Expiratory-inspiratory Research Articles

Plausible presynaptic effects of opioids on pontine inspiratory circuits: New insights from a joint neural biomechanical model

Administration of opioids significantly effects tidal volume, respiratory rate, and blunts CO2 responsiveness. The precise neural mechanisms that determine the respiratory depressant effects of opioids are controversial. One hypothesis is that mu‐opioid agonists hyperpolarize neurons located in the pons and this action prolongs inspiratory cycle duration. We tested the plausibility of this hypothesis by employing a neuromechanical model of the respiratory control system. We targeted medullary inspiratory neuron axon terminals that influence 4 neuronal populations within the pons that had an inspiratory component to their discharge (inspiratory (I), expiratory/inspiratory (EI), rostral inspiratory/expiratory (rIE), and caudal inspiratory/expiratory (cIE)) neurons). We systematically decreased the conductance of these synapses by 25, 50, 75 and 100 percent and monitored the effect on the respiratory motor pattern. Simulations revealed that decreasing the conductance of synapses from medullary inspiratory neurons to neuronal populations in the pons altered the breathing pattern. In general, a reduction in synaptic conductance from medullary inspiratory neurons to each of the 4 pontine neuron populations decreased their excitability. Decreasing the synaptic conductance from the medullary inspiratory decrementing (I‐Dec) population to the: 1) I pons population resulted in a decrease in phrenic burst frequency and a decrease in the Inspiratory‐Driver (I‐Driver) population excitability, 2) EI pons population resulted in a decrease in I pons excitability and phrenic neurogram magnitude, 3) rIE population did not reveal significant changes in the breathing pattern from control, and 4) cIE population resulted a decrease in I‐Driver population excitability, phrenic neurogram amplitude and phrenic burst frequency. Decreasing conductance of synapses from the inspiratory augmenting (I‐Aug) population to the I pons, cIE, or rIE populations resulted in decreases in phrenic neurogram magnitude. Our simulation data support the plausibility of presynaptic effects of opioids within the pontine respiratory group that induce respiratory depression. Further, these presynaptic effects can induce selective alterations in inspiratory drive and/or breathing cycle timing.

Reduction in Pulse Pressure during Standing Can Distinguish Neurogenic Orthostatic Hypotension.

Background: We investigated whether changes in the pulse pressure (PP) reduction ratio during the head-up tilt test (HUTT) can aid in distinguishing neurogenic orthostatic hypotension (OH) from non-neurogenic OH. Methods: We enrolled consecutive patients with NOH and non-neurogenic OH between January 2015 and October 2018. We compared the Valsalva ratio, the presence or absence of late phase II and IV overshoot, the pressure recovery time, and the PP reduction ratio during HUTT between the two OH groups. Results: The expiratory–inspiratory (E:I) ratio and Valsalva ratio were significantly decreased in the NOH group (p = 0.026, p < 0.001, respectively). The absence of late phase II and phase IV overshoot was more frequent in the NOH group than in the non-neurogenic OH group (p = 0.001, p < 0.001, respectively). The pressure recovery time was significantly prolonged in the NOH group (p < 0.001), which exhibited increases in the PP reduction ratio (1—minimal PP/baseline PP) during the HUTT (p < 0.001). We calculated the cutoff point for the PP reduction ratio during HUTT, which exhibited an area under the receiver operating characteristic curve of 0.766 (0.659–0.840, 95% confidence interval). The cutoff value for the PP reduction ratio during HUTT (0.571) exhibited sensitivity of 0.879 and specificity of 0.516. Conclusions: Increases in the PP reduction ratio during HUTT may be a meaningful NOH laboratory marker.

Pre‐inspiratory and inspiratory hypoglossal motor output during hypoxia induced plasticity in the rat

Respiratory discharge in the hypoglossal (XII) nerve is composed of pre‐inspiratory (pre‐I) and inspiratory (I) activity. Our first purpose was to test the hypothesis that hypoxia‐induced plasticity in XII motor output is differentially expressed in pre‐I vs. I XII bursting. Short‐term potentiation (STP) of XII motor output was induced in vagotomized and ventilated rats by isocapnic hypoxia. Both pre‐I and I XII discharge abruptly increased at beginning of hypoxia, and the relative increase in amplitude was much greater for pre‐I vs. I bursting. In addition, STP was expressed in I but not pre‐I bursting following hypoxia. Specifically, I activity remained elevated following hypoxia but pre‐I bursting abruptly returned to pre‐hypoxia levels. Our second purpose was to test the hypothesis that STP of I XII activity results from recruitment of silent XII motoneurons (MNs) vs. rate coding of active MNs. Single fiber recordings were used to classify XII MNs as I, expiratory‐inspiratory (E‐I), or silent based on baseline discharge patterns. STP of I XII activity following hypoxia was associated with increased discharge frequency in active I and silent MNs, but not E‐I MNs. We conclude that the expression of respiratory plasticity is differentially regulated between pre‐I and I XII activity. Moreover, both recruitment of silent MNs and rate coding of active I MNs contribute to STP of XII motor output following hypoxia.

Pulmonary C-fiber receptor activation abolishes uncoupled facial nerve activity from phrenic bursting during positive end-expired pressure in the rat

Phasic respiratory bursting in the facial nerve (FN) can be uncoupled from phrenic bursting by application of 9 cmH(2)O positive end-expired pressure (PEEP). This response reflects excitation of expiratory-inspiratory (EI) and preinspiratory (Pre-I) facial neurons during the Pre-I period and inhibition of EI neurons during inspiration (I). Because activation of pulmonary C-fiber (PCF) receptors can inhibit the discharge of EI and Pre-I neurons, we hypothesized that PCF receptor activation via capsaicin would attenuate or abolish uncoupled FN bursting with an increase from 3 cmH(2)O (baseline) to 9 cmH(2)O PEEP. Neurograms were recorded in the FN and phrenic nerve in anesthetized, ventilated, vagally intact adult Wistar rats. Increasing PEEP to 9 cmH(2)O resulted in a persistent rhythmic discharge in the FN during phrenic quiescence (i.e., uncoupled bursting). Combination of PEEP with intrajugular capsaicin injection severely attenuated or eliminated uncoupled bursting in the FN (P < 0.05). Additional experiments examined the pattern of facial motoneuron (vs. neurogram) bursting during PEEP application and capsaicin treatment. These single-fiber recordings confirmed that Pre-I and EI (but not I) neurons continued to burst during PEEP-induced phrenic apnea. Capsaicin treatment during PEEP substantially inhibited Pre-I and EI neuron discharge. Finally, analyses of FN and motoneuron bursting across the respiratory cycle indicated that the inhibitory effects of capsaicin were more pronounced during the Pre-I period. We conclude that activation of PCF receptors can inhibit FN bursting during PEEP-induced phrenic apnea by inhibiting EI and I facial motoneuron discharge.

Inhibition of respiratory‐related activity of the facial nerve by pulmonary vagal C‐fiber activation in the rat

We have previously reported that respiratory-related facial nerve activity can be modulated by hypercapnia, lung inflation, and positive end-expired pressure (PEEP). Whether respiratory-related rhythmic activities of the facial nerve could be modulated by pulmonary C-fiber activation is unclear. Activity of the facial and phrenic nerve was recorded simultaneously in the anesthetized and ventilated adult rat. Activation pulmonary C-fiber by intra-jugular injection of capsaicin produced a dose-dependent reduction of amplitude and onset of the facial nerve activity. Furthermore, uncoupled facial activity (persistent rhythmic activity during phrenic cessation) evoked by increasing PEEP could be also suppressed by capsaicin injection. Single fiber recording from the facial nerve revealed that capsaicin treatment produced inhibition on activity of expiratory-inspiratory (EI) motoneuron during expiration such that became inspiratory motoneurons and of pre-inspiratory motoneurons. In addition, capsaicin injection could attenuate the uncoupled activity of EI from the phrenic burst caused by PEEP manipulation. These results implied that capsaicin might differentially inhibit pre-inspiratory than inspiratory facial activity.

Uncoupling of upper airway motor activity from phrenic bursting by positive end-expired pressure in the rat

Phasic bursting in the hypoglossal nerve can be uncoupled from phrenic bursting by application of positive end-expired pressure (PEEP). We wished to determine whether similar uncoupling can also be induced in other respiratory-modulated upper airway (UAW) motor outputs. Discharge of the facial, hypoglossal, superior laryngeal, recurrent laryngeal, and phrenic nerves was recorded in anesthetized, ventilated rats during stepwise changes in PEEP with a normocapnic, hyperoxic background. Application of 3- to 6-cmH(2)O PEEP caused the onset inspiratory (I) UAW nerve bursting to precede the phrenic burst but did not uncouple bursting. In contrast, application of 9- to 12-cmH(2)O PEEP uncoupled UAW neurograms such that rhythmic bursting occurred during periods of phrenic quiescence. Single-fiber recording experiments were conducted to determine whether a specific population of UAW motoneurons is recruited during uncoupled bursting. The data indicate that expiratory-inspiratory (EI) motoneurons remained active, while I motoneurons did not fire during uncoupled UAW bursting. Finally, we examined the relationship between motoneuron discharge rate and PEEP during coupled UAW and phrenic bursting. EI discharge rate was linearly related to PEEP during preinspiration, but showed no relationship to PEEP during inspiration. Our results demonstrate that multiple UAW motor outputs can be uncoupled from phrenic bursting, and this response is associated with bursting of EI nerve fibers. The relationship between PEEP and EI motoneuron discharge rate differs during preinspiratory and I periods; this may indicate that bursting during these phases of the respiratory cycle is controlled by distinct neuronal outputs.

Characteristics of pre‐inspiratory and decoupled activities of the upper airway motoneurons in the rat

Inspiratory activities of the upper airway motor nerves (UAWMN) commence before phrenic burst. These pre-inspiratory (Pre-I) activities of the UAWMN may play an important role in the stabilization of UAW patency. To get insight into the mechanism for this preceding onset of the UAW motoneurons, we investigated influence of different level of positive end-expired pressure (PEEP) on pre-I activities of UAWMN in the first part of the current study. Activities of UAWMN, including the facial, hypoglossal, and superior laryngeal nerves, and the phrenic nerve were recorded simultaneously in anesthetized and artificially ventilated rats. Our results showed that Pre-I activities of UAWMN were all increased and even decoupled from phrenic burst (a response activity during phrenic cessation) by the increase of PEEP to a level between 6–12 cmH2O. Further increased PEEP to a level of 15 cmH2O produced, however, an inhibition on Pre-I and decoupled activities. In the second part, we monitored single fiber activities on each of the UAWMN and found that decoupled activity was primarily due to the persistence of activities of expiratory-inspiratory (EI) motoneurons during phrenic burst cessation. Our data suggest that signals from changes in PEEP might induce either excitation or inhibition on Pre-I and decoupled activities of UAWMN. They might also indicate that rhythmic activities of UAWMN could be uncoupled from the phrenic nerve burst by increasing PEEP.

Coordination of swallowing and phases of respiration during added respiratory loads in awake subjects.

In order to test the hypothesis that different types of respiratory mechanical loads may differently modify the coordination of respiration and swallowing, we investigated the coordination of respiration and swallowing during resistive and elastic loads in 14 healthy subjects. Ventilation was monitored with a pneumotachograph and reflex swallowing was elicited by continuous infusion of distilled water into the pharynx (3 ml/min) and recorded on a submental electromyogram while the subject breathed through a device with a flow-resistive load (180 cm H2O/L/s), an elastic load (70 cm H2O/L), or without any external load. We found that addition of a flow-resistive load did not influence the frequency of swallowing, whereas addition of an elastic load caused a significant increase in swallowing frequency during continuous infusion of water. Analysis of the timing of swallowing in relation to respiratory cycle phase revealed that with flow-resistive loading, swallows occurred preferentially during the inspiratory-expiratory (I-E) transition, whereas with elastic loading, swallows occurred preferentially during the expiratory-inspiratory (E-I) transition. Signs of laryngeal irritation were observed most often during the elastic loading following E-I swallows. These results indicate that different types of respiratory mechanical loads can differently modify this coordination of respiration and swallowing, and suggest that the coordination may be compromised more with elastic loading than with flow-resistive loading.

Respiratory phase resetting and airflow changes induced by swallowing in humans.

1. Relationships between the timing of respiration and deglutition were studied in thirty awake healthy subjects at rest. Deglutition was monitored by submental electromyography, pharyngeal manometry and videofluoroscopy. Respiration was recorded by measurement of oronasal airflow and chest wall movement. Three types of deglutition were studied: injected bolus swallows, spontaneous swallows, and visually cued swallows of boluses previously placed in the mouth. 2. The effect of each swallow on respiratory rhythm was characterized by measurement of cophase, defined as the interval between the onset of deglutitive submental EMG activity to the onset of subsequent rescheduled inspirations. Cophase was determined for swallows initiated at different phases of the respiratory cycle. In all subjects deglutition caused phase resetting of respiratory rhythm. Cophase was largest for swallows initiated near the the inspiratory-expiratory (E-I) transition and smallest for swallows initiated near the expiratory-inspiratory (E-I) transition. The pattern of respiratory resetting by deglutition was topologically classified as type 0. This pattern was shown for swallows induced by bolus injection or visual cue, and for spontaneous swallows. 3. The incidence of spontaneous deglutition was influenced by the position of the swallow in the respiratory cycle. Few spontaneous swallows were initiated near the E-I transition whereas most occurred from late inspiration to mid-expiration. 4. Deglutition caused an abrupt decrease in airflow leading to an interval of apnoea, followed by a period of expiration. The duration of deglutition apnoea for spontaneous swallows was shorter than that for 5 ml bolus swallows, and was unaffected by the respiratory phase of swallow initiation. The period of expiration after swallowing was longest for swallows initiated at the I-E transition, and shortest for E-I swallows. 5. The intervals between bolus injection and the onset of deglutition apnoea, and the timing of swallowing events, were not significantly altered by the phase in the respiratory cycle at which swallowing was exhibited. 6. To quantify the relationship between bolus flow and respiration, we determined the latencies between cessation of inspiratory airflow and arrival of the bolus at the larynx (alpha), and between laryngeal bolus departure and resumption of inspiratory airflow (delta). Both values were dependent upon the respiratory phase of swallowing. The lowest values for alpha and delta were found for early-inspiratory and late-expiratory swallows, respectively. 7. We conclude that swallowing causes respiratory phase resetting with a pattern that is characteristic of the strong perturbations of an attractor-cycle oscillator.(ABSTRACT TRUNCATED AT 400 WORDS)

Bifurcations of the respiratory pattern produced with phasic vagal stimulation in the rat

Geometric methods from nonlinear dynamics are employed to evaluate dynamic processing of vagal afferent information by the respiratory central pattern generator (RCPG). While measuring airflow and diaphragm EMG, we applied brief electrical stimuli (40- to 130-ms duration) to one afferent vagus of bilaterally vagotomized urethan-anesthetized rats during every breath at various phases of the respiratory cycle. Stimuli applied during early or late inspiration of every breath evoke highly predictable one-dimensional responses: reversible (graded inhibition) or irreversible (off-switching) inhibition of inspiratory activity, respectively. Stimulation during midinspiration produces higher-dimensional oscillations that wander unpredictably over a continuum of graded inhibition and off-switching; "spiral" attractors and "horseshoe" return maps at this phase are characteristic of Silnikov's bifurcation. Stimuli applied during early expiration always prolonged expiratory duration, but those delivered during midexpiration evoked unpredictable wandering between prolongations and shortening of expiratory duration. A narrow time window surrounds the expiratory-inspiratory (E-I) transition, where stimuli elicit either breaths of short duration and low amplitude (irreversible E-I transition, decreased total respiratory cycle duration) or transient bursts of inspiratory activity at the E-I transition followed by a prolonged breath (reversible E-I transition, increased total respiratory cycle duration). We conclude that RCPG "gating" of and adaptation to vagal feedback combine to produce complex breath-to-breath dynamics in the rat that are consistent with low-dimensional chaos.

Medullary respiratory-related neurons with axonal connections to rostral pons and their function in termination of inspiration.

In urethane-anaesthetized, paralyzed and artificially ventilated rabbits, medullary respiration-related neurons (RRU) were classified according to the phase relation of their burst discharge to phrenic nerve activity. Phase-bound inspiratory (I) or expiratory (E) neurons were discriminated from phase-spanning expiratory-inspiratory (EI) or inspiratory-expiratory (IE) units. Mechanisms of termination of inspiration by electrical stimulation of rostral pontine nuclei (Nc. parabrachialis medialis; Lc. coeruleus) were examined firstly to demonstrate whether RRU receive descending excitatory and inhibitory afferents as well as ascending efferents and secondly to analyse the time course of the neuronal pathways involved. Of 120 RRU, 38 neurons were demonstrated to receive pontine afferents. About 33% of all E neurons became orthodromically excited during rostral pons stimulation whereas 18.2% of all I cells became orthodromically inhibited. Some RRU were shown to project up to the rostral pons. 50% of these were of the phase-spanning IE type. The onset of inspiratory inhibition induced by rostral pons stimulation occurred 3.4 ms after the onset of single electrical pulse stimulation. Based on these results a neuronal model for a pontine mechanism terminating inspiration is proposed.

Characterization of respiratory-modulated activities of hypoglossal motoneurons.

In decerebrate, vagotomized, paralyzed, and ventilated cats, activities of the phrenic nerve and single hypoglossal nerve fibers were monitored. The great majority of hypoglossal neuronal activities were inspiratory (I), discharging during a period approximating that of phrenic. Many were not active at normocapnia but were recruited in hypercapnia or hypoxia. Once recruited, discharge frequencies, which rose quickly to near maximal levels in early to midinspiration, significantly increased with further augmentations of drive. Also, the onset of activities became progressively earlier, compared with phrenic discharge, in hypercapnia or hypoxia. Smaller numbers of hypoglossal fiber activities, having inspiratory-expiratory (I-E), expiratory (E), expiratory-inspiratory (E-I), or tonic discharge patterns, were also recorded. Activities of E, I-E, and those I fibers that became I-E in high drive may underlie the early burst of expiratory activity of the hypoglossal nerve. It is concluded that the firing and recruitment patterns of hypoglossal neurons differ from those of phrenic motoneurons. However, responses to chemoreceptor stimuli are similar among the two neuronal groups.

Inhibitory action of vagal nerve and spinal cord afferents on discharge pattern of bulbar respiratory modulated neurons.

Single vagal nerve stimuli delivered during burst discharge of respiratory modulated neurons entailed lengthening of an interspike interval in 37% of all units tested. Occasionally stimuli delivered to the spinal cord caused lengthening of interspike intervals in respiratory modulated neurons and in other bulbar units the discharge of which was not modulated with respiration. Vagal stimuli often entailed lengthening of the following interspike interval, while the interval during which stimuli were applied remained unaltered; latencies suggested that inhibitory pathways were polysynaptic. In expiratory-inspiratory (EI) and inspiratory (I) neurons, lengthenings of intervals roughly doubled those noted in inspiratory-expiratory (IE) and expiratory (E) units. Lengthening of intervals depended on stimulus incidence within the intervals and was greatest when stimuli were delivered during the late part of the intervals. In EI and I units, lengthening of intervals occurred mainly during the middle part of burst discharge, in IE and E neurons, however, towards the end of the burst. Conditioning of discharge of respiratory modulated neurons could be demonstrated.

Metabolic control of respiratory neuronal activity and the accompanying changes in breathing movements of the rabbit

The property of the neuronal membrane to be permeable to metabolic modifiers of two regulatory enzymes has been utilized to manipulate the spike activity of inspiratory (I) and expiratory-inspiratory (EI) neurons of the bulbar respiratory centre. The neurons have been classified according to their response to lung distention or collapse (alpha- or beta-type) and to hyperventilation (tonic firing denoted by "+", cessation of activity by "-"). Using extracellular microelectrodes for single unit recording, the medulla oblongata was superfused with a metabolite-containing CSF. The various neuronal sub-types exhibited a differential activating or inhibitory response to one or several metabolic effectors. For example Ialpha+ units were activated by 5 mM glucose-6-phosphatase (G-6-P) and 3.5 mM 3-phosphoglycerate (3-PGA), which both inhibited Ibeta+ neurons, while 5 mM AMP inhibited Ialpha+ much more strongly than Ibeta+ cells. The spike density of Ialpha- and Ibeta- neurons was increased in the presence of 2.5 mM fructose-6-phosphate and 3.5--5 mM AMP, but became reduced by G-6-P. In contrast, 3 mM fructose-1,6-diphosphate and 5 mM 3-PGA activated the Ialpha- but inhibited the Ibeta- neurons. The EIbeta units were characteristically activated by 10 mM citrate, which inhibited all I-type neurons. Activations of the Ialpha and Ibeta neurons led to an accelerated respiratory rate and a higher tidal volume, while the opposite was true for EIbeta neurons. Intravenous injection of metabolites could not duplicate the striking effects under local applications.