Tonic and phasic drive to medullary respiratory neurons during periodic breathing

It is unknown how central neural activity produces the repetitive termination and restart of periodic breathing (PB). We hypothesized that inspiratory and expiratory neural activities would be greatest during the waxing phase and least during the waning phase. We analyzed diaphragmatic and medullary respiratory neural activities during PB in intact unanesthetized adult cats. Diaphragmatic activity was increased and phasic during the waxing phase and was decreased and tonic during the waning phase. Activity of expiratory (n=21) and inspiratory (n=40) neurons was generally increased and phasic during the waxing phase and was decreased and more tonic during the waning phase. During apneas associated with PB, diaphragmatic activity was silent and most, but not all, inspiratory cells were inactive whereas most expiratory cells decreased activity but remained tonically active. We suggest that reduced strength of reciprocal inhibition, secondary to reduced respiratory drive, allows for simultaneous tonic activity of inspiratory and expiratory neurons of the central pattern generator, ultimately resulting in central apnea.     

Tonic and phasic phenomena underlying eye movements during sleep in the cat

Mammalian sleep is not a homogenous state, and different variables have traditionally been used to distinguish different periods during sleep. Of these variables, eye movement is one of the most paradigmatic, and has been used to differentiate between the so-called rapid eye movement (REM) and non-REM (NREM) sleep periods. Despite this, eye movements during sleep are poorly understood, and the behaviour of the oculomotor system remains almost unknown. In the present work, we recorded binocular eye movements during the sleep–wake cycle of adult cats by the scleral search-coil technique. During alertness, eye movements consisted of conjugated saccades and eye fixations. During NREM sleep, eye movements were slow and mostly unconjugated. The two eyes moved upwardly and in the abducting direction, producing a tonic divergence and elevation of the visual axis. During the transition period between NREM and REM sleep, rapid monocular eye movements of low amplitude in the abducting direction occurred in coincidence with ponto-geniculo-occipital waves. Along REM sleep, the eyes tended to maintain a tonic convergence and depression, broken by high-frequency bursts of complex rapid eye movements. In the horizontal plane, each eye movement in the burst comprised two consecutive movements in opposite directions, which were more evident in the eye that performed the abducting movements. In the vertical plane, rapid eye movements were always upward. Comparisons of the characteristics of eye movements during the sleep–wake cycle reveal the uniqueness of eye movements during sleep, and the noteworthy existence of tonic and phasic phenomena in the oculomotor system, not observed until now.     

Tonic and phasic discharge patterns in toe flexor gamma-motoneurons during locomotion in the decerebrate cat.

To investigate the specificity of fusimotor (gamma) drive during locomotion, gamma-efferents were recorded from the flexor digitorum longus (FDL) and flexor hallucis longus (FHL) nerves in a decerebrate cat preparation. These nerves innervate hindlimb muscles that differ in some aspects of their mechanical action. For both FHL and FDL two stereotyped patterns of gamma activity were distinguished. Tonic units fired throughout the step cycle and had less modulation, but higher minimum rates, than phasic units, which were mainly recruited with ankle extensor [soleus (SOL)] electromyogram (EMG) activity. Differences in the relative timing of these patterns were apparent. In FHL the activity of phasic and most tonic neurons peaked after EMG onset. With FDL, tonic units generally reached maximum rate before, while phasic units peaked after, the beginning of EMG activity. During locomotion FHL and FDL alpha activity were rhythmically recruited with SOL. However, consistent with previous reports, FHL and FDL differed in their patterns of alpha activity. FHL was stereotyped while FDL was variable. Both FHL and FDL had activity related to ankle extensor EMG, but only FDL exhibited a peak around the end of this phase. No corresponding gamma activity was observed in FDL. In conclusion, 1) FHL and FDL received tonic and phasic fusimotor drive; 2) there was no alpha/gamma linkage for the late FDL alpha burst; 3) phasic gamma-efferents in both muscles received similar inputs, linked to plantar flexor alpha activity; and 4) tonic gamma-efferents differed, to the extent that they were modulated at all. The FHL units peaked with the plantar flexor alphas. The FDL neurons generally peaked before alpha activity even began.     

Origin of phasic synaptic inhibition in myotomal motoneurons during fictive locomotion in the lamprey

The periodic membrane potential fluctuations in motoneurons during fictive locomotion in the lamprey, a primitive vertebrate, involve phasic synaptic excitation and inhibition. This paper investigates the origin of the phasic synaptic input to lamprey myotomal motoneurons in the in vitro spinal cord preparation with regard to the relative contribution of descending propriospinal input from interneurons in the local segment. The synaptic drive to myotomal motoneurons in the most rostral and the most caudal part of the spinal cord preparation are compared before and after selective spinal cord lesions. Current clamp recordings of the same cell before and after lesion showed that neither the excitatory phase nor the inhibitory phase was abolished after interruption of the descending or the ascending ipsilateral input, or after interrupting crossing segmental input by a local longitudinal midline incision. None of these sources thus appears to be alone responsible for the phasic synaptic drive. To quantitatively evaluate these effects, and in particular the contribution from the descending propriospinal fibres to the inhibitory phase, voltage clamp recordings were made in combination with a spinal cord hemisection just rostral to the motoneuron. The input from propriospinal interneurons in approximately 15 rostral segments may be responsible for as much as 70% of the phase of inhibitory current during the locomotor cycle. In accordance with these findings, a similar voltage clamp analysis of rostrally and caudally located motoneurons showed that the average peak-to-peak amplitude of the current fluctuations in rostral cells was approximately 50% of that in caudal cells.     

Activity of respiratory laryngeal motoneurons during fictive coughing and swallowing

Membrane potential changes and discharges from 28 laryngeal motoneurons were recorded intracellularly in the caudal nucleus ambiguus of decerebrate, paralyzed and ventilated cats. Electrical activities were recorded from 17 expiratory laryngeal motoneurons (ELMs) with maximal depolarizing membrane potential in early expiration, and from 11 inspiratory laryngeal motoneurons (ILMs) with maximal depolarizing membrane potential in inspiration. Activities during breathing were compared with those observed during fictive coughing and swallowing evoked by electrical stimulation of the superior laryngeal nerves. These non-respiratory behaviors were evidenced in paralyzed animals by characteristic discharge patterns of the phrenic, abdominal nerves and pharyngeal branch of the vagus nerve. We recorded the activity of 11 ELMs and 5 ILMs during coughing in which ELMs, but not ILMs, exhibited increased membrane depolarization and discharge frequencies. Membrane depolarization and discharge frequencies of all ELMs were also significantly increased during swallowing. In addition, membrane depolarization of most ELMs (15/17) was preceded by a short-lasting hyperpolarization due to chloride-dependent inhibitory mechanisms occurring at the onset of swallowing. Out of 10 ILMs tested during swallowing, 7 exhibited membrane depolarization, preceded in 5 cases by a short-lasting hyperpolarization. Discharge frequencies of ILMs were significantly reduced during swallowing. The same pattern of phasic activities of ILMs and ELMs was observed during coughing and breathing, suggesting the involvement of similar excitatory pathways in both behaviors. These results imply that the duration of activation and the discharge frequency of neurons of the central generator for breathing that drive laryngeal motoneurons are enhanced during coughing. During swallowing, in addition to central excitatory mechanisms, laryngeal motoneurons are subjected to an initial inhibition of unknown origin. This inhibition probably contributes to the temporal organization of the swallowing motor sequence. Received: 3 December 1998 / Accepted: 26 June 1999     

Discharge patterns of hypoglossal motoneurons during fictive breathing, coughing, and swallowing

We performed a series of experiments to study the intracellular activity of 58 hypoglossal motoneurons (HMs) in decerebrate, paralyzed, and ventilated cats. Changes in membrane potentials (MP) and discharge activities were evaluated during fictive breathing (FB), swallowing (FS), and coughing (FC). FS and FC were elicited by electrical stimulation of the superior laryngeal nerves. FB, FS, and FC all exhibited characteristic discharge patterns of the phrenic, abdominal, pharyngeal branch of the vagus, and hypoglossal nerves. Thirty-nine HMs displayed respiratory modulation, and 19 were nonrespiratory modulated. Nine HMs did not exhibit MP changes during FB, FS, and FC. During FS, 49 HMs exhibited MP changes consisting of depolarization, hyperpolarization or hyperpolarization-depolarization. HMs involved in FS were either respiratory modulated (n = 38) or not (n = 11). Only 20 HMs displayed MP changes and/or discharge activity during FC. All but two HMs fired during the expiratory phase of FC or at the end of this reflex. All HMs involved in FC (n = 20) were also modulated during both FB and FS. Our results suggest that the XII nucleus is functionally divided into common and distinct subsets of HMs based on their spontaneous activities and responses observed during FS and FC. The changes in MP and discharge frequencies observed during the three behaviors also suggest that HMs are driven by specific premotor neurons during FS, whereas a common premotor pathway is involved during FB and FC.     

Interactions between volitional and automatic breathing during respiratory apraxia

The sites and forms of interactions between voluntary breathing acts and automatic respiratory rhythm generation are the subject of considerable research interest. We report here observations of the control of breathing in a patient suffering from an advanced form of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome). This patient demonstrated a severely compromised ability to perform volitional respiratory acts upon command, despite exacerbated behavioural and automatic control of respiration. The presence of residual volitional control of breathing in this patient provided interesting insights concerning the interaction between the automatic and the voluntary control of respiration. We observed that (1) when the subjects was asked to inspire voluntarily he could at best mobilize a volume similar to spontaneous VT and only very slowly; (2) automatic breathing movements persisted, superimposed onto the active voluntary movements, with an amplitude that decreased when the inspiratory activity, albeit weak, reached its maximal level; (3) during breath holding both the amplitude and the frequency of the basal spontaneous rhythmic activity were depressed. This observation therefore supports the idea of a strong interaction between volitional and automatic breathing in the form of an inhibition of automatic activity during voluntary breathing. Although, the site of interaction (spinal versus supraspinal) could not be determined during volitional inspiration, the effect of breath holding on the frequency of the spontaneous breathing activity supports the view that a volitional breathing arrest has some inhibitory effects on the respiratory oscillator at the medullary level. Finally, in an attempt to reconcile the persistence of a rhythmic activity during voluntary inspiration and expiration with previous data from the literature, it is proposed that the normal suppression of the automatic activity during voluntary inspiration relies on cortical and sub-cortical structures involved in the planning, i.e. the praxic component, of a respiratory task rather than on projections originating from the primary motor cortex.     

Arousal thresholds during human tonic and phasic REM sleep

The goal of the present study was to investigate arousal thresholds (ATs) in tonic and phasic episodes of rapid eye movement (REM) sleep, and to compare the frequency spectrum of these sub‐states of REM to non‐REM (NREM) stages of sleep. We found the two REM stages to differ with regard to behavioural responses to external acoustic stimuli. The AT in tonic REM was indifferent from that in sleep stage 2, and ATs in phasic REM were similar to those in slow‐wave sleep (stage 4). NREM and REM stages of similar behavioural thresholds were distinctly different with regard to their frequency pattern. These data provide further evidence that REM sleep should not be regarded a uniform state. Regarding electroencephalogram frequency spectra, we found that the two REM stages were more similar to each other than to NREM stages with similar responsivity. Ocular activity such as ponto‐geniculo‐occipital‐like waves and microsaccades are discussed as likely modulators of behavioural responsiveness and cortical processing of auditory information in the two REM sub‐states.     

Development of synaptic transmission to respiratory motoneurons

Respiratory motoneurons provide the exclusive drive to respiratory muscles and therefore are a key relay between brainstem neural circuits that generate respiratory rhythm and respiratory muscles that control moment of gases into and out of the airways and lungs. This review is focused on postnatal development of fast ionotropic synaptic transmission to respiratory motoneurons, with a focus on hypoglossal motoneurons (HMs). Glutamatergic synaptic transmission to HMs involves activation of both non-NMDA and NMDA receptors and during the postnatal period co-activation of these receptors located at the same synapse may occur. Further, the relative role of each receptor type in inspiratory-phase motoneuron depolarization is dependent on the type of preparation used (in vitro versus in vivo; neonatal versus adult). Respiratory motoneurons receive both glycinergic and GABAergic inhibitory synaptic inputs. During inspiration phrenic and HMs receive concurrent excitatory and inhibitory synaptic inputs. During postnatal development in HMs GABAergic and glycinergic synaptic inputs have slow kinetics and are depolarizing and with postnatal development they become faster and hyperpolarizing. Additionally shunting inhibition may play an important role in synaptic processing by respiratory motoneurons.     

Discharge patterns of human genioglossus motor units during sleep onset

STUDY OBJECTIVES: Multiunit electromyogram recordings of genioglossus have demonstrated an abrupt reduction in the muscle's activity at sleep onset. Recent evidence from single motor unit recordings indicates that the human genioglossus muscle consists of motor units with a variety of discharge patterns. The aim of the present study was to determine the effect of sleep onset on the activity of individual motor units as a function of their particular discharge pattern. DESIGN: Genioglossus activity was assessed using intramuscular fine-wire electrodes via a percutaneous approach. Sleep onsets (alpha-to-theta transitions) were identified and the genioglossus electromyogram recordings analyzed for single motor unit activity. SETTING: Sleep research laboratory. PARTICIPANTS: Sleep and respiratory data were collected in 8 healthy subjects (6 men). MEASUREMENTS AND RESULTS: One hundred twenty-seven motor units were identified: 23% inspiratory phasic, 45% inspiratory tonic, 4% expiratory phasic, 9% expiratory tonic, 16% tonic, and 3% other. Approximately 50% of inspiratory units (phasic and tonic) ceased activity entirely at sleep onset, whereas those inspiratory units that continued to be active showed a reduction in the proportion of each breath over which they were active. However, the rate of discharge of inspiratory units during the period they did fire was not altered. In contrast, tonic and expiratory units were unaffected by sleep onset, maintaining their discharge pattern over the alpha-to-theta transition. CONCLUSIONS: Central control of inspiratory motoneuron output differs from that of tonic and expiratory units during sleep onset, suggesting that the maintenance of airway patency during sleep may become more reliant on the stiffening properties of tonic and expiratory modulated motor units.     

Imposed breathing pattern alters respiratory work during exercise

Previous studies have shown the existence of an ideal respiratory rate (f _R) for a given ventilation at which the respiratory work rate (J·s^–1) is minimum. The purpose of the present study was to measure the effect off _R, tidal volume and breathing pattern on the respiratory work per breath and respiratory work rate during exercise on a cycle ergometer. Three work rates on the cycle ergometer were used and at each work rate the ventilation was kept constant. Two different breathing patterns were applied at each ventilation. Nine male trained cyclists [mean (SD) maximum oxygen consumption, 57 (5.47) ml·kg^–1·min^–1] participated in this study. The results indicated that there was a significant difference in the respiratory work per breath, with different breathing patterns at a given ventilation and for all levels of ventilation. There was no significant difference in the respiratory work rate with different breathing patterns at a given ventilation and for all levels of ventilation. In addition, the respiratory work per breath and respiratory work rate were increased with increasing ventilation. Thus, the data indicated that the manipulation of tidal volume, respiratory rate and breathing pattern had no significant effect on the energy cost of breathing for a given ventilation. The absence of this significant effect on respiratory work rate was observed across a range of ventilation from 24 to 72 l·min^–1. These findings suggest that the breathing pattern is predominantly an expression of the function of the higher respiratory brain center instead of energy economy, at least within this range of ventilation.     

Alpha-7 and alpha-4 nicotinic receptor subunit immunoreactivity in genioglossus muscle motoneurons

In the present study, immunohistochemistry combined with retrograde labeling techniques were used to determine if hypoglossal motoneurons (HMNs), retrogradely labeled after cholera toxin B subunit (CTB) injection to the genioglossus muscle in rats, show immunoreactivity for alpha-7 and alpha-4 subunits of nicotinic acetylcholine receptors (nAChRs). CTB-positive HMNs projecting to the genioglossus muscle were consistently labeled throughout the rostrocaudal extent of the hypoglossal nuclei with the greatest labeling at and caudal to area postrema. Alpha-7 subunit immunoreactivity was found in 39.44+/-5.10% of 870 CTB-labeled motoneurons and the alpha-4 subunit in 51.01+/-3.71% of 983 CTB-positive neurons. Rostrally, the number of genioglossal motoneurons demonstrating immunoreactivity for the alpha-7 subunit was 45.85+/-10.04% compared to 34.96+/-5.11% at and caudal to area postrema (P>0.1). The number of genioglossal motoneurons that showed immunoreactivity for the alpha-4 subunit was 55.03+/-4.83% at and caudal to area postrema compared to 42.98+/-3.90% in rostral areas (P=0.074). These results demonstrate that nAChR immunoreactivity is present in genioglossal motoneurons and suggest a role for alpha-7 and alpha-4 subunits containing nAChRs in the regulation of upper airway patency.     

Oxygenation and breathing pattern during phasic and tonic REM in patients with chronic obstructive pulmonary disease

Oxygen desaturation in chronic obstructive pulmonary disease (COPD) occurs during sleep and is most marked in REM sleep. REM is not a homogeneous state, consisting of phasic REM (PREM) (REMs, myoclonic twitches) and tonic REM (TREM) (muscle atonia, desynchronized electroencephalogram). In normals, onset of PREM produces transient changes in breathing pattern with a decrease in respiratory amplitude and an increase in frequency, which produce reductions in oxygen saturation (SaO2). Because it is reasonable to expect such breathing pattern changes to cause more desaturation in COPD, and because systematic all-night studies of PREM and TREM have not been reported, we studied 18 patients with severe COPD [Forced expiratory volume in one second (FEV1) = 25.7 +/- 3.5 (SEM) % predicted] during sleep and monitored SaO2 and breathing pattern in PREM and TREM. PREM made up 19.7% of total REM (4.6% total sleep time) but was associated with 81.7% of the total REM desaturations of greater than 5% (57.9% of all sleep desaturations of greater than 5%). With PREM onset, breathing pattern changed 72.5% of the time, most often with a transient decrease in amplitude and increase in frequency. Even though 27.5% of PREM was not associated with changes in breathing pattern and many PREM segments were very short, we were still able to show highly significant SaO2 differences between PREM and TREM. Mean TREM SaO2 was 88.0 +/- 1.2%; mean PREM SaO2 was 86.6 +/- 1.4%, with mean nadir SaO2 for individual PREM segments falling to 84.8 +/- 1.5%. Mean awake SaO2 was 89.7 +/- 0.8%. We conclude that in COPD the transition from TREM to PREM is associated with breathing pattern changes and oxygen desaturation. Differences in breathing pattern with PREM onset may be related to different effects of PREM processes on respiratory neurons and diaphragm motor neurons.     

Spinal respiratory motoneurons and interneurons

Maintenance of life among higher vertebrates depends on permanent, rhythmic and coordinated activity of respiratory muscles. Fundamental to our understanding of breathing is an appreciation for the neural components involved in the generation, maintenance and modulation of respiratory rhythm. Multidisciplinary studies have revealed important perspectives about the spinal and supraspinal components contributing to breathing, but a complete understanding of respiratory pathways and their interconnectivity remains unknown. Definition of these pathways is essential for understanding how respiratory processes may be affected by injury or disease. The present review highlights our current understanding of the distribution of spinal motoneurons and interneurons involved in mammalian respiratory activity and how they are affected by injury or disease in the central nervous system.     

Firing patterns of human genioglossus motor units during voluntary tongue movement

The tongue participates in a range of complex oromotor behaviors, including mastication, swallowing, respiration, and speech. Previous electromyographic studies of the human tongue have focused on respiratory-related tongue muscle activities and their role in maintaining upper airway patency. Remarkably, the activities of human hypoglossal motor units have not been studied during the execution of voluntary maneuvers. We recorded single motor unit activity using tungsten microelectrodes in the genioglossus muscle of 10 healthy human subjects performing both slow tongue protrusions and a static holding maneuver. Displacement of the tongue was detected by an isotonic transducer coupled to the lingual surface through a customized lever arm. For protrusion trials, the firing rate at recruitment was 13.1 +/- 3 Hz and increased steeply to an average of 24 +/- 6 Hz, often with very modest increases in tongue protrusion. For the static holding task, the average firing rate was 16.1 +/- 4 Hz, which is surprisingly high relative to limb motor units. The average coefficient of variation of interspike intervals was approximately 20% (range, 10-28%). These are the first recordings of their type obtained in human subjects and provide an initial glimpse into the voluntary control of hypoglossal motoneurons during tongue movements presumably instigated by activity in the motor cortex.