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Chi-sang Poon - One of the best experts on this subject based on the ideXlab platform.

  • Mechanisms of respiratory-ventilator entrainment and its buffering by differentiator-type nonassociative learning.
    2013
    Co-Authors: Shawna M. Macdonald, Gang Song, Chi-sang Poon
    Abstract:

    (Possible reciprocal connections for all paths are not shown.) In the absence of PEEP (top panel), phasic volume-related inputs entrain the respiratory rhythm generator (I-E) via the nucleus tractus solitarius (NTS) which also modulates the pneumotaxic center in dorsolateral pons (dl-pons). Immediately upon the application of PEEP (middle panel), tonic activities in the NTS and dl-pons elicit the Hering-Breuer Reflex prolongation of expiration and shortening of inspiration, momentarily impairing entrainment. Finally, habituation of the NTS and desensitization of the pneumotaxic center (bottom panel) eventually buffer the effect of PEEP, restoring the respiratory rhythm. Sustained stimulation of dl-pons produces similar Hering-Breuer Reflex and desensitization effects as PEEP.

  • Modulation of Hering-Breuer Reflex by Ventrolateral Pons
    Advances in experimental medicine and biology, 2008
    Co-Authors: Hui Wang, Heng Zhang, Gang Song, Chi-sang Poon
    Abstract:

    The vagally-mediated Hering-Breuer Reflex (HBR) is known to be modulated by the classic pneumotaxic center in the dorsolateral pons. In this work, we investigated whether the HBR was also modulated by the ventrolateral pons (vl-pons). Experiments were performed on urethane anesthetized adult rats. The HBR was elicited by electrical stimulation of the vagus nerve and its strength was compared before and after electrical stimulation or microinjection of MK-801 (non-competitive NMDA receptor antagonist) at the vl-pons. We found that the inspiratory inhibition and expiratory prolongation effects of the HBR were strengthened after electrical stimulation at the vl-pons but were weakened after microinjecting MK-801. Results suggested that the vl-pons could influence the respiratory rhythm by modulating the strength of HBR via NMDA receptor-mediated neurotransmission.

  • habituation desensitization and sensitization of the Hering Breuer Reflex in normal and mecp2 y knockout mice
    The Journal of Physiology, 2007
    Co-Authors: Chi-sang Poon, Gang Song
    Abstract:

    In an interesting study published recently in The Journal of Physiology,Stettner et al. (2007) reported that Mecp2−/y knockout (KO) mice devoid of the X-linked methyl-CpG binding protein 2 gene demonstrated prolonged and highly variable postinspiratory vagal efferent activity that correlated with the characteristic breathing arrhythmias in these mutant animals. Furthermore, glutamate microinjections into the pontine Kolliker–Fuse nucleus evoked significantly longer apnoeas with enhanced postinspiratory vagal discharge compared with wild-type (WT) controls. Finally, the authors provided data to suggest that repetitive electrical stimulation of vagal afferents also elicited significantly longer Hering–Breuer Reflex (HBR)-like apnoeas in the Mecp2−/y KO mice without any sign of ‘desensitization’ of the Reflex. We applaud the authors' elaboration of impaired vagal-pontine control of the respiratory rhythm in Mecp2−/y KO mice. However, we feel obliged to point out that their notion of differing ‘desensitization’ of the vagally induced HBR apnoeas in wild-type and Mecp2−/y KO animals is problematic and is at variance with current understanding of non-associative learning in brain pathways in general and in vagal-pontine mediation of the HBR in particular. Comparison with previous related studies is important because not only does it help to put the significance of the work in perspective, but in this case, it also reveals major discrepancies in interpretation of the results that point to a very different conclusion. For many decades, non-associative learning in the parlance of the behavioural neuroscience literature has been generally thought of as a dual process (habituation or sensitization) corresponding to activity-dependent down- or up-regulation of the response to a continuous or repetitive stimulus (Groves & Thompson, 1970). The notion of desensitization as a novel (and non-trivial) form of non-associative learning was first introduced in this Journal by Siniaia et al. (2000) precisely in the context of fictive HBR modulation of the respiratory frequency (particularly expiratory duration (Poon et al. 2000)) induced by low-intensity, high-frequency vagal electrical stimulation. This notion has led to a general framework of non-associative learning with four base modes (habituation, desensitization, primary sensitization and secondary sensitization), which has proved to harmoniously unify the functional characteristics of non-associative learning reported in many brain systems across animal phyla and sensory modalities (Poon & Young, 2006). Conventionally, habituation is characterized as (among other functional criteria) a down-regulating adaptation with short-term memory (Groves & Thompson, 1970; Poon & Young, 2006). Importantly, the latter remains latent post-stimulation and is activated (recalled) only when stimulated again – a process which has been termed ‘input gating’ (Young et al. 2003; Poon & Young, 2006). Desensitization is distinguished from habituation by the explicit expression of post-stimulation memory rebound and recovery, as desensitization (i.e. secondary habituation) is not subject to input gating. The exponential down-regulation effects of habituation and desensitization have been likened to those of a monophasic or biphasic (without or with memory rebound) neural differentiator or high-pass filter (Poon & Siniaia, 2000; Poon et al. 2000; Poon & Young, 2006). In the vagally induced HBR, desensitization was abolished after lesioning of the Kolliker–Fuse nucleus or systemic administration of the non-competitive NMDA receptor antagonist MK-801 (Poon et al. 2000; Siniaia et al. 2000). A working scheme of vagal-pontine mediation of the HBR and its habituation and desensitization has been proposed previously (Poon & Siniaia, 2000; Siniaia et al. 2000; Poon, 2004; Song & Poon, 2004). The authors of this paper stated that ‘All WT preparations showed a clear desensitization of the HBR in response to repetitive vagal stimulation’. However, from the presented data (Fig. 7A in Stettner et al. 2007) it appears that the shortening of the apnoea duration after repetitive stimulation reflected habituation (in the classical sense) of the HBR instead of desensitization, since a memory rebound was not evident at the cessation of vagal stimulation. Indeed, if anything, the expiratory duration remained longer immediately after both the 1st and 15th stimulation trial compared with resting conditions, showing the memory effects of concomitant secondary (not primary; see Poon & Young, 2006) sensitization of the HBR instead. This post-stimulation sensitization memory appeared to be accentuated in the Mecp2−/y KO animals, as indicated by the sustained apnoeas extending well beyond the vagal stimulation period (Fig. 7B and C). The mechanism of this peculiar secondary sensitization (instead of desensitization) of the HBR in wild-type and Mecp2−/y KO animals is unclear but could potentially result from activation of rapidly adapting pulmonary stretch receptor fibres or even cardiopulmonary C-fibres, as such secondary sensitization effects were not elicited by low-intensity, high-frequency (15–40 μA, 40–80 Hz) vagal electrical stimulation in rats (Poon et al. 2000; Siniaia et al. 2000). The authors also used a repetitive vagal stimulation protocol to induce non-associative learning of the HBR, apparently because the evoked apnoea was not habituated within the 10 s stimulation period due to the strength of the stimulation. Such a repetitive stimulation protocol is routine in studies of non-associative learning in invertebrate sensorimotor pathways to allow for refractory (‘output gating’) of the resultant motor response (Poon & Young, 2006). Since the mammalian respiratory motor response is non-refractory, a continuous (and sufficiently long) vagal stimulus should be as effective as a repetitive one in discerning habituation, sensitization and desensitization (Young et al. 2003), but neither protocol was found to induce secondary sensitization when vagal stimulation was kept at low intensities to obviate artifacts and nerve fatigue in rats (MacDonald et al. 2004). These caveats aside, the authors have provided convincing evidence of deranged vagal-pontine modulation of the respiratory rhythm in Mecp2−/y KO mice, which, when viewed in the proper light, reveals diminished habituation and accentuated secondary sensitization of fictive HBR. The potential roles of pontine postinspiratory activity in mediating the abnormal habituation, desensitization and sensitization of the HBR and resultant breathing arrhythmias remain to be clarified, although neurons with postinspiratory (early expiratory) discharges have been previously identified in the vicinity of the Kolliker–Fuse nucleus in the rat (Song et al. 2006). This non-associative learning perspective should help illuminate the pathogenesis of breathing abnormalities in these mutant animals or those with DNA hypomethylation (Fan et al. 2001), and in patients with Rett syndrome caused by mutations of the MECP2 gene.

  • Habituation, desensitization and sensitization of the Hering–Breuer Reflex in normal and Mecp2−/y knockout mice
    The Journal of Physiology, 2007
    Co-Authors: Chi-sang Poon, Gang Song
    Abstract:

    In an interesting study published recently in The Journal of Physiology,Stettner et al. (2007) reported that Mecp2−/y knockout (KO) mice devoid of the X-linked methyl-CpG binding protein 2 gene demonstrated prolonged and highly variable postinspiratory vagal efferent activity that correlated with the characteristic breathing arrhythmias in these mutant animals. Furthermore, glutamate microinjections into the pontine Kolliker–Fuse nucleus evoked significantly longer apnoeas with enhanced postinspiratory vagal discharge compared with wild-type (WT) controls. Finally, the authors provided data to suggest that repetitive electrical stimulation of vagal afferents also elicited significantly longer Hering–Breuer Reflex (HBR)-like apnoeas in the Mecp2−/y KO mice without any sign of ‘desensitization’ of the Reflex. We applaud the authors' elaboration of impaired vagal-pontine control of the respiratory rhythm in Mecp2−/y KO mice. However, we feel obliged to point out that their notion of differing ‘desensitization’ of the vagally induced HBR apnoeas in wild-type and Mecp2−/y KO animals is problematic and is at variance with current understanding of non-associative learning in brain pathways in general and in vagal-pontine mediation of the HBR in particular. Comparison with previous related studies is important because not only does it help to put the significance of the work in perspective, but in this case, it also reveals major discrepancies in interpretation of the results that point to a very different conclusion. For many decades, non-associative learning in the parlance of the behavioural neuroscience literature has been generally thought of as a dual process (habituation or sensitization) corresponding to activity-dependent down- or up-regulation of the response to a continuous or repetitive stimulus (Groves & Thompson, 1970). The notion of desensitization as a novel (and non-trivial) form of non-associative learning was first introduced in this Journal by Siniaia et al. (2000) precisely in the context of fictive HBR modulation of the respiratory frequency (particularly expiratory duration (Poon et al. 2000)) induced by low-intensity, high-frequency vagal electrical stimulation. This notion has led to a general framework of non-associative learning with four base modes (habituation, desensitization, primary sensitization and secondary sensitization), which has proved to harmoniously unify the functional characteristics of non-associative learning reported in many brain systems across animal phyla and sensory modalities (Poon & Young, 2006). Conventionally, habituation is characterized as (among other functional criteria) a down-regulating adaptation with short-term memory (Groves & Thompson, 1970; Poon & Young, 2006). Importantly, the latter remains latent post-stimulation and is activated (recalled) only when stimulated again – a process which has been termed ‘input gating’ (Young et al. 2003; Poon & Young, 2006). Desensitization is distinguished from habituation by the explicit expression of post-stimulation memory rebound and recovery, as desensitization (i.e. secondary habituation) is not subject to input gating. The exponential down-regulation effects of habituation and desensitization have been likened to those of a monophasic or biphasic (without or with memory rebound) neural differentiator or high-pass filter (Poon & Siniaia, 2000; Poon et al. 2000; Poon & Young, 2006). In the vagally induced HBR, desensitization was abolished after lesioning of the Kolliker–Fuse nucleus or systemic administration of the non-competitive NMDA receptor antagonist MK-801 (Poon et al. 2000; Siniaia et al. 2000). A working scheme of vagal-pontine mediation of the HBR and its habituation and desensitization has been proposed previously (Poon & Siniaia, 2000; Siniaia et al. 2000; Poon, 2004; Song & Poon, 2004). The authors of this paper stated that ‘All WT preparations showed a clear desensitization of the HBR in response to repetitive vagal stimulation’. However, from the presented data (Fig. 7A in Stettner et al. 2007) it appears that the shortening of the apnoea duration after repetitive stimulation reflected habituation (in the classical sense) of the HBR instead of desensitization, since a memory rebound was not evident at the cessation of vagal stimulation. Indeed, if anything, the expiratory duration remained longer immediately after both the 1st and 15th stimulation trial compared with resting conditions, showing the memory effects of concomitant secondary (not primary; see Poon & Young, 2006) sensitization of the HBR instead. This post-stimulation sensitization memory appeared to be accentuated in the Mecp2−/y KO animals, as indicated by the sustained apnoeas extending well beyond the vagal stimulation period (Fig. 7B and C). The mechanism of this peculiar secondary sensitization (instead of desensitization) of the HBR in wild-type and Mecp2−/y KO animals is unclear but could potentially result from activation of rapidly adapting pulmonary stretch receptor fibres or even cardiopulmonary C-fibres, as such secondary sensitization effects were not elicited by low-intensity, high-frequency (15–40 μA, 40–80 Hz) vagal electrical stimulation in rats (Poon et al. 2000; Siniaia et al. 2000). The authors also used a repetitive vagal stimulation protocol to induce non-associative learning of the HBR, apparently because the evoked apnoea was not habituated within the 10 s stimulation period due to the strength of the stimulation. Such a repetitive stimulation protocol is routine in studies of non-associative learning in invertebrate sensorimotor pathways to allow for refractory (‘output gating’) of the resultant motor response (Poon & Young, 2006). Since the mammalian respiratory motor response is non-refractory, a continuous (and sufficiently long) vagal stimulus should be as effective as a repetitive one in discerning habituation, sensitization and desensitization (Young et al. 2003), but neither protocol was found to induce secondary sensitization when vagal stimulation was kept at low intensities to obviate artifacts and nerve fatigue in rats (MacDonald et al. 2004). These caveats aside, the authors have provided convincing evidence of deranged vagal-pontine modulation of the respiratory rhythm in Mecp2−/y KO mice, which, when viewed in the proper light, reveals diminished habituation and accentuated secondary sensitization of fictive HBR. The potential roles of pontine postinspiratory activity in mediating the abnormal habituation, desensitization and sensitization of the HBR and resultant breathing arrhythmias remain to be clarified, although neurons with postinspiratory (early expiratory) discharges have been previously identified in the vicinity of the Kolliker–Fuse nucleus in the rat (Song et al. 2006). This non-associative learning perspective should help illuminate the pathogenesis of breathing abnormalities in these mutant animals or those with DNA hypomethylation (Fan et al. 2001), and in patients with Rett syndrome caused by mutations of the MECP2 gene.

  • Nonassociative learning promotes respiratory entrainment to mechanical ventilation.
    PloS one, 2007
    Co-Authors: Shawna M. Macdonald, Gang Song, Chi-sang Poon
    Abstract:

    Background. Patient-ventilator synchrony is a major concern in critical care and is influenced by phasic lung-volume feedback control of the respiratory rhythm. Routine clinical application of positive end-expiratory pressure (PEEP) introduces a tonic input which, if unopposed, might disrupt respiratory-ventilator entrainment through sustained activation of the vagallymediated Hering-Breuer Reflex. We suggest that this potential adverse effect may be averted by two differentiator forms of nonassociative learning (habituation and desensitization) of the Hering-Breuer Reflex via pontomedullary pathways. Methodology/Principal Findings. We tested these hypotheses in 17 urethane-anesthetized adult Sprague-Dawley rats under controlled mechanical ventilation. Without PEEP, phrenic discharge was entrained 1:1 to the ventilator rhythm. Application of PEEP momentarily dampened the entrainment to higher ratios but this effect was gradually adapted by nonassociative learning. Bilateral electrolytic lesions of the pneumotaxic center weakened the adaptation to PEEP, whereas sustained stimulation of the pneumotaxic center weakened the entrainment independent of PEEP. In all cases, entrainment was abolished after vagotomy. Conclusions/Significance. Our results demonstrate an important functional role for pneumotaxic desensitization and extra-pontine habituation of the Hering-Breuer Reflex elicited by lung inflation: acting as buffers or high-pass filters against tonic vagal volume input, these differentiator forms of nonassociative learning help to restore respiratory-ventilator entrainment in the face of PEEP. Such central sites-specific habituation and desensitization of the Hering-Breuer Reflex provide a useful experimental model of nonassociative learning in mammals that is of particular significance in understanding respiratory rhythmogenesis and coupled-oscillator entrainment mechanisms, and in the clinical management of mechanical ventilation in respiratory failure.

Jing J Yoon - One of the best experts on this subject based on the ideXlab platform.

  • Hering-Breuer Reflex and sleep state in the preterm infant.
    Pediatric pulmonology, 2003
    Co-Authors: Ivan L Hand, Lawrence Noble, Michelle Wilks, Maehee Kim, Edith Towler, Jing J Yoon
    Abstract:

    The aim of this study was to determine the effect of sleep state on the Hering-Breuer inflation Reflex in the preterm infant. Seventeen nonintubated, premature infants, ranging in birth weight from 980–2,440 g with postconceptual ages of 30–36 weeks, were studied. In each infant, pulmonary function testing, including the Hering-Breuer inflation Reflex, was obtained using the SensorMedics 2600 during active and quiet sleep states in supine position. The strength of the Hering-Breuer inflation Reflex was quantified by the measurement of the percent prolongation of expiration after an occluded breath. Sleep states were categorized by the criteria of Prechtl. There was a significant difference in Hering-Breuer activity in active (REM) vs. quiet (non-REM) sleep, with a consistently stronger Reflex in the active sleep state. The mean percent prolongation of expiration was 419% in active sleep vs. 87% in quiet sleep. Analysis of the data, using a paired t-test, revealed a mean difference of 331 ± 185% between active and quiet sleep (P = 0.000). In conclusion, significant differences in the strength of the Hering-Breuer inflation Reflex occur in relation to sleep state, and may explain the variability of the Reflex described in previous studies. Measurement of the Hering-Breuer inflation Reflex may be affected by pulmonary stretch receptors as well as chest wall afferents in the preterm infant. Pediatr Pulmonol. 2004; 37:61–64. © 2004 Wiley-Liss, Inc.

  • the Hering Breuer Reflex and sleep state in the premature infant 1663
    Pediatric Research, 1998
    Co-Authors: Ivan L Hand, Lawrence Noble, Michelle Wilks, Maehee Kim, Jing J Yoon
    Abstract:

    Objective: The Hering-Breuer Reflex is an important Reflex in the control of breathing and a critical component in the measurement of passive respiratory mechanics in the newborn. There is conflicting data however, on the strength of this Reflex in different sleep states. The aim of this study was to determine the effects of sleep states on the Hering-Breuer Reflex.

  • The Hering-Breuer Reflex and Sleep State in the Premature Infant ♦ 1663
    Pediatric Research, 1998
    Co-Authors: Ivan L Hand, Lawrence Noble, Michelle Wilks, Maehee Kim, Jing J Yoon
    Abstract:

    Objective: The Hering-Breuer Reflex is an important Reflex in the control of breathing and a critical component in the measurement of passive respiratory mechanics in the newborn. There is conflicting data however, on the strength of this Reflex in different sleep states. The aim of this study was to determine the effects of sleep states on the Hering-Breuer Reflex.

Ivan L Hand - One of the best experts on this subject based on the ideXlab platform.

  • The effects of positioning on the Hering-Breuer Reflex in the preterm infant.
    Pediatric pulmonology, 2006
    Co-Authors: Ivan L Hand, Lawrence Noble, Donna Geiss
    Abstract:

    The aim of this study was to determine the effect of positioning on the Hering-Breuer inflation Reflex (HBIR) in the preterm infant. Seven, non-intubated, premature infants, ranging in birthweight from 732 to 1450 g with post-conceptual ages of 32–36 weeks were studied. In each infant, pulmonary function testing, including the HBIR was obtained using the SensorMedics 2600 during quiet sleep in the supine and prone position. The strength of the HBIR was quantified by the measurement of the percent prolongation of expiration after an occluded breath. Sleep states were categorized by the criteria of Prechtl. There was a significant difference in Hering-Breuer activity in the prone position versus the supine position with a consistently stronger Reflex in the prone position. The mean percent prolongation of expiration was 237 ± 108% in the prone position versus 95 ± 32% in the supine position. Analysis of the data, using paired t-testing revealed a mean difference of 142 ± 119% between prone and supine positions (P = 0.028). Significant differences in the strength of the HBIR occur in relation to positioning in the preterm infant. Newborn positioning may affect pulmonary Reflexes and may play a role in control of breathing. Pediatr Pulmonol. 2007; 42:37–40. © 2006 Wiley-Liss, Inc.

  • Hering-Breuer Reflex and sleep state in the preterm infant.
    Pediatric pulmonology, 2003
    Co-Authors: Ivan L Hand, Lawrence Noble, Michelle Wilks, Maehee Kim, Edith Towler, Jing J Yoon
    Abstract:

    The aim of this study was to determine the effect of sleep state on the Hering-Breuer inflation Reflex in the preterm infant. Seventeen nonintubated, premature infants, ranging in birth weight from 980–2,440 g with postconceptual ages of 30–36 weeks, were studied. In each infant, pulmonary function testing, including the Hering-Breuer inflation Reflex, was obtained using the SensorMedics 2600 during active and quiet sleep states in supine position. The strength of the Hering-Breuer inflation Reflex was quantified by the measurement of the percent prolongation of expiration after an occluded breath. Sleep states were categorized by the criteria of Prechtl. There was a significant difference in Hering-Breuer activity in active (REM) vs. quiet (non-REM) sleep, with a consistently stronger Reflex in the active sleep state. The mean percent prolongation of expiration was 419% in active sleep vs. 87% in quiet sleep. Analysis of the data, using a paired t-test, revealed a mean difference of 331 ± 185% between active and quiet sleep (P = 0.000). In conclusion, significant differences in the strength of the Hering-Breuer inflation Reflex occur in relation to sleep state, and may explain the variability of the Reflex described in previous studies. Measurement of the Hering-Breuer inflation Reflex may be affected by pulmonary stretch receptors as well as chest wall afferents in the preterm infant. Pediatr Pulmonol. 2004; 37:61–64. © 2004 Wiley-Liss, Inc.

  • the Hering Breuer Reflex and sleep state in the premature infant 1663
    Pediatric Research, 1998
    Co-Authors: Ivan L Hand, Lawrence Noble, Michelle Wilks, Maehee Kim, Jing J Yoon
    Abstract:

    Objective: The Hering-Breuer Reflex is an important Reflex in the control of breathing and a critical component in the measurement of passive respiratory mechanics in the newborn. There is conflicting data however, on the strength of this Reflex in different sleep states. The aim of this study was to determine the effects of sleep states on the Hering-Breuer Reflex.

  • The Hering-Breuer Reflex and Sleep State in the Premature Infant ♦ 1663
    Pediatric Research, 1998
    Co-Authors: Ivan L Hand, Lawrence Noble, Michelle Wilks, Maehee Kim, Jing J Yoon
    Abstract:

    Objective: The Hering-Breuer Reflex is an important Reflex in the control of breathing and a critical component in the measurement of passive respiratory mechanics in the newborn. There is conflicting data however, on the strength of this Reflex in different sleep states. The aim of this study was to determine the effects of sleep states on the Hering-Breuer Reflex.

Anne Greenough - One of the best experts on this subject based on the ideXlab platform.

  • Hering-Breuer Reflex, lung volume and position in prematurely born infants.
    Pediatric pulmonology, 2008
    Co-Authors: Francesca Landolfo, Tolulope Saiki, Janet L. Peacock, Simon Hannam, Gerrard F. Rafferty, Anne Greenough
    Abstract:

    OBJECTIVES: To investigate the effect of position on the strength of the Hering-Breuer Reflex in prematurely born infants and determine whether any differences seen were related to differences in lung or tidal volume between positions. WORKING HYPOTHESIS: Position related differences in the strength of the Hering-Breuer Reflex relate to differences in lung or tidal volume. STUDY DESIGN: Prospective observational study. PATIENT/SUBJECT SELECTION: Eighteen infants, median gestational age 30 (range 25-32) weeks were studied. METHODOLOGY: Infants were examined in the supine and prone position, each position was maintained for 2 hr. At the end of each 2-hr period, the strength of the Hering-Breuer Reflex was assessed by determining the prolongation of expiration following an end inspiratory occlusion. In addition, tidal volume and functional residual capacity (FRC) were assessed in each position. RESULTS: The strength of the Hering-Breuer Reflex was greater (P = 0.01) and the mean FRC was higher (P < 0.0001) in the prone compared to the supine position. The position related differences in the strength of the Reflex correlated significantly with position related differences in FRC (P = 0.05). CONCLUSIONS: The Hering-Breuer Reflex is stronger in the prone compared to the supine position. Our results suggest this is explained by position related differences in lung volume.

  • Comparative effects of theophylline and caffeine on respiratory function of prematurely bora infants
    Early human development, 1998
    Co-Authors: B Laubscher, Anne Greenough, Gabriel Dimitriou
    Abstract:

    The aim of this study was to determine the relative effects of theophylline and caffeine on neonatal respiratory function. Fifty-three preterm infants (45 infants with a median gestational age of 28 weeks, range 24–34 weeks completed the protocol) were randomized to receive either theophylline (loading dose 4 mg/kg followed by 4 mg/kg/day) or caffeine (loading dose 10 mg/kg followed by 5 mg/kg/day). Compliance of the respiratory system (CRS), strength of Hering Breuer Reflex and the inspired oxygen concentration requirement were measured immediately prior to, 24 h and 7 days after commencing therapy. There was no statistically significant difference in the patient characteristics of the two groups, but only the theophylline group contained immature infants (i.e. < 26 weeks gestational age (n = 7)). At 24 h, there was a significant improvement in CRS and reduction in supplementary oxygen requirements in the caffeine group (p < 0.01), in the theophylline group no such significant effects were seen. In the study population overall, after 7 days of treatment in both the theophylline and caffeine groups there was an improvement in CRS (p < 0.05 and p < 0.01 respectively) and a reduction in the inspired oxygen concentration (p < 0.05 and p < 0.01 respectively). There was, however, a significant reduction in the strength of the Hering Breuer Reflex only in the caffeine group (p < 0.05) and this was a decrease which related to the change in CRS (p < 0.05). The only statistically significant difference in the magnitude of change in CRS, Reflex strength or supplementary oxygen requirements between the two groups was that the reduction in inspired oxygen requirement in the caffeine group was greater man that in the theophylline treated infants at 24 h (p < 0.05). We conclude theophylline and caffeine have similar effects on neonatal respiratory function, but our results suggest caffeine administration may be associated with an earlier onset of action.

  • The Hering-Breuer Reflex in ventilated children.
    Respiratory medicine, 1996
    Co-Authors: F. Giffin, Anne Greenough, S. Naik
    Abstract:

    Abstract The authors tested the hypothesis that, in the paediatric population, the Hering-Breuer Reflex would be provoked by the positive pressure inflation of mechanical ventilation (IPPV), and that the strength of the Reflex would relate to the child's age and compliance of the respiratory system (CRS). During IPPV, changes in air flow, volume and airway pressure were recorded simultaneously. From the traces, expiratory times and CRS were calculated. The mean expiratory time (Te 1 ) prior to each inflation and the mean expiratory time (Te 2 ) immediately following an inflation were determined. The presence of the Reflex was indicated by Te 2 being longer than Te 1 , and the strength of the Reflex was calculated as the difference between Te 2 and Te 1 expressed as a percentage of Te 1 . Twenty children were studied who had a mean age of 0·7 years (range 0·1–9·8 years). The Reflex was provoked in 19 of the 20 patients and was not seen in the oldest patient. The strength of the Reflex varied from 22 to 144% and was inversely related to postnatal age significantly ( r = −0·73) but not CRS or inflation volume. It is concluded that the Hering-Breuer Reflex is provoked during IPPV in young children; whether, as in neonates, this influences the efficacy of ventilation deserves investigation.

  • 276 INFLUENCE OF LUNG FUNCTION AND Reflex ACTIVITY ON THE SUCCESS OF PATIENT TRIGGERED VENTILATION
    Pediatric Research, 1994
    Co-Authors: Anne Greenough, Vivien Chan, Kazuhiko Muramatsu
    Abstract:

    During patient triggered ventilation (PTV) each of the infant's respiratory efforts will trigger a positive pressure inflation, providing that the respiratory effort is of sufficient magnitude to exceed the critical trigger level. It is likely therefore that the nature of the infant's lung function and respiratory Reflex activity will influence the success of PTV. The aim of this study was to test that hypothesis. 20 premature infants (median gestational age 29 weeks) in the recovery stage of respiratory distress were studied at a median postnatal age of 2.5 days. Lung function was assessed by measurement of compliance using a single breath technique. Reflex activity was assessed by measurement of the strength of the Hering Breuer Reflex, indicated by the degree of prolongation of expiration following end inspiratory occlusion. PTV was considered to have failed if the infant became apnoeic or required an increased level of respiratory support. PTV failed ultimately in 6 infants, compliance of the respiratory system of those 6 infants did not differ significantly from the rest of the cohon, but the Hering Breuer Reflex was significantly weaker (p

  • Influence of lung function and Reflex activity on the success of patient-triggered ventilation
    Early human development, 1994
    Co-Authors: V. Chan, Anne Greenough, Kazuhiko Muramatsu
    Abstract:

    The influence of lung function and Reflex activity on the success of patient-triggered ventilation (PTV) has been determined. Lung function was assessed by measurement of compliance using a single breath technique. Reflex activity was assessed by measurement of the strength of Hering Breuer Reflex indicated by the degree of prolongation of expiration following end inspiratory occlusion. PTV was considered to have failed if the infant became apnoeic or required an increased level of respiratory support. Twenty premature infants (median gestational age 29 weeks) in the recovery stage of respiratory distress, were studied at a median postnatal age of 2.5 days. PTV failed ultimately in six infants, although compliance of the respiratory system of that group did not differ significantly from the rest of the cohort, their Hering Breuer Reflex was significantly weaker (P < 0.01). In addition, the infants in whom PTV failed were significantly more immature and of lower birthweight (P < 0.01) compared with those in whom it succeeded. We conclude that failure of PTV is more likely in immature infants who have a weak Hering Breuer Reflex.

Gang Song - One of the best experts on this subject based on the ideXlab platform.

  • Mechanisms of respiratory-ventilator entrainment and its buffering by differentiator-type nonassociative learning.
    2013
    Co-Authors: Shawna M. Macdonald, Gang Song, Chi-sang Poon
    Abstract:

    (Possible reciprocal connections for all paths are not shown.) In the absence of PEEP (top panel), phasic volume-related inputs entrain the respiratory rhythm generator (I-E) via the nucleus tractus solitarius (NTS) which also modulates the pneumotaxic center in dorsolateral pons (dl-pons). Immediately upon the application of PEEP (middle panel), tonic activities in the NTS and dl-pons elicit the Hering-Breuer Reflex prolongation of expiration and shortening of inspiration, momentarily impairing entrainment. Finally, habituation of the NTS and desensitization of the pneumotaxic center (bottom panel) eventually buffer the effect of PEEP, restoring the respiratory rhythm. Sustained stimulation of dl-pons produces similar Hering-Breuer Reflex and desensitization effects as PEEP.

  • Modulation of Hering-Breuer Reflex by Ventrolateral Pons
    Advances in experimental medicine and biology, 2008
    Co-Authors: Hui Wang, Heng Zhang, Gang Song, Chi-sang Poon
    Abstract:

    The vagally-mediated Hering-Breuer Reflex (HBR) is known to be modulated by the classic pneumotaxic center in the dorsolateral pons. In this work, we investigated whether the HBR was also modulated by the ventrolateral pons (vl-pons). Experiments were performed on urethane anesthetized adult rats. The HBR was elicited by electrical stimulation of the vagus nerve and its strength was compared before and after electrical stimulation or microinjection of MK-801 (non-competitive NMDA receptor antagonist) at the vl-pons. We found that the inspiratory inhibition and expiratory prolongation effects of the HBR were strengthened after electrical stimulation at the vl-pons but were weakened after microinjecting MK-801. Results suggested that the vl-pons could influence the respiratory rhythm by modulating the strength of HBR via NMDA receptor-mediated neurotransmission.

  • habituation desensitization and sensitization of the Hering Breuer Reflex in normal and mecp2 y knockout mice
    The Journal of Physiology, 2007
    Co-Authors: Chi-sang Poon, Gang Song
    Abstract:

    In an interesting study published recently in The Journal of Physiology,Stettner et al. (2007) reported that Mecp2−/y knockout (KO) mice devoid of the X-linked methyl-CpG binding protein 2 gene demonstrated prolonged and highly variable postinspiratory vagal efferent activity that correlated with the characteristic breathing arrhythmias in these mutant animals. Furthermore, glutamate microinjections into the pontine Kolliker–Fuse nucleus evoked significantly longer apnoeas with enhanced postinspiratory vagal discharge compared with wild-type (WT) controls. Finally, the authors provided data to suggest that repetitive electrical stimulation of vagal afferents also elicited significantly longer Hering–Breuer Reflex (HBR)-like apnoeas in the Mecp2−/y KO mice without any sign of ‘desensitization’ of the Reflex. We applaud the authors' elaboration of impaired vagal-pontine control of the respiratory rhythm in Mecp2−/y KO mice. However, we feel obliged to point out that their notion of differing ‘desensitization’ of the vagally induced HBR apnoeas in wild-type and Mecp2−/y KO animals is problematic and is at variance with current understanding of non-associative learning in brain pathways in general and in vagal-pontine mediation of the HBR in particular. Comparison with previous related studies is important because not only does it help to put the significance of the work in perspective, but in this case, it also reveals major discrepancies in interpretation of the results that point to a very different conclusion. For many decades, non-associative learning in the parlance of the behavioural neuroscience literature has been generally thought of as a dual process (habituation or sensitization) corresponding to activity-dependent down- or up-regulation of the response to a continuous or repetitive stimulus (Groves & Thompson, 1970). The notion of desensitization as a novel (and non-trivial) form of non-associative learning was first introduced in this Journal by Siniaia et al. (2000) precisely in the context of fictive HBR modulation of the respiratory frequency (particularly expiratory duration (Poon et al. 2000)) induced by low-intensity, high-frequency vagal electrical stimulation. This notion has led to a general framework of non-associative learning with four base modes (habituation, desensitization, primary sensitization and secondary sensitization), which has proved to harmoniously unify the functional characteristics of non-associative learning reported in many brain systems across animal phyla and sensory modalities (Poon & Young, 2006). Conventionally, habituation is characterized as (among other functional criteria) a down-regulating adaptation with short-term memory (Groves & Thompson, 1970; Poon & Young, 2006). Importantly, the latter remains latent post-stimulation and is activated (recalled) only when stimulated again – a process which has been termed ‘input gating’ (Young et al. 2003; Poon & Young, 2006). Desensitization is distinguished from habituation by the explicit expression of post-stimulation memory rebound and recovery, as desensitization (i.e. secondary habituation) is not subject to input gating. The exponential down-regulation effects of habituation and desensitization have been likened to those of a monophasic or biphasic (without or with memory rebound) neural differentiator or high-pass filter (Poon & Siniaia, 2000; Poon et al. 2000; Poon & Young, 2006). In the vagally induced HBR, desensitization was abolished after lesioning of the Kolliker–Fuse nucleus or systemic administration of the non-competitive NMDA receptor antagonist MK-801 (Poon et al. 2000; Siniaia et al. 2000). A working scheme of vagal-pontine mediation of the HBR and its habituation and desensitization has been proposed previously (Poon & Siniaia, 2000; Siniaia et al. 2000; Poon, 2004; Song & Poon, 2004). The authors of this paper stated that ‘All WT preparations showed a clear desensitization of the HBR in response to repetitive vagal stimulation’. However, from the presented data (Fig. 7A in Stettner et al. 2007) it appears that the shortening of the apnoea duration after repetitive stimulation reflected habituation (in the classical sense) of the HBR instead of desensitization, since a memory rebound was not evident at the cessation of vagal stimulation. Indeed, if anything, the expiratory duration remained longer immediately after both the 1st and 15th stimulation trial compared with resting conditions, showing the memory effects of concomitant secondary (not primary; see Poon & Young, 2006) sensitization of the HBR instead. This post-stimulation sensitization memory appeared to be accentuated in the Mecp2−/y KO animals, as indicated by the sustained apnoeas extending well beyond the vagal stimulation period (Fig. 7B and C). The mechanism of this peculiar secondary sensitization (instead of desensitization) of the HBR in wild-type and Mecp2−/y KO animals is unclear but could potentially result from activation of rapidly adapting pulmonary stretch receptor fibres or even cardiopulmonary C-fibres, as such secondary sensitization effects were not elicited by low-intensity, high-frequency (15–40 μA, 40–80 Hz) vagal electrical stimulation in rats (Poon et al. 2000; Siniaia et al. 2000). The authors also used a repetitive vagal stimulation protocol to induce non-associative learning of the HBR, apparently because the evoked apnoea was not habituated within the 10 s stimulation period due to the strength of the stimulation. Such a repetitive stimulation protocol is routine in studies of non-associative learning in invertebrate sensorimotor pathways to allow for refractory (‘output gating’) of the resultant motor response (Poon & Young, 2006). Since the mammalian respiratory motor response is non-refractory, a continuous (and sufficiently long) vagal stimulus should be as effective as a repetitive one in discerning habituation, sensitization and desensitization (Young et al. 2003), but neither protocol was found to induce secondary sensitization when vagal stimulation was kept at low intensities to obviate artifacts and nerve fatigue in rats (MacDonald et al. 2004). These caveats aside, the authors have provided convincing evidence of deranged vagal-pontine modulation of the respiratory rhythm in Mecp2−/y KO mice, which, when viewed in the proper light, reveals diminished habituation and accentuated secondary sensitization of fictive HBR. The potential roles of pontine postinspiratory activity in mediating the abnormal habituation, desensitization and sensitization of the HBR and resultant breathing arrhythmias remain to be clarified, although neurons with postinspiratory (early expiratory) discharges have been previously identified in the vicinity of the Kolliker–Fuse nucleus in the rat (Song et al. 2006). This non-associative learning perspective should help illuminate the pathogenesis of breathing abnormalities in these mutant animals or those with DNA hypomethylation (Fan et al. 2001), and in patients with Rett syndrome caused by mutations of the MECP2 gene.

  • Habituation, desensitization and sensitization of the Hering–Breuer Reflex in normal and Mecp2−/y knockout mice
    The Journal of Physiology, 2007
    Co-Authors: Chi-sang Poon, Gang Song
    Abstract:

    In an interesting study published recently in The Journal of Physiology,Stettner et al. (2007) reported that Mecp2−/y knockout (KO) mice devoid of the X-linked methyl-CpG binding protein 2 gene demonstrated prolonged and highly variable postinspiratory vagal efferent activity that correlated with the characteristic breathing arrhythmias in these mutant animals. Furthermore, glutamate microinjections into the pontine Kolliker–Fuse nucleus evoked significantly longer apnoeas with enhanced postinspiratory vagal discharge compared with wild-type (WT) controls. Finally, the authors provided data to suggest that repetitive electrical stimulation of vagal afferents also elicited significantly longer Hering–Breuer Reflex (HBR)-like apnoeas in the Mecp2−/y KO mice without any sign of ‘desensitization’ of the Reflex. We applaud the authors' elaboration of impaired vagal-pontine control of the respiratory rhythm in Mecp2−/y KO mice. However, we feel obliged to point out that their notion of differing ‘desensitization’ of the vagally induced HBR apnoeas in wild-type and Mecp2−/y KO animals is problematic and is at variance with current understanding of non-associative learning in brain pathways in general and in vagal-pontine mediation of the HBR in particular. Comparison with previous related studies is important because not only does it help to put the significance of the work in perspective, but in this case, it also reveals major discrepancies in interpretation of the results that point to a very different conclusion. For many decades, non-associative learning in the parlance of the behavioural neuroscience literature has been generally thought of as a dual process (habituation or sensitization) corresponding to activity-dependent down- or up-regulation of the response to a continuous or repetitive stimulus (Groves & Thompson, 1970). The notion of desensitization as a novel (and non-trivial) form of non-associative learning was first introduced in this Journal by Siniaia et al. (2000) precisely in the context of fictive HBR modulation of the respiratory frequency (particularly expiratory duration (Poon et al. 2000)) induced by low-intensity, high-frequency vagal electrical stimulation. This notion has led to a general framework of non-associative learning with four base modes (habituation, desensitization, primary sensitization and secondary sensitization), which has proved to harmoniously unify the functional characteristics of non-associative learning reported in many brain systems across animal phyla and sensory modalities (Poon & Young, 2006). Conventionally, habituation is characterized as (among other functional criteria) a down-regulating adaptation with short-term memory (Groves & Thompson, 1970; Poon & Young, 2006). Importantly, the latter remains latent post-stimulation and is activated (recalled) only when stimulated again – a process which has been termed ‘input gating’ (Young et al. 2003; Poon & Young, 2006). Desensitization is distinguished from habituation by the explicit expression of post-stimulation memory rebound and recovery, as desensitization (i.e. secondary habituation) is not subject to input gating. The exponential down-regulation effects of habituation and desensitization have been likened to those of a monophasic or biphasic (without or with memory rebound) neural differentiator or high-pass filter (Poon & Siniaia, 2000; Poon et al. 2000; Poon & Young, 2006). In the vagally induced HBR, desensitization was abolished after lesioning of the Kolliker–Fuse nucleus or systemic administration of the non-competitive NMDA receptor antagonist MK-801 (Poon et al. 2000; Siniaia et al. 2000). A working scheme of vagal-pontine mediation of the HBR and its habituation and desensitization has been proposed previously (Poon & Siniaia, 2000; Siniaia et al. 2000; Poon, 2004; Song & Poon, 2004). The authors of this paper stated that ‘All WT preparations showed a clear desensitization of the HBR in response to repetitive vagal stimulation’. However, from the presented data (Fig. 7A in Stettner et al. 2007) it appears that the shortening of the apnoea duration after repetitive stimulation reflected habituation (in the classical sense) of the HBR instead of desensitization, since a memory rebound was not evident at the cessation of vagal stimulation. Indeed, if anything, the expiratory duration remained longer immediately after both the 1st and 15th stimulation trial compared with resting conditions, showing the memory effects of concomitant secondary (not primary; see Poon & Young, 2006) sensitization of the HBR instead. This post-stimulation sensitization memory appeared to be accentuated in the Mecp2−/y KO animals, as indicated by the sustained apnoeas extending well beyond the vagal stimulation period (Fig. 7B and C). The mechanism of this peculiar secondary sensitization (instead of desensitization) of the HBR in wild-type and Mecp2−/y KO animals is unclear but could potentially result from activation of rapidly adapting pulmonary stretch receptor fibres or even cardiopulmonary C-fibres, as such secondary sensitization effects were not elicited by low-intensity, high-frequency (15–40 μA, 40–80 Hz) vagal electrical stimulation in rats (Poon et al. 2000; Siniaia et al. 2000). The authors also used a repetitive vagal stimulation protocol to induce non-associative learning of the HBR, apparently because the evoked apnoea was not habituated within the 10 s stimulation period due to the strength of the stimulation. Such a repetitive stimulation protocol is routine in studies of non-associative learning in invertebrate sensorimotor pathways to allow for refractory (‘output gating’) of the resultant motor response (Poon & Young, 2006). Since the mammalian respiratory motor response is non-refractory, a continuous (and sufficiently long) vagal stimulus should be as effective as a repetitive one in discerning habituation, sensitization and desensitization (Young et al. 2003), but neither protocol was found to induce secondary sensitization when vagal stimulation was kept at low intensities to obviate artifacts and nerve fatigue in rats (MacDonald et al. 2004). These caveats aside, the authors have provided convincing evidence of deranged vagal-pontine modulation of the respiratory rhythm in Mecp2−/y KO mice, which, when viewed in the proper light, reveals diminished habituation and accentuated secondary sensitization of fictive HBR. The potential roles of pontine postinspiratory activity in mediating the abnormal habituation, desensitization and sensitization of the HBR and resultant breathing arrhythmias remain to be clarified, although neurons with postinspiratory (early expiratory) discharges have been previously identified in the vicinity of the Kolliker–Fuse nucleus in the rat (Song et al. 2006). This non-associative learning perspective should help illuminate the pathogenesis of breathing abnormalities in these mutant animals or those with DNA hypomethylation (Fan et al. 2001), and in patients with Rett syndrome caused by mutations of the MECP2 gene.

  • Nonassociative learning promotes respiratory entrainment to mechanical ventilation.
    PloS one, 2007
    Co-Authors: Shawna M. Macdonald, Gang Song, Chi-sang Poon
    Abstract:

    Background. Patient-ventilator synchrony is a major concern in critical care and is influenced by phasic lung-volume feedback control of the respiratory rhythm. Routine clinical application of positive end-expiratory pressure (PEEP) introduces a tonic input which, if unopposed, might disrupt respiratory-ventilator entrainment through sustained activation of the vagallymediated Hering-Breuer Reflex. We suggest that this potential adverse effect may be averted by two differentiator forms of nonassociative learning (habituation and desensitization) of the Hering-Breuer Reflex via pontomedullary pathways. Methodology/Principal Findings. We tested these hypotheses in 17 urethane-anesthetized adult Sprague-Dawley rats under controlled mechanical ventilation. Without PEEP, phrenic discharge was entrained 1:1 to the ventilator rhythm. Application of PEEP momentarily dampened the entrainment to higher ratios but this effect was gradually adapted by nonassociative learning. Bilateral electrolytic lesions of the pneumotaxic center weakened the adaptation to PEEP, whereas sustained stimulation of the pneumotaxic center weakened the entrainment independent of PEEP. In all cases, entrainment was abolished after vagotomy. Conclusions/Significance. Our results demonstrate an important functional role for pneumotaxic desensitization and extra-pontine habituation of the Hering-Breuer Reflex elicited by lung inflation: acting as buffers or high-pass filters against tonic vagal volume input, these differentiator forms of nonassociative learning help to restore respiratory-ventilator entrainment in the face of PEEP. Such central sites-specific habituation and desensitization of the Hering-Breuer Reflex provide a useful experimental model of nonassociative learning in mammals that is of particular significance in understanding respiratory rhythmogenesis and coupled-oscillator entrainment mechanisms, and in the clinical management of mechanical ventilation in respiratory failure.