomy significantly weakened the effect of halothane to increase the respiratory rate but did not modify the effect of sevoflurane. With 1.0-1.5 MAC, both anesthetics severely decreased the phrenic power spectra and the potency difference became indistinct. The present findings demonstrate that sevoflurane has a weaker depressive effect on the respiratory nerve discharge and a smaller effect on the neural respiratory rate than halothane when the effects of 0.5 MAC were compared.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypovitaminosis A: A model for sudden infant death syndrome.

The cause of sudden infant death syndrome (SIDS) is unknown. It is the leading cause of death from age one month to one year in North America. The purpose of this essay is to generate some testable hypotheses as to the cause of SIDS by drawing attention to distinct epidemiological parallels between SIDS and a newly recognized form of enamel hypoplasia, termed localized hypoplasia of the primary canine tooth (LHPC), which has been attributed to vitamin A deficiency. LHPC and SIDS share a common epidemiological profile: winter seasonality, occurrence at 3-5 months, and affecting apparently healthy children, but with increased incidence in socio economically disadvantaged families particularly racial/ethnic minorities (except Hispanics who show a reduced incidence), previously compromised infant health, less prenatal counselling, and less breastfeeding. Vitamin A has pervasive functions throughout the body including bone growth and maintenance of epithelial membranes. It is proposed that SIDS is due in part to hypovitaminosis A through one of several mechanisms: imbalanced basicranial growth producing mechanical constriction on the respiratory nerves passing through the jugular foramen; or through compromised myelination and/or maturation of the brain stem and cranial nerves involved in respiration; or through pharyngeal collapse due to mandibular undergrowth; or dysfunction of hypoxia-sensitive epithelial cells in the trachea. It is recommended that assay of hypoxia-sensitive epithelial cells in the trachea. It is recommended that assay of the retinyl ester content of the liver of SIDS victims be included in autopsy protocol. © 1995 Wiley-Liss, Inc.

Brain areas essential or non-essential for emesis

This study was undertaken to better delineate those brain regions that are either essential or non-essential for vomiting. Fictive vomiting, identified by a characteristic pattern of respiratory nerve discharge, was induced by a combination of emetic drugs and electrical stimulation of abdominal vagal afferents in decerebrate, paralyzed cats. Regions non-essential for coordinating vomiting included the entire cerebellum, structures rostral to the medullary retrofacial nucleus, and spinal cord. Fictive coughing was also elicited following cerebellar removal but was not studied after other procedures. The respiratory-related components of fictive vomiting were abolished by large lesions or kainic acid injections in the lateral medulla at the level of the retrofacial nucleus, where respiratory pre-motor and motor neurons are known to exist. Electrical stimulation of this region of the brainstem failed to evoke vomiting. The results of the present study are consistent with our previous electrical stimulation [ Brain Res., 270 (1983) 154–158] and c- fos [ J. Neurosci., 14 (1994) 871–888] studies and the hypothesis that emesis is coordinated not by a unique, well-defined ‘vomiting center’ but rather by a distributed control system located in the medulla between the levels of the obex and the retrofacial nucleus.

Quantitative Assessment of the Effect of Chronic Phrenicotomy on the Induction of the Crossed Phrenic Phenomenon

The present study was carried out to determine if chronic peripheral phrenicotomy has a functional influence on the plasticity that is normally demonstrated by phrenic motoneurons in the spinal cord following spinal cord injury. Young adult female Sprague-Dawley rats were divided into an experimental and a control group. Left intrathoracic phrenicotomies were carried out at 1, 2, 3, and 4 weeks prior to induction of the crossed phrenic phenomenon and crossed phrenic nerve activity recording in the experimental group. Control animals were not subjected to chronic phrenicotomy. In each animal the crossed phrenic phenomenon was induced by left C2 spinal cord hemisection and turning off the ventilator. The reflex-induced activity in the phrenic nerve ipsilateral to hemisection is defined as "crossed phrenic nerve activity." All animals were subjected to spinal cord hemisection 24 h before crossed phrenic nerve activity recording. The results showed that there is a transient but statistically significant depression of crossed phrenic nerve activity at 2 weeks postphrenicotomy and a recovery to the normal activity level at 4 weeks postphrenicotomy. One control experiment was carried out to assess the effects of phrenicotomy on respiratory activity that is normally present in the phrenic nerve (i.e., not reflex-induced). This "primary respiratory nerve activity" is different from crossed phrenic nerve activity in that the phrenic motoneurons are driven by different bulbospinal respiratory pathways. The results indicated a marked decrease in primary respiratory nerve activity at 1 week after phrenicotomy with no significant recovery by the 4th week after phrenicotomy. Two other control experiments were performed to rule out the possibility that the alteration in crossed phrenic nerve activity in the experimental animals is the result of (1) conduction changes in the transected phrenic nerve fibers or (2) reinnervation of the diaphragm by the transected phrenic nerves. From the results, we conclude that the depression of crossed phrenic nerve activity at 2 weeks postphrenicotomy is most likely due to transient changes in the phrenic nucleus that prevent the expression of the crossed phrenic nerve activity. The conditions which cause a depression of the reflex activity at 2 weeks are no longer present at 4 weeks postphrenicotomy. The mechanism for the depression of reflex activity at 2 weeks is as yet unknown.

Pulmonary Management of the ALS Patient

Amyotrophic lateral sclerosis (ALS) is a chronic progressive motor neuron disease with a poor prognosis which eventually weakens and paralyzes the respiratory muscles. ALS is characterized by progressive degeneration of both cortical and alpha motor neurons of the final common pathway. Early symptoms usually begin with alpha motor neuron involvement and then progress to include cortical motor neuron involvement. Degeneration of respiratory nerve centers in the anterior horn at the C3-C5 levels results in respiratory muscle fatigue, respiratory failure and eventually death. Treatment consists of preventing respiratory complications and supporting lung function for as long as possible. One case example of a critically ill patient with ALS highlights nursing concerns. With advanced directives and durable power of attorney, the patient now has better means available for making known the decision of whether to accept or reject mechanical ventilation.

Vestibular effects on respiratory outflow in the decerebrate cat

Recording were made from phrenic, abdominal and intercostal nerves following electrical stimulation of the vestibular nerve to test for the presence of vestibulo-respiratory connections in cats that were decerebrate, paralyzed, and artificially ventilated. Short stimulus trains (2 or 3 shocks) at intensities ≤125 μA typically elicited responses bilaterally in all of the respiratory in all of the respiratory nerves: the onset latency of the evoked activity was <15 ms from the effective shock. The mean peak-to-peak amplitudes of integrated vestibulo-respiratory responses were 15% of the average amplitude of spontaneous respiratory-related discharges in the case of the phrenic nerve and 100% in the case of the abdominal nerve. The vestibulo-respiratory reflexes, as well as vestibulo-sympathetic responses recorded from the splanchnic nerve, could be abolished by injections of the excitotoxin kainic acid confined primarily to the medial and adjacent inferior vestibular nuclei. The physiological role of vestibulo-respiratory connections is yet to be determined, but possible functions include adjustments of respiration during changes in posture, assistance in venous return to the heart during movements that might lead to orthostatic hypotension, and direct participation in the execution of specific movements and the maintenance of some postures.

Effects of microinjection of L-glutamate into locus coeruleus complex area on respiration.

The experiments were performed on 55 rabbits vagotomied, anesthetized with urethane and immobilized with flaxedil. Injection of L-glutamate (L-glu) into the locus coeruleus complex (Lc-Sc) area led to a marked increase in respiratory frequency (RF) and phrenic nerve discharge rate (phr.d) (16 +/- 3.5% and 6.5 +/- 2.5%; P < 0.01 and P < 0.05, respectively), a decrease in inspiratory and expiratory duration, and no obvious change in blood pressure (Bp) was observed. While prazosin (0.5 micrograms/microliters), yohimbin (4 micrograms/microliters) and propranolol (2 micrograms/microliters) were preinjected into the nuclei tractus solitraii (NTS) respectively, the above-mentioned effects of L-glu on respiration was blocked. These results indicate that the excitation of neurons in the Lc-Sc can induce an increase in RF and phr. d and the excitative effect of L-glu on RF was mediated by alpha 1, alpha 2 and beta-receptors in the NTS, while the effect on phr.d was mediated differently.

Weakness of short-term synchronization among respiratory nerve activities during fictive vomiting.

In decerebrate, paralyzed cats, phrenic (PHR) and lumbar abdominal (ABD) nerve discharges during both neural respiration and fictive vomiting (FV) were subjected to spectral and coherence analyses. During respiration, PHR discharge exhibited high-frequency oscillation (HFO), manifested as a narrow spectral peak (range 57-90 Hz) in autospectra and left-right coherence spectra. During FV, the following occurred: 1) the HFO peak disappeared and was replaced by a broad peak with higher modal frequency (range 84-120 Hz), indicating elimination of inputs from the medullary inspiratory pattern generator. 2) Left-right PHR coherence spectra had no distinct peaks, indicating that correlations between opposite PHR discharges were now not frequency specific. 3) Although ABD and PHR autospectra were similar, PHR-ABD coherences were near zero, indicating lack of common inputs on a short time scale. 4) Nonzero coherences between ABD nerves were confined to ipsilateral pairs. Thus coherence analysis indicates that the outputs of the vomiting pattern generator are temporally dispersed on a short time scale and are not necessarily common to different motoneuron populations.

Regeneration of free grafted respiratory epithelium on severely altered lamina propria.

The lamina propria of nasal mucosa has been thought to play a key role in function and metabolism of respiratory epithelia by allowing exchange of various substances and migratory cells from blood vessels into the epithelium. Here we show that the lamina propria of mucosa transplanted to rat rectus abdominis muscle looses its typical structure and becomes vascularized connective tissue. In the subepithelial space of free grafted respiratory epithelia nasal glands, ducts and nerves degenerate and are no more detectable 3 weeks after transplantation. By contrast the epithelial cell layer regenerates, resulting in a healthy appearing mucosa. Histological and functional controls revealed that regenerated respiratory epithelium lies on a layer of vascularized connective tissue and displays normal cellular differentiation and ciliary function. The present experiments demonstrate that the lamina propria can be replaced by vascularized connective tissue without functional loss of the overlaying epithelium. Thus the results argue against a key role of lamina propria in mucosal function.

Activity of respiratory-related oropharyngeal and laryngeal motoneurones during fictive vomiting in the decerebrate cat

Activities of respiratory laryngeal and oropharyngeal respiratory nerves were studied during fictive vomiting elicited by supradiaphragmatic vagus nerve stimulation in the decerebrate cat. Inspiratory laryngeal nerves were strongly inhibited throughout the retching and expulsion phase. Glossopharyngeal, hypoglossal and expiratory laryngeal nerves were coactivated with the phrenic and abdominal nerve bursts. The pharyngeal branch of the vagus nerve discharged during the phrenic and abdominal inter-burst of the retching phase, and was silent during the abdominal expulsion. These activities permit speculation about the role of upper airway muscles during vomiting.

The role of neural connections crossed at the cervical level in determining rhythm and amplitude of respiration in cats and rabbits

The part played by crossed cervical pathways in determining respiratory rhythm and phrenic nerve amplitude was studied in rabbits and cats. The animals were anesthetized with halothane, paralyzed, vagotomized and mechanically ventilated. All decussating brain stem pathways were surgically interrupted. This resulted in asynchronous firing of the respiratory nerves on the left and right side of the body. However, both frequency and amplitude of the respiratory output depended on the mutual phase relationships due to neural connections crossed at the cervical level. Analysis of the mutual phase and amplitude relationships lead to the following conclusions. a. Phrenic motor neurons receive during inspiration a considerable amount of excitation via diffused pathways crossing the midline at C4-C6 level. b. Phrenic motor neurons are actively inhibited via crossed cervical pathways. c. The level of tonic bias transmitted via descending bulbo-spinal pathways significantly influences the magnitude of PhN output. d. Activity of phrenic motor neurons is transmitted back to the bulbar respiratory centers via an ascending spino-bulbar pathway.

External respiratory nerve of Bell (long thoracic nerve).

External respiratory nerve of Bell (long thoracic nerve).

Naloxone enhances the response to hypercampia of spinal and cranial respiratory nerves

To assess the effects of endogenous opiates on respiratory muscle responses to CO 2, naloxone was administered intravenously to paralyzed, vagotomized and artificially ventilated cats anesthetized with alpha-chloralose. Neural activity was recorded from the phrenic, hypoglossal *HG), glossopharyngeal (GP) and recurrent laryngeal (RL) nerves. Before naloxone, phasic activity began first in the phrenic at a P et CO2 of 30.0±1.8 Torr, followed by the RL at a P et CO2 of 33.5±1.7 Torr, the HG at a P et CO2 of 39.9±2.1 Torr and the GP at a P et CO2 of 42.5±2.2 Torr during CO 2 rebreathing. Naloxone had no significant effect on the apneic threshold of any of the nerves studied. Naloxone did, however, increase respiratory frequency ( P<0.01) mainly by causing a significant ( P<0.01) shortening of TE as it had no significant effect on TI. Naloxone also significantly the rate at which peak nerve activity increased with CO 2 in the HG ( P<0.01) at the GP ( P<0.01) nerves, but not in the phrenic and RL nerves. Instead, the maximum activity produced by hypercapnia and the P et CO2 level at which maximum activity occurred in the phrenic, but not the RL, increased after naloxone. The result of these effects was that naloxone extended the range over which the HG and GP behaved proportionally with the phrenic, but it did not change the curvilinear nature of these relationships.

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.

Modification by chemical stimuli of temporal difference in the onset of inspiratory activity between vagal (superior laryngeal) or hypoglossal and phrenic nerves of the rat.

Temporal differences in the onset of inspiratory activities between the efferent vagal (superior laryngeal, Xsl) or hypoglossal (XII) and phrenic (Phr) nerves were measured at various levels of chemical stimuli in the halothane-anesthetized, vagotomized, and artificially ventilated rat. The onset of Xsl (XII) inspiratory activities always preceded the abrupt start of the Phr discharge. Hyperoxic hypocapnia due to hyperventilation delayed the start of inspiratory activity (reduction in respiratory frequency) and shortened the difference in onset time between the cranial (Xsl, XII) and Phr nerve discharges (Td). During respiratory stimulation due to asphyxia (progressive hypoxia and hypercapnia), the start of Xsl (XII) inspiratory activity became progressively earlier than that of Phr discharge, which extremely prolonged the Td. Severe asphyxia, however, retarded the start of inspiratory activities with accompanying long Td and slow respiratory frequency. The early but gradually augmenting inspiratory activity of the Xsl (XII) nerve was always followed by large bursts synchronized with Phr discharges during altered chemical stimuli. The termination of inspiratory activity, which occurred simultaneously in the three respiratory nerves, was not significantly affected by changes in chemical stimuli except for extreme hypocapnia. The results indicate that changes in chemical stimuli not only alter the start of inspiratory activity but also influence the transition from the initial slow onset to the final synchronized inspiratory activity in the Xsl (XII) nerve. The apparent dissociation of the onset time between the Xsl (XII) and Phr nerve discharges shows that the temporal aspect of the brain stem process(es) for starting inspiratory activities may not be determined from the trajectory of Phr discharges only.

Increased bronchial reactivity to histamine in diabetic autonomic neuropathy.

1. Twelve male diabetic patients inhaled nebulized histamine in doubling concentrations from 0.03 mg/ml to 32 mg/ml until they reached the maximum concentration or until their forced expiratory volume in 1 s (FEV1.0) fell by at least 20%. Six had evidence of severe autonomic neuropathy (DAN), while the other six did not. 2. More of the DAN group decreased their FEV1.0 on histamine inhalation by at least 20% (P less than 0.02) and more of them decreased their maximal flow at 50% vital capacity by at least 20% than those in the group without DAN (P less than 0.05). 3. The fall in FEV1.0 and in maximal flow at 50% of vital capacity was greater (P less than 0.05) in the DAN group than in the group without DAN. 4. This suggests that diabetic patients with autonomic neuropathy have increased bronchial reactivity to histamine. This could either be due to differential damage of the respiratory autonomic nerves or, alternatively, to denervation hypersensitivity.

Recovery of motor behavior after cross-reinnervation of forelimb muscles by respiratory nerve in cats

Recovery of motor behavior after cross-reinnervation of forelimb muscles by respiratory nerve in cats

Electrical stimulation of arterial and central chemosensory afferents at different times in the respiratory cycle of the cat: II. Responses of respiratory muscles and their motor nerves.

The response patterns of the electrical activity of the respiratory motor nerves and muscles to brief electrical stimulation of the arterial and the intracranial chemosensory afferents were studied in anesthetized cats. Stimulation during inspiration increased the activity of phrenic nerve and the inspiratory muscles (intercostal, diaphragm) with a latency of 15-25 ms, whereas expiratory muscle activity in the following expiration remained almost unaltered. Stimulation during expiration increased the activity of expiratory nerves and muscles (intercostal, abdominal) after a delay of 80-120 ms. The later the stimulation occurred in the ins or expiratory period the larger the increase in amplitude and in steepness of rise of the respective integrated activity in respiratory nerves and muscles. Stimulation in early inspiration shortened the discharge period of inspiratory muscles, whereas excitation in early expiration caused an earlier onset and prolonged the activity in the expiratory muscles. Stimulation in the late phase of ins- or expiration prolonged the discharge of the respective nerves and muscles. Both the arterial (carotid sinus nerve, CSN, and aortic nerve, AN) and intracranial chemosensory (VM) afferents stimuli were able to affect both the inspiratory and the expiratory mechanisms. The restriction of the effects to the phase of the stimulus suggests a mechanism by which these afferents, when activated during inspiration, effectively project only to inspiratory neurones, and vice versa for expiration.