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1 Department of Physiology, Dartmouth Medical School, Dartmouth – Hitchcock Medical Center, Lebanon, NH 03756, USA
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(Received 26 September 2006;
accepted after revision 23 November 2006; first published online 30 November 2006)
Corresponding author W. M. St-John: Department of Physiology, Dartmouth Medical School, Dartmouth – Hitchcock Medical Center, Lebanon, NH 03756, USA. Email: walter.m.stjohn{at}dartmouth.edu
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Introduction |
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Many contemporary studies using in vivo preparations have confirmed Lumsden's basic observations concerning differences in the patterns of automatic ventilation (see St-John, 1990, 1996, 1998; Duffin, 2003 for review). Thus, the rate of rise of integrated activity of the phrenic nerve is much greater in gasping than in either eupnoea or apneusis. Numerous other characteristics of ventilatory activity differ among the patterns, with differences between eupnoea and gasping being the most marked. In eupnoea, respiratory-modulated activities of cranial nerves commence before that of the phrenic nerve, and both cranial and spinal nerves have significant discharges in neural expiration between phrenic bursts. These differences in times of onset of cranial and spinal nerves and expiratory discharges are reduced or completely eliminated in gasping. Another marked difference is in the high-frequency oscillations in the discharges of cranial and phrenic nerves. While the origin of these high-frequency oscillations is undefined, these oscillations have been considered as signatures of the basic mechanisms underlying the various patterns of automatic ventilatory activity (Richardson & Mitchell, 1982; Richardson, 1986; Cohen et al. 1987; Funk & Parkis, 2002). The peak in these high-frequency oscillations is significantly higher in gasping than in eupnoea. In apneusis, a lower peak frequency compared with eupnoea has been reported (Berger et al. 1978; Richardson & Mitchell, 1982).
Many of the differences between eupnoea, apneusis and gasping reported for in vivo preparations have also been found for the in situ preparations of the juvenile and neonatal rat. Following ablations of the rostral pons, a prolongation of the duration of the phrenic burst is recorded, leading to the conclusion that in situ preparations exhibit apneusis (St-John & Paton, 2000). In situ, exposure to severe hypoxia or ischaemia changes the augmenting pattern of phrenic discharge to a decrementing pattern as in gasping in vivo (St Jacques & St-John, 2000; St-John & Paton, 2000, 2002, 2003a; Paton et al. 2006). With the change to this decrementing discharge, the differences in the time of onset of activities of cranial and spinal nerves are significantly reduced, expiratory activities are reduced or eliminated and peak frequencies in high-frequency oscillations of nerve activities become significantly higher (St Jacques & St-John, 2000; St-John & Paton, 2000, 2002, 2003a; Leiter & St-John, 2004; Paton et al. 2006). These findings lead to the conclusion that in situ preparations clearly exhibit patterns of automatic ventilatory activity comparable to eupnoea, apneusis and gasping in vivo. Yet some differences between findings in vivo and in situ exist. As we have detailed in several reports, these differences represent not the preparations per se, but the hypothermia at which the in situ preparation is maintained (St Jacques & St-John, 2000; St-John & Leiter, 2003). In hypothermia, differences between eupnoea and gasping in the frequency of phrenic bursts, durations of the burst and peak integrated height are lessened. Hence, for phrenic discharge in hypothermia, a switch from an incrementing to a decrementing pattern is the primary distinguishing feature between phrenic discharge in eupnoea and gasping in situ.
Numerous studies using in vivo preparations have confirmed Lumsden's finding that gasping is the one pattern of automatic ventilatory activity that can be reproducibly obtained following the separation of pons from medulla. However, in a minority of experiments, patterns other than gasping are reported. These exceptions have included ataxia, Biot's breathing or even respiratory movements that appeared eupnoeic. In some studies, it is reported that these other ‘respiratory patterns’ are altered to gasping following a further, caudal transection (Hoff & Breckenridge, 1949; Wang et al. 1957; Breckenridge & Hoff, 1958; St-John, 1990). We have also found that, whereas gasping follows transections between pons and medulla of the in situ preparation, these other patterns are also recorded (St-John & Paton, 2000; St-John et al. 2002; Paton et al. 2006). Yet, a fundamental problem is to define whether these ‘non-gasping’ patterns represent variants of gasping, eupnoea, or neither. We hypothesized that a comparison of peaks in the high-frequency oscillations of phrenic discharge might define the relationship between these ‘non-gasping’ medullary patterns and eupnoea or gasping. We have used the in situ preparation of the juvenile rat to evaluate this hypothesis.
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Methods |
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Twenty-eight perfused preparations of the juvenile rat were used. The preparation was identical to that previously described (Paton, 1996; St-John & Paton, 2000). Under halothane anaesthesia, the portion of the body caudal to the diaphragm was removed. Halothane anaesthesia was discontinued, and the preparation was immersed in ice-cold artificial cerebrospinal fluid and decerebrated at a precollicular level. The preparation was bisected below the diaphragm, sectioning the aorta, and was immediately plunged into ice cold cerebrospinal fluid. No respiratory movements and, usually, no heart beat was noted. Decerebration followed within approximately one minute. There was no evidence of perception of stimuli. A partial or complete cerebellectomy was performed so that the floor of the IVth ventricle was visible. The preparation was adjusted so that this floor of the IVth ventricle was horizontal.
The descending aorta was cannulated and perfusion was commenced. The perfusate contained the following in distilled water: magnesium sulphate (MgSO4, 1.25 mM), potassium phosphate (KH2PO4, 1.25 mM), potassium chloride (KCl, 5.0 mM), sodium bicarbonate (NaHCO3, 25 mM), sodium chloride (NaCl, 125 mM), calcium chloride (CaCl2, 2.5 mM), dextrose (10 mM) and Ficoll 70 (0.1785 mM).
Control conditions were established with the perfusate equilibrated with 95% O2–5% CO2 at 31°C. This temperature was measured as the perfusate entered the aorta. The temperature of the perfusate was regulated by a heat exchanger. Efferent activities of one or both phrenic nerves were recorded with suction electrodes.
To characterize the ventilatory cycle, activity of the phrenic nerve was filtered at 0.6–6.0 kHz and integrated (50 ms time constant). For power spectral analysis of phrenic discharge, activities were also amplified and filtered at 1–500 Hz. In some studies, this activity was further processed by an adaptive filter (HumBug, Quest Scientific, North Vancouver, British Columbia, Canada). Data were digitized at 1 kHz and stored on disk.
Experimental protocol
Three groups of preparations were used: (1) precollicular preparations (n = 6) underwent only a precollicular brainstem transection; (2) midpontile preparations (n = 12) underwent a precollicular brainstem transection followed by a transection at a rostral to midpontile level; and (3) pontomedullary preparations (n = 10) had a precollicular brainstem transection followed by a transection at the pontomedullary junction.
After the start of perfusion, recordings were obtained for all groups as soon as rhythmic activities began. Thirty to 60 min thereafter, ‘baseline activity’ was recorded in eupnoea, with the perfusate being equilibrated with 95% O2–5% CO2. In the precollicular group of six preparations, perfusion was temporarily terminated (ischaemia). Within approximately 1 min, the incrementing pattern of eupnoea was replaced by the decrementing pattern of gasping. After a minimum of five gasps were recorded, the perfusion was recommenced and the eupnoeic pattern was gradually re-established. Approximately 10 min thereafter, the preparation was again exposed to ischaemia and gasping was recorded. Three to five of these alterations from eupnoea to gasping were produced in each preparation.
In the midpontile and pontomedullary transection groups, neural activities were initially recorded following the precollicular transection, with the perfusate equilibrated with 95% O2–5% CO2. The brainstem was then transected at either a rostral to midpontile level or a caudal pontile level. For a rostral to midpontile transection, the brainstem was sectioned in a perpendicular plane, commencing at the rostral border of the middle cerebellar peduncle (Fig. 1). The caudal transection was commenced immediately caudal to the inferior cerebellar peduncles (Fig. 1). Transections were performed slowly, over approximately 15 min, using fine scissors and a blunt spatula. Recordings were obtained in hyperoxia a minimum of 30 min after the completion of the transection. Ischaemia was then introduced and recordings obtained. In some preparations, multiple groups of recordings were obtained in hyperoxia and ischaemia. However, we did not obtain recordings following both pontile transections in the same preparation because the first transection was followed by multiple periods of ischaemia.
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Analyses of data
Integrated phrenic activity was analysed as to the duration of the burst (neural inspiratory, tI), period between bursts (tE), peak height, and time to reach peak height, expressed as a percentage of tI. The duration of the burst was the time between the onset of integrated phrenic discharge and its rapid decline. The period between bursts was the time between this rapid decline and the start of the next phrenic burst.
Power spectra of phrenic activity were computed using a fast Fourier transform as previously described (St-John & Leiter, 2003). The relative power at each frequency was defined for individual respiratory cycles, and these data were then averaged for all cycles that were examined. Peak frequency in the power spectra was identified by the analysis program (St-John & Leiter, 2003). The power at the peak frequency had to be higher than 10% above that at the other frequencies or we concluded that no peak frequency could be identified.
In the 11 preparations in which activities of both phrenic nerves were recorded, the cross-spectral density and coherence between these activities were computed. Cross-spectra were obtained from the fast Fourier transforms of each neural activity. We calculated the average coherence at the peak frequency in the power spectra of each phrenic nerve. Coherence has values between 0.0 and 1.0, representing no coherence and complete coherence, respectively. Statistical evaluations were by a Wilcoxon test.
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Results |
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In preparations having an intact pontile and medullary brainstem, integrated activity of the phrenic nerve was characterized by an incrementing pattern, with peak discharge being achieved after most of the burst was completed (Fig. 2). The duration of the phrenic burst, period between bursts and peak height varied little between respiratory cycles.
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Following transections, the duration of the phrenic burst was significantly increased (Table 1), with some cycles having a sustained discharge typical of apneusis (Fig. 5).
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In the six preparations in which activities of both phrenic nerves were recorded, the coherences at the peak frequencies were the same in eupnoea (0.66 ± 0.02), following the rostral pontile transections (0.71 ± 0.04) and in gasping (0.62 ± 0.04). Such similarity indicates that the same premotor neuronal activities define the phrenic discharge during the three patterns (e.g. Cohen et al. 1987; Funk & Parkis, 2002).
Brainstem transections at pontomedullary junction
Following removal of all or the great majority of pons, the pattern of phrenic activity was markedly altered compared with that recorded following the precollicular decerebration. Indeed, following the transection at the pontomedullary junction, phrenic discharge had multiple patterns which were expressed in the same preparation. These patterns included high-amplitude, decrementing discharges, which were classified as gasps (Fig. 7). Another pattern was a number of bursts superimposed upon a tonic discharge (Fig. 8). Integrated records of these multiple bursts showed multiple peaks during a single cycle. In some cycles, the maximum of integrated discharge was achieved at the end of the cycle whereas, in others, the maximum was close to the beginning of the cycle. A final pattern was an incrementing discharge, with peak activity being achieved at the end of the cycle (Figs 8 and 9). This final pattern, which was similar to the eupnoeic pattern following the precollicular transection, was intermixed with the other patterns that had multiple peaks in a single cycle.
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As is evident from Figs 7 and 8 and Table 1, the frequency of phrenic bursts was significantly increased and their peak height was significantly reduced following the transection at the pontomedullary junction. In addition to the pattern of phrenic discharge, the peak in the high-frequency oscillations was greatly altered following the removal of pons. We performed three different analyses of these high-frequency oscillations. The first analysis was of data from all cycles in which the duration of the phrenic burst was in excess of 256 ms. As noted in the Methods, 256 ms was the duration chosen for analysis under all conditions. In two of 10 preparations, no peak in the high-frequency oscillations could be discerned. For the others, peak frequencies fell significantly (Figs 4 and 6). For the second analysis, we only analysed cycles in which peak integrated phrenic discharge was in excess of 50% of control values. Again, high-frequency oscillations had no peak frequency in two preparations. In the others, peak frequencies fell significantly (e.g. Figs 4 and 6). Finally, in eight preparations, incrementing phrenic discharges were observed and only cycles having such discharges were analysed. In three of the preparations, no peak in the high-frequency oscillations could be discerned. For the others, peaks were between 27 and 48 Hz (Fig. 9).
As shown in Figs 7 and 8, upon exposure to ischaemia, integrated phrenic discharge was again altered to the decrementing pattern typical of gasping. Compared with values in hyperoxia, the frequency of phrenic bursts and the time to reach peak integrated height fell significantly, and the peak integrated height rose significantly in gasping of preparations having a brainstem transection at the pontomedullary junction (Table 1). However, as opposed to preparations having an intact pons, only five of 10 preparations exhibited peaks in high-frequency oscillations typical of those of gasping. These peak frequencies were between 121 and 144 Hz. In the other preparations, no peak frequency was evident. Since peak frequencies could be recorded in only half of the preparations in gasping, no statistical evaluations are presented in Fig. 4.
For five preparations in which activities of both phrenic nerves were recorded, the coherences at the peak frequencies were not significantly different in eupnoea (0.65 ± 0.04), following the caudal pontile transection (0.58 ± 0.02) and in gasping (0.64 ± 0.01).
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Discussion |
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Changes in phrenic discharge following removal of the rostral pontile pneumotaxic centre
In preparations having an intact pons and medulla, peaks in high-frequency oscillations during eupnoea and gasping were identical to those that we have previously reported for the in situ perfused preparation (St-John & Leiter, 2003; Leiter & St-John, 2004). With removal of the rostral pons, the pattern of phrenic discharge was altered to one comparable to apneusis, in which the duration of the phrenic burst was prolonged in many ventilatory cycles. This observation is in agreement and is consistent with our earlier work demonstrating that in rodents, as in all other species examined, a rostral pontile ‘pneumotaxic centre’ influences automatic ventilatory activity from the day of birth (Fung & St-John, 1995; St-John & Paton, 2000). Moreover, the reduction in the peak frequency in high-frequency oscillations of phrenic activity is in agreement with observations following damage to the dorsolateral pons in previous studies (Berger et al. 1978; Richardson & Mitchell, 1982). Yet, this reduction does not necessarily imply that rostral pontile mechanisms exert only a modulatory influence on high-frequency oscillations generated by a unique mechanism for ventilatory neurogenesis in the medulla (Berger et al. 1978; Funk & Parkis, 2002). Indeed, a unique medullary mechanism for generating high-frequency oscillations is incompatible with our finding that peak frequencies in the power spectra were again shifted to significantly higher levels during gasping induced by anoxia in the same preparation.
Changes in phrenic discharge following total removal of pons
Following the total removal of pons by a transection at the pontomedullary junction, the pattern of activity of the phrenic nerve was markedly altered and the peak in high-frequency oscillations was shifted to a value lower than that during eupnoea. These changes are of importance from several aspects. First, the changes in the pattern of phrenic discharge reinforce the concept, first proposed by Lumsden (1923), that caudal pontile mechanisms significantly influence automatic ventilatory activity. Second, the finding that high-frequency oscillations were the same in preparations having a variety of patterns following removal of the rostral pons demonstrates that high-frequency oscillations alone are not a definitive signature of a respiratory pattern. Indeed, many factors, including anaesthesia and brainstem lesions, can alter or eliminate high-frequency oscillations with no change in the pattern of automatic ventilatory activity (see Funk & Parkis, 2002 for review).
Generation of respiratory rhythms by medullary mechanisms
Gasping. In vivo, gasping has been the one pattern of ventilatory activity which has been obtained reproducibly following the isolation of medulla from pons. However, in a minority of in vivo preparations, other patterns have also been obtained (see discussion by St-John (1990); St-John & Paton, 2003b). In situ, we have obtained these other patterns with much greater frequency than in vivo (Paton et al. 2006). Thus, the removal of pontile influences alone may not be sufficient to release medullary mechanisms for gasping. In addition, an alteration in the chemical content of the extracellular and/or intracellular environment is hypothesized to be essential (St-John et al. 2002; Paton et al. 2006). This change in environment, which would be induced by medullary hypoxia, includes a change in the balance between the potassium currents and persistent sodium current. Following a brainstem transection at the pontomedullary junction, medullary hypoxia, and the other changes in the extracellular milieu needed to produce gasping, might be more likely for in vivo preparations, in which hypotension follows transection, than for in situ preparations, in which perfusion is maintained constant by an extracorporeal circuit.
Non-gasping patterns. A fundamental question concerns the relationship between the ‘non-gasping’ phrenic patterns that are generated by the isolated medulla with respiratory patterns generated by the preparation having an intact pons and medulla. As noted in the previous section changes in phrenic discharge following total removal of pons and in the Results, the great majority of these ‘non-gasping’ rhythmic activities differed markedly in pattern from the eupnoeic pattern of the preparation having an intact pons. Yet, the integrated phrenic discharge in some cycles in some preparations did have an incrementing pattern like that of eupnoea. Does this mean that eupnoea is generated by medullary mechanism alone with pons exerting only ‘modulatory influence’? A contrasting view would be that gasping and all non-gasping medullary rhythms are generated by a mechanism or mechanisms which differ from that responsible for the neurogenesis of eupnoea. Concerning neurogenesis of eupnoea, we have recently reported that gasping is generated by the discharge of medullary pacemakers (Paton et al. 2006). A ‘hallmark’ of such pacemakers is an asynchronous discharge between different neurones (see e.g. Rybak et al. 2003 for review). Hence, we hypothesize that at least some ‘non-gasping’ medullary rhythms may represent ‘incomplete’ gasps or the discharge of pacemaker neurones involved with neither the neurogenesis of eupnoea or gasping.
A contrasting view has recently been presented by Ramirez & Viemari (2005) who concluded that the isolated medulla of an in situ mouse preparation can generate a eupnoeic rhythm. However, recordings in their in situ preparation were only obtained following a transection at the pontomedullary junction. As is true for gasping, this medullary rhythm was eliminated following administration of riluzole, a blocker of persistent sodium channels. However, for in situ preparations having an intact pons, the eupnoeic bursts of phrenic discharge continue following administrations of the same concentrations of riluzole. These concentrations are 10-fold above those at which gasping is eliminated (St-John et al. 2006). These results in which riluzole failed to eliminate the eupnoeic rhythm and the results of the present study demonstrating different peak frequencies in high-frequency oscillations during eupnoea and ‘non-gasping’ medullary rhythms do not support the conclusion of Ramirez & Viemari (2005) as to the generation of eupnoea by medullary mechanisms alone.
Neurogenesis of eupnoea: pontile and medullary pacemakers and circuits
We have long maintained that different mechanisms underlie the neurogenesis of eupnoea and gasping. A pontomedullary neuronal circuit is essential for eupnoea. Within this circuit are medullary neurones which have potential pacemaker mechanisms that can be released to generate gasping (e.g. St-John, 1990; St-John & Paton, 2002, 2003a; Rybak et al. 2003; Paton et al. 2006). Based upon evaluations using in vitro preparations, a number of investigators proposed that the discharge of pacemakers within the medullary ‘pre-Botzinger’ complex generated eupnoea. However, this proposal has now been modified to become a hybrid ‘pacemaker’ circuit model or even a localized neuronal circuit (Smith et al. 2000; Feldman et al. 2003; Mellen et al. 2003; Ramirez & Viemari, 2005). The anatomical limits of this neuronal circuit appear to be expanding, with one laboratory proposing that interconnections between neurones of the ‘pre-Botzinger’ complex and those of the ‘pre-I’ region of the rostroventral medulla are necessary for both eupnoeic inspiration and expiration (Feldman et al. 2003; Mellen et al. 2003; Janczewski & Feldman, 2006). Based upon results of the present experiments involving brainstem transections, we conclude that this expansion of the neural circuit for eupnoea should include neuronal elements of the rostral pontile pneumotaxic centre and also the caudal pons, as originally proposed by Lumsden (1923).
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References |
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