Effect of dorsolateral pontine lesions on diaphragmatic activity during REMS

Muscle atonia is a feature of normal rapid-eye-movement sleep (REMS). The suppression of accessory respiratory muscle activity has been investigated and a role for sleep-disordered breathing hypothesized, but the suppression of diaphragmatic activity has rarely been considered. We hypothesized that the activity of the diaphragm was suppressed by an area of the dorsolateral pons during REMS. Lesions in this region have previously been shown to abolish the atonia of REMS. The diaphragmatic electromyogram (EMG) activity was analyzed in five naturally sleeping cats before and after pontine lesions leading to REMS without atonia. Although respiratory timing parameters were not altered by the lesion, the inspiratory rate of rise was significantly increased in all cats, and the brief pauses (40-100 ms) in the diaphragmatic EMG normally seen in REMS were virtually abolished. We conclude that the dorsolateral pons has a role in suppressing diaphragmatic activation during REMS. This suppression affects the average rate of rise of diaphragmatic activity and also leads to brief intermittent complete cessation of ongoing muscle activity. These decrements in diaphragm activity could jeopardize ventilation during REMS.     

Carbachol models of REM sleep: recent developments and new directions

Since the early '60s, injections of a broad-spectrum muscarinic cholinergic agonist, carbachol, into the medial pontine reticular formation (mPRF) of cats have been extensively used as a tool with which to study the neural mechanisms of rapid eye movement (REM) sleep. During the last decade, new carbachol models of REM sleep were introduced, including chronically instrumented/behaving rats and "reduced" preparations such as decerebrate or anesthetized cats and rats. The combined results from these distinct models show interspecies similarities and differences. The dual nature, both REM sleep-promoting and wakefulness (or arousal)-promoting, of the cholinergic effects exerted within the mPRF is more strongly expressed in rats than in cats. This strengthens the possibility suggested by earlier central neuronal recordings that active wakefulness and REM sleep have extensive common neuronal substrates, and may have evolved from a common behavioral state. Carbachol studies using different intact and reduced models also suggest that powerful REM sleep episode-terminating effects originate in suprapontine structures. In contrast, the timing of REM sleep-like episodes in decerebrate models is determined by a pontomedullary neuronal network responsible for the generation of an ultradian cycle similar to the basic rest-activity cycle of N. Kleitman. Other presumed species differences, such as the more widespread distribution of carbachol-sensitive sites or the relative failure of carbachol to increase the duration of REM sleep episodes in rats when compared to cats, may be of a quantitative or technical nature. While carbachol and many other neurotransmitters and peptides microinjected into the mPRF evoke, enhance or suppress REM sleep, the most sensitive site(s) of their actions have not been fully mapped, and the nature of the cellular and neurochemical interactions taking place at the sites where carbachol triggers the REM sleep-like state remain largely unknown. Similarly, little is known about the pathways between the mPRF and medial medullary reticular formation, but the existing evidence suggests that they are reciprocal and essential for the generation of both natural and carbachol-induced REM sleep. Studies of the mesopontine cholinergic neurons, which are hypothesized to be the main source of endogenous acetylcholine for the mPRF, need to be extended to neurons of the mPRF and cells located functionally downstream from this important site for REM sleep, or both REM sleep and active wakefulness.     

Rapid shallow breathing caused by pulmonary vascular congestion in cats

The vasculature of one lung of unanesthetized spontaneously breathing decerebrate cats was isolated and congested with blood. Such pulmonary vascular congestion (PVC) consistently resulted in a shallow tachypnea associated with expiratory activation of the diaphragm and thyroarytenoid muscles, signifying augmented expiratory braking. With progressive increases in pulmonary vascular pressure, tachypnea and expiratory braking increased progressively and ultimately obscured phasic activity in the diaphragm and thyroarytenoid. Thus the apnea caused by PVC constitutes not an arrest of neural respiratory activity but rather a continuous activation of thoracic inspiratory and laryngeal adductor muscles. When capsaicin, a neurotoxin that activates nonmyelinated afferents, was injected into the pulmonary artery of the isolated lung, it produced changes in timing and distribution of respiratory motor output that resembled those with PVC but were more abrupt in onset. Capsaicin, applied perineurally to the cervical vagi, preferentially blocked the conduction of nonmyelinated afferent fibers. This procedure, which produced little degradation in Hering-Breuer reflexes, eliminated tachypnea and expiratory braking caused by PVC or capsaicin injection. The results indicate that activation of pulmonary vagal afferent fibers of C or A-delta category in unanesthetized cats reflexly modifies the respiratory motor output in a way that resembles the human response to PVC or pulmonary embolism. This is a brain stem reflex.     

Medullary neurons mediating the inhibition of inspiration by intercostal muscle tendon organs?

Studies were conducted to test the hypothesis that nonrespiratory-modulated units are last-order interneurons mediating the effects of intercostal muscle tendon organs on medullary inspiratory neuron activity. Vagotomized, anesthetized, or decerebrate cats were used. Results show the following. 1) Afferents from different receptor types (i.e., intercostal tendon organs and chest wall cutaneous receptors) that inhibit medullary inspiratory neuron activities evoke the same units. 2) Gastrocnemius muscle group I afferent fibers evoke some of the same units as intercostal afferents but do not alter respiratory activity. 3) The "pneumotaxic center" and laryngeal nerve afferents, which inhibit medullary inspiratory activity, evoke different medullary units than intercostal afferents. 4) Evoked units are not active in spontaneously breathing cats. Additional results suggest that a few respiratory neurons near the retrofacial nucleus may be involved in the mediation of the inspiratory inhibitory effects of intercostal tendon organs. These results do not establish the mechanism by which intercostal muscle tendon organs reduces medullary inspiratory activity.     

Inhibition of vestibulospinal reflexes following cholinergic activation of the dorsal pontine reticular formation

1. The multiunit EMG activity of the forelimb extensor muscle triceps brachii was recorded in precollicular decerebrate cats, either at rest or during roll tilt of the animal at 0.15Hz, +/- 10 degrees leading to sinusoidal stimulation of labyrinth receptors. Both the spontaneous EMG activity as well as the labyrinthine-induced EMG responses were tested before and after pontine microinjection of a cholinergic agonist. 2. Local injection of the cholinergic agonist carbachol into the dorsal aspect of the pontine tegmentum (usually 0.25 microliter, 0.01-0.2 microgram/microliter) produced a state of postural atonia, and abolished both the spontaneous EMG activity as well as the EMG responses of the triceps brachii to sinusoidal stimulation of labyrinth receptors. This suppression was generally ipsilateral to the side of the injection and persisted throughout the episode of postural atonia, but sometimes it involved also the contralateral limbs. In these instances it could be accompanied by a spontaneous nystagmus, interspersed at regular intervals with bursts of rapid eye movements. 3. Similar effects were also obtained following injection of carbachol in the gigantocellular tegmental field (FTG) (0.25 microliter, 0.5-1.0 microgram/microliter). However, this structure was not critically responsible for the phenomena reported above, which persisted unaltered after kainic acid lesion of the FTG performed ipsilaterally to the side of the pontine injection. 4. Local infusion of the muscarinic blocker atropine sulphate reversed the effects of carbachol injection into the dorsal aspect of the pontine tegmentum, thus indicating that muscarinic receptors were involved. 5. It is postulated that the postural atonia as well as the tonic depression of vestibulospinal reflexes, which occur in the decerebrate cat after local injection of a cholinergic agonist depends, at least in part, on the activation of cholinoceptive neurons located in dorsal pontine reticular structures. These may in turn excite medullary reticulospinal neurons, which are finally responsible for the inhibition of extensor motoneurons.     

Combined antagonism of aminergic excitatory and amino acid inhibitory receptors in the XII nucleus abolishes REM sleep-like depression of hypoglossal motoneuronal activity

It is hypothesized that the suppression of motor activity (atonia) that occurs during REM sleep is caused by the combined inhibition of motoneurons by glycine or GABA and withdrawal of excitation mediated by serotonin and norepinephrine. However, it is not known whether these mechanisms can fully account for the atonia. In urethane-anesthetized, paralyzed and artificially ventilated rats, REM sleep-like episodes can be repeatedly elicited by microinjections of a cholinergic agonist, carbachol, into the dorsomedial pons. We used this model to determine whether microinjections of a combination of antagonists of serotonergic, adrenergic, GABA(A) and glycinergic receptors (methysergide, prazosin, bicuculline and strychnine) into the XII nucleus can abolish the carbachol-induced depression of XII motoneuronal activity. REM sleep-like episodes were elicited prior to, and at different times after, antagonist microinjections. In all six rats studied, the depression of XII motoneuronal activity did not occur when tested 30-60 min after the antagonists, whereas other characteristic features of the response (latency, duration, the appearance of hippocampal theta rhythm, activation of the cortical EEG, slowing of the respiratory rate) remained intact. The carbachol-induced depression partially recovered after 2-3 hours. We conclude that the REM sleep-like depression of XII motoneuronal activity can be fully accounted for by all or some of the following mechanisms: a withdrawal of motoneuronal excitation mediated by norepinephrine and serotonin and increased inhibition mediated by GABA and glycine.     

Internal intercostal nerve discharges in the cat: influence of chemical stimuli

We studied the influence of central and peripheral chemoreceptor stimulation on the activities of the phrenic and internal intercostal (iic) nerves in decerebrate, vagotomized, and paralyzed cats with bilateral pneumothoraces. Whole iic nerves of the rostral thorax (T2-T5) usually discharged during neural inspiration, whereas those of the caudal thorax (T7-T11) were primarily active during neural expiration. Filaments of rostral iic nerves that terminated in iic muscles generally discharged during expiration, suggesting that inspiratory activity recorded in whole iic nerves may have innervated other structures, possibly parasternal muscles. All nerves were phasically active at hyperoxic normocapnia and increased their activities systematically with hypercapnia. Isocapnic hypoxia or intra-arterial NaCN injection consistently increased phrenic and inspiratory iic nerve activities. In contrast, expiratory iic nerve discharges were either decreased (10 cats) or increased (7 cats) by hypoxia. Furthermore, expiratory responses to NaCN were highly variable and could not be predicted from the corresponding response to hypoxia. The results show that central and peripheral chemoreceptor stimulation can affect inspiratory and expiratory motoneuron activities differentially. The variable effects of hypoxia on expiratory iic nerve activity may reflect a relatively weak influence of carotid body afferents on expiratory bulbospinal neurons. However, the possibility that the magnitude of expiratory motoneuron activity is influenced by the intensity of the preceding centrally generated inspiratory discharge is also discussed.     

Muscle tone regulation during REM sleep: neural circuitry and clinical significance

Rapid eye movement (REM) sleep is a distinct behavioral state characterized by an activated cortical and hippocampal electroencephalogram (EEG) and concurrent muscle atonia. Research conducted over the past 50 years has revealed the neuronal circuits responsible for the generation and maintenance of REM sleep, as well as the pathways involved in generating the cardinal signs of REM sleep such as cortical activation and muscle atonia. The generation and maintenance of REM sleep appear to involve a widespread network in the pons and medulla. The caudal laterodorsal tegmental nucleus (cLDT) and sublaterodorsal nucleus (SLD) within the dorsolateral pons contain REM-on neurons, and the ventrolateral periaqueductal grey (vlPAG) contains REM-off neurons. The interaction between these structures is proposed to regulate REM sleep amounts. The cLDT-SLD neurons project to the basal forebrain via the parabrachial-precoeruleus (PB-PC) complex, and this pathway may be critical for the EEG activation seen during REM sleep. Descending SLD glutamatergic projections activate the ventromedial medulla, and spinal cord interneurons mediate muscle atonia and suppress phasic muscle twitches in spinal musculature. In contrast, phasic muscle twitches in the masseter muscles may be driven by glutamatergic neurons in the rostral parvicellular reticular nucleus (PCRt); however, the brain region responsible for generating phasic twitches in the other cranial muscles including facial muscles and tongue are not clear.     

Role of costal and crural diaphragm and parasternal intercostals during coughing in cats

The inspiratory phase of coughs often consists of large inspired volumes and increased motor discharge to the costal diaphragm. Furthermore, diaphragm electrical activity may persist into the early expiratory portion of coughs. To examine the role of other inspiratory muscles during coughing, electromyograms (EMG) recorded from the crural diaphragm (Dcr) and parasternal intercostal (PSIC) muscles were compared to EMG of the costal diaphragm (Dco) in anesthetized cats. Tracheal or laryngeal stimulation typically produced a series of coughs, with variable increases in peak inspiratory EMGs of all three muscles. On average, peak inspiratory EMG of Dco increased to 346 +/- 60% of control (P less than 0.001), Dcr to 514 +/- 82% of control (P less than 0.0002), and PSIC to 574 +/- 61% of control (P less than 0.0005). Augmentations of Dcr and PSIC EMG were both significantly greater than of Dco EMG (P less than 0.05 and P less than 0.002, respectively). In most animals, EMG of Dco correlated significantly with EMG of Dcr and of PSIC during different size coughs. Electrical activity of all three muscles persisted into the expiratory portions of many (but not all) coughs. The duration of expiratory activity lasted on average 0.17 +/- 0.03 s for Dco, 0.25 +/- 0.06 s for Dcr, and 0.31 +/- 0.09 s for PSIC. These results suggest that multiple respiratory muscles are recruited during inspiration of coughs, and that the persistence of electrical activity into expiration of coughs is not unique to the costal diaphragm.     

Scoring atonia during normal and pathological rapid eye movement sleep: Visual and automatic quantification methods

One of the essential features of rapid eye movement (REM) sleep behavior disorder is REM sleep without atonia seen during nocturnal polysomnographic recordings. In this paper we provide an overview about the varied scoring criteria proposed for visual analysis of loss of atonia during REM sleep. The automatic quantification of loss of atonia overcomes many of the limitations of visual scoring and these new approaches are reviewed. Finally, the contributions of these automatic methods to the understanding of the complex mechanisms underlying muscle atonia and motor suppression during REM sleep are briefly illustrated.

     

Cholinergic microstimulation of the peribrachial nucleus in the cat. II. Delayed and prolonged increases in REM sleep.

The hypothesis that REM sleep is cholinergically mediated is supported by the identification of a cholinoceptive trigger zone in the FTG. Since this trigger zone is devoid of cholinergic neurons, the aim of the present study was to test the hypothesis that a cholinergic drive for REM sleep may come from the cholinergic cells of the PBL region. Chronically implanted freely moving cats with electrodes for sleep and PGO wave recordings were used. Guide tubes were implanted for carbachol microinjections (4 micrograms/250 nl) in the PBL and FTG. All microinjections were delivered in close vicinity of ChAT+ cholinergic cells in the PBL region. Results showed that a single unilateral carbachol microinjection into the PBL induced sustained (24 hr) state-independent ipsilateral PGO wave activity. This PGO wave activity was followed by a prolonged enhancement of REM sleep lasting for more than six days. We also observed that REM enhancement was followed by a delayed but marked enhancement of S sleep episodes with PGO waves (SP), which are normally brief transitions from S to REM sleep. Our findings strongly support the hypothesis that cholinergic drive for REM sleep comes from the lateral pontine tegmentum and we suggest that the PBL region plays a major role in both PGO wave generation and long-term regulation of REM sleep induction.     

Arterial pulse modulated activity is expressed in respiratory neural output.

Although it is well-established that sympathetic activity is modulated with respiration, it is unknown whether neural control of respiration is reciprocally influenced by cardiovascular function. Even though previous studies have suggested the existence of pulse modulation in respiratory neurons, they could not exclude the possibility that such cells were involved in cardiovascular rather than respiratory motor control, owing to neuroanatomic and functional overlaps between brain stem neurons involved in respiratory and cardiovascular control. The aim of this study was to test the hypothesis that respiratory motoneurons and putative premotoneurons are modulated by arterial pulse. An existing data set composed of 72 well-characterized, respiratory-modulated brain stem motoneurons and putative premotoneurons was analyzed using delta(2), a recently described statistic that quantifies the magnitude of arterial pulse-modulated spike activity [Dick TE and Morris KF. J Physiol 556: 959-970, 2004]. Neuronal activity was recorded in the rostral and caudal ventral respiratory groups of 19 decerebrate, neuromuscular-blocked, ventilated cats. Axonal projections were identified by rectified and unrectified spike-triggered averages of recurrent laryngeal nerve activity or by antidromic activation from spinal stimulation electrodes. The firing rates of approximately 30% of these neurons were modulated in phase with both the respiratory and cardiac cycles. Furthermore, arterial pulse modulation occurred preferentially in the expiratory phase in that only expiratory neurons had high delta(2) values and only expiratory activity had significant delta(2) values after partitioning tonic activity into the inspiratory and expiratory phases. The results demonstrate that both respiratory motoneurons and putative premotoneuronal activity can be pulse modulated. We conclude that a cardiac cycle-related modulation is expressed in respiratory motor activity, complementing the long-recognized respiratory modulation of sympathetic nerve activity.     

Ventilation during early and late rapid-eye-movement sleep in normal humans.

Because successive rapid-eye-movement (REM) sleep periods in the night are longer in duration and have more phasic events, ventilation during late REM sleep might be more affected than in earlier episodes. Despite the increase in eye movement density (EMD) in late REM sleep, average minute ventilation was, however, not reduced compared with that in early REM sleep. Decreases in rib cage motion (mean inspiratory flow of the rib cage) in association with increasing EMD were offset by increments in respiratory frequency. Apart from expiratory time, there were no significant changes in the slopes of the relationships between EMD and specific ventilatory components, from early to late REM sleep periods. However, there was an increase in the number of episodes when ventilation was reduced during late REM sleep. Changes in ventilatory pattern during late REM sleep are due to changes in the underlying nature of REM sleep. The ventilatory response during eye movements is, however, subject specific. Some subjects exhibit large decrements in mean inspiratory flow of the rib cage and increments in respiratory frequency during bursts of eye movement, whereas other individuals demonstrate only small changes in these ventilatory parameters.     

Control of motoneuron function and muscle tone during REM sleep, REM sleep behavior disorder and cataplexy/narcolepsy

REM sleep triggers a potent suppression of postural muscle tone - i.e., REM atonia. However, motor control during REM sleep is paradoxical because overall brain activity is maximal, but motor output is minimal. The skeletal motor system remains quiescent during REM sleep because somatic motoneurons are powerfully inactivated. Determining the mechanisms triggering loss of motoneuron function during REM sleep is important because breakdown in REM sleep motor control underlies sleep disorders such as REM sleep behavior disorder (RBD) and cataplexy/narcolepsy. For example, RBD is characterized by dramatic REM motor activation resulting in dream enactment and subsequent patient injury. In contrast, cataplexy a pathognomonic symptom of narcolepsy - is caused by the involuntary onset of REM-like atonia during wakefulness. This review highlights recent work from my laboratory that examines how motoneuron function is lost during normal REM sleep and it also identifies potential biochemical mechanisms underlying abnormal motor control in both RBD and cataplexy. First, I show that both GABAB and GABAA/glycine mediated inhibition of motoneurons is required for generating REM atonia. Next, I show that impaired GABA and glycine neurotransmission triggers the cardinal features of RBD in a transgenic mouse model. Last, I show that loss of an excitatory noradrenergic drive onto motoneurons is, at least in part, responsible for the loss of postural muscle tone during cataplexy in narcoleptic mice. Together, this research indicates that multiple transmitters systems are responsible for regulating postural muscle tone during REM sleep, RBD and cataplexy.     

Medullary inspiratory activity: influence of intercostal tendon organs and muscle spindle endings

Studies were conducted to determine the effects of intercostal muscle spindle endings (MSEs) and tendon organs (TOs) on medullary inspiratory activity in decerebrate and allobarbital-anesthetized cats. Impeded muscle contractions, elicited by electrical stimulation of the peripheral cut end of the T6 ventral root, were used to stimulate external and internal intercostal TOs without MSEs. Impeded contractions of either the external or internal intercostal muscles reduced phrenic and medullary inspiratory neuronal activities. Vibration was used to selectively stimulate external or internal intercostal MSEs (90 and 40 micron amplitude, respectively). Selective stimulation of either external or internal intercostal MSEs did not change phrenic or medullary inspiratory neuronal activities. It is concluded that both external and internal intercostal TOs have a generalized inhibitory effect on medullary inspiratory activity and intercostal MSEs have no effect on medullary inspiratory activity.     

Cholinergic mechanisms related to REM sleep. III. Tonic and phasic inhibition of monosynaptic reflexes induced by an anticholinesterase in the decerebrate cat

The depression of the postural activity induced by intravenous injection of eserine sulphate (0.1 mg/kg), an anticholinesterase, has been studied in precollicular decerebrate cats. The extensor and flexor monosynaptic reflexes elicited by single shock stimulation of the GS, P1-FDHL and DP nerves are tonically depressed during the episodes of postural atonia induced by the anticholinesterase. A further phasic depression of the monosynaptic reflexes occurs during the bursts of rapid eye movements (REM) typical of these episodes. These changes in spinal reflex activity closely resemble the tonic depression of the spinal reflexes described in the unrestrained cats during the desynchronized sleep as well as the phasic depression of the spinal reflexes characteristic of the hypnic bursts of REM. Results obtained after spinal cord section indicate that both the tonic and the phasic depression of the spinal reflexes induced by eserine are due to active inhibitory influences originating from supraspinal structures. A complete bilateral destruction of the vestibular nuclei or limited to the medial and descending vestibular nuclei abolishes not only the cholinergically induced bursts of REM, as reported in a previous paper, but also the related phasic depression of the monosynaptic reflexes. These findings can be related with previous observations showing that a bilateral lesion of the vestibular nuclei abolishes the REM bursts of desynchronized sleep, as well as the related phasic inhibition of the spinal reflexes. The tonic depression of the monosynaptic reflexes induced by the anticholinesterase, on the other hand, remains unmodified by this vestibular lesion. This depression, therefore, can be attributed to supraspinal descending inhibitory volleys originating from extravestibular structures.     

Microinjection of DLH into the region of the caudal ventral respiratory column in the cat: evidence for an endogenous cough-suppressant mechanism.

The caudal ventral respiratory column (cVRC) contains premotor expiratory neurons that play an important role in cough-related expiratory activity of chest wall and abdominal muscles. Microinjection of d,l-homocysteic acid (DLH) was used to test the hypothesis that local activation of cVRC neurons can suppress the cough reflex. DLH (20-50 mM, 10-30 nl) was injected into the region of cVRC in nine anesthetized spontaneously breathing cats. Repetitive coughing was elicited by mechanical stimulation of the intrathoracic airways. Electromyograms (EMG) were recorded bilaterally from inspiratory parasternal and expiratory transversus abdominis (ABD) and unilaterally from laryngeal posterior cricoarytenoid and thyroarytenoid muscles. Unilateral microinjection of DLH (1-1.5 nmol) elicited bilateral increases in tonic and phasic respiratory ABD EMG activity, and it altered the respiratory pattern and laryngeal motor activities. However, DLH also decreased cough frequency by 51 +/- 7% compared with control (P < 0.001) and the amplitude of the contralateral (-35 +/- 3%; P < 0.001) and ipsilateral (-34 +/- 5%; P < 0.001) ABD EMGs during postinjection coughs compared with control. The cough alterations were much less pronounced after microinjection of a lower dose of DLH (0.34-0.8 nmol). No cough depression was observed after microinjections of vehicle. These results suggest that an endogenous cough suppressant neuronal network in the region of the cVRC may exist, and this network may be involved in the control of cough reflex excitability.     

Medullary expiratory activity: influence of intercostal tendon organs and muscle spindle endings

Studies were conducted to determine the effects of intercostal muscle spindle endings (MSEs) and tendon organs (TOs) on medullary expiratory activity in decerebrate cats. Impeded intercostal muscle contractions, elicited by electrical stimulation of the peripheral cut end of the T6 ventral root, were used to stimulate intercostal TOs without MSEs. Impeded contractions of the intercostal muscles augmented expiratory laryngeal motoneuron activity, and either had no effect on or reduced the activity of bulbospinal expiratory neurons. Vibration was used to stimulate intercostal MSEs. Intercostal MSEs had no effect on medullary expiratory neuron activity. It is concluded that both external and internal intercostal TOs have an excitatory effect on expiratory laryngeal motoneuron activity and an inhibitory effect on a subpopulation of expiratory neurons driving intercostal and/or abdominal muscles, and intercostal MSEs have no direct influence on medullary expiratory activity.     

Respiratory pattern changes produced by intercostal muscle/rib vibration

Large-amplitude vibration of the intercostal muscles/ribs has an inhibitory effect on inspiratory motor output. This effect has been attributed, in part, to the stimulation of intercostal muscle tendon organs. Intercostal muscle/rib vibration can also produce a decrease or increase in respiratory frequency. Studies were conducted 1) to determine whether, in addition to intercostal tendon organs, costovertebral joint mechanoreceptors (CVJR's) contribute to the inspiratory inhibitory effect of intercostal muscle/rib vibration (IMV) and 2) to explain the different respiratory frequency responses to IMV previously reported. Phrenic (C5) activity was monitored in paralyzed thoracotomized, artificially ventilated cats. Vibration (125 Hz) at amplitudes greater than 1,200 micron of one T6 intercostal space in decerebrated vagotomized rats reduced phrenic activity. This response was still present but weaker in some animals after denervation of the T6 intercostal muscles. Subsequent denervation of the T6 CVJR's by dorsal root sections eliminated this effect. Respiratory frequency decreased during simultaneous vibration (greater than 1,200 micron) of the T5 and T7 intercostal spaces in vagotomized cats. Respiratory frequency increased during IMV of two intercostal spaces (greater than 1,300 micron) in vagal intact cats. The use of different anesthetics (pentobarbital, allobarbital) did not alter these results. We conclude that CVJR's may contribute to the inhibitory effect of IMV on medullary inspiratory activity. The presence or absence of pulmonary vagal afferents can account for the different respiratory frequency responses to IMV, and different anesthetics did not influence these results.     

Stimulation of vagal C-fibers alters timing and distribution of respiratory motor output in cats

Pulmonary vascular congestion or pulmonary embolism in humans produces shallow tachypnea, and indirect experimental evidence suggests that this characteristic breathing pattern may result from activation of vagal unmyelinated afferents from the lung. We have investigated, in decerebrate cats, reflex changes in breathing pattern and in the activation of the diaphragm, posterior cricoarytenoid, and thyroarytenoid muscles caused by activating C-fiber afferents in the vagus nerve. The right vagus nerve was sectioned distal to the origin of the recurrent laryngeal nerve, eliminating vagal afferent traffic although preserving motor innervation of the larynx on that side. The left cervical vagus was stimulated electrically, and efferent activation of the laryngeal muscles was avoided by cutting the left recurrent laryngeal nerve. Transmission to the brain of vagal afferent traffic resulting from this stimulation was controlled by graded cold block of the nerve cranial to the site of application of the stimulus. Activation of C-fibers, when A-fibers were blocked, significantly decreased respiratory period and amplitude of diaphragm inspiratory burst. In addition, this selective activation of vagal C-fibers augmented postinspiratory activity of the diaphragm and recruited phasic expiratory bursts in the thyroarytenoid. We conclude that, in unanesthetized decerebrate cats, afferent traffic of vagal C-fibers initiates a pontomedullary reflex that increases respiratory frequency, decreases tidal volume, and augments braking of expiratory airflow.