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J Appl Physiol 99: 691-698, 2005. First published March 10, 2005; doi:10.1152/japplphysiol.01124.2004
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Arterial pulse modulated activity is expressed in respiratory neural output

Thomas E. Dick,1 Roger Shannon,2 Bruce G. Lindsey,2 Sarah C. Nuding,2 Lauren S. Segers,2 David M. Baekey,2 and Kendall F. Morris2

1Division of Pulmonary and Critical Care Medicine, Departments of Medicine and Neurosciences, University Hospitals Research Institute, Case Western Reserve University, Cleveland, Ohio; and 2Department of Physiology and Biophysics, University of South Florida Health Sciences Center, Tampa, Florida

Submitted 7 October 2004 ; accepted in final form 4 March 2005


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

control of respiration; homeostasis; laryngeal motoneurons; cardiorespiratory coupling

BECAUSE OF THE FUNDAMENTAL physiological and pathophysiological importance of respiration and blood circulation, and the integral functional relationships between these systems, much research has focused on the neural mechanisms involved in coordinating the functions of the cardiovascular and respiratory systems. For example, it has long been recognized that sympathetic activity is modulated with respiration (1). However, although it seems reasonable to anticipate that cardiorespiratory coupling would be reciprocal in nature, presently it is unknown whether the respiratory activity is modulated with cardiovascular function.

To determine whether the respiratory control system is modulated in accordance with cardiovascular function, we recently characterized the activities of medullary respiratory neurons using {delta}2, a new statistical tool that quantifies the consistency and strength of arterial pulse-modulated activity in extracellular neural recordings (12). The {delta}2 statistic is based on the analysis of variance and the {eta}2 statistic (30); it is a ratio of the variance attributed to the pulse to the total variance and, as such, is a number between 0 and 1. As {delta}2 values approach 0, less of the variance in the activity pattern is related to pulse, whereas, as they approach 1, more of the variance is related to the pulse.

In our previous study, we analyzed recordings of the rostral and caudal ventral respiratory groups in vagally intact, decerebrate cats (12). The data analyzed comprised a portion of an existing data set that had formed the basis of a series of papers concerning the control of cough and the expiration reflex (3, 4, 34, 35). In that study, we found that the activities of ~50% of the neurons in the sample were correlated significantly with pulse. Furthermore, the {delta}2 values were greater for expiratory (E) than inspiratory (I) activity, such that a greater percentage of the E neurons were modulated with pulse and exhibited high (>0.3) {delta}2 values (12). We speculated that these pulse-modulated neurons not only expressed respiratory-modulated activity but also had a respiratory-related function. However, we could not exclude the possibility that some of the cells in question were associated with the control of the cardiovascular, rather than the respiratory, system. This was because, although medullary respiratory and cardiovascular neuron populations appear to be distinct, they are codistributed neuroanatomically (15, 16).

Accordingly, in the present study, we tested the hypothesis that the activity of medullary respiratory control neurons is modulated with arterial pulse. An extended data set was analyzed for the presence of functionally identified respiratory-modulated activity and included bulbospinal premotoneurons and upper airway motor and premotoneurons, located in the ambiguus and retroambigualis nuclei. These neurons were distinguished by their axonal projection targets and functional associations and thus were not only respiratory modulated, but also respiratory related. Furthermore, in this highly characterized data set, we found that E activity was preferentially pulse modulated, compared with I activity.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
An existing set of medullary single-unit recordings in which arterial blood pressure was recorded was analyzed for this study. The methods for data acquisition have been described in detail (3, 4, 34, 35). Recordings were made in decerebrate, vagally intact, neuromuscular blocked (gallamine triethiodide, 4.0 mg·kg–1·h–1 iv), and ventilated cats (n = 28, adult, 2.5–4.1 kg, either sex) using surgical, experimental, and euthanasia procedures approved by the University of South Florida's Animal Care and Use Committee. Because vagi were intact, the ventilator's inflation phase was triggered by phrenic nerve activity during the recording session to coordinate pulmonary stretch receptor feedback with I motor activity.

For decerebration, animals were initially anesthetized with isoflurane (2–5%) and given atropine (0.5 mg/kg im) and dexamethasone (2.0 mg/kg iv) to reduce mucus secretions and neural edema, respectively. A femoral artery was catheterized for monitoring blood pressure and for sampling blood gases, and a femoral vein was catheterized for administering fluids and drugs. The external carotid arteries were ligated bilaterally rostral to the lingual arteries to minimize intracranial bleeding. Animals were positioned in a stereotaxic frame, and a craniotomy was formed in the parietal plates. The brain stem was transected midcollicularly, and neural tissue rostral to the transection was aspirated.

Whole nerve recordings.   Whole nerve recordings were from the left fifth cervical phrenic nerve root and the right recurrent laryngeal nerve (RLN). The proximal cut ends of these nerves were desheathed, placed on a bipolar silver electrode, and covered in mineral oil. Nerve signals were amplified and filtered (band pass 0.1–5 kHz, Grass P511 amplifiers) and integrated with a leaky resistor-capacitor circuit (0.2 s time constant, Grass) and recorded on a polygraph and magnetic tape.

Single neuronal extracellular recordings.   During the preparatory surgery, a bilateral thoracotomy was formed to minimize movement associated with ventilation. During the experiment and single-neuron recordings, end-tidal CO2 was maintained between 4.0 and 5.0%. Arterial blood pressure was maintained at 100 mmHg by administering intravenously 5% dextrose in 0.45% NaCl, 5% dextran, or lactated Ringer solution. Arterial PO2, PCO2, pH, and HCO3– concentration were analyzed hourly and corrected to normal limits. Rectal temperature was maintained at 38.0 ± 0.5°C. Of these variables, arterial blood pressure, tracheal pressure, and end-tidal CO2 were recorded on magnetic tape. The right side of the medulla was searched with planar electrode (n = 8) arrays (n = 2) of tungsten microelectrodes (impedance = 10–12 M{Omega}). Signals were amplified, filtered (band pass 0.1–5 kHz, Grass P511 amplifiers), monitored, and recorded on magnetic tape. The medullary surface was covered with a pool of warm mineral oil.

The stereotaxic coordinates of the electrodes were referenced to the obex. Activity was recorded from areas in the ventrolateral medulla at the following stereotaxic coordinates: 3.0–5.5 mm rostral to obex, 3.0–4.5 mm lateral to midline, 3.0–5.5 mm below the dorsal surface, and 2.0 mm rostral to 4.0 mm caudal to obex, 3.0–4.5 mm lateral to midline, and 2.5–4.5 mm below the dorsal surface (Fig. 1A).



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  		Fig. 1. Activity of a premotoneuron (largest action potential) that was modulated with respiration and pulse [see Fig. 4B for respiratory cycle-triggered histograms (rCTH) and pulse cycle-triggered histograms (pCTHs)]. Activity is displayed as a polygraphic trace (A), as an overlay (B), and as an autocorrelation histogram (ACH). A: traces from the top: recorded medullary action potentials, acceptance pulse for the largest action potential, acceptance pulse for arterial pulse, which served as the trigger for the pCTH, arterial pulse, and integrated phrenic nerve activity (PNA). The arrows indicate those trigger pulses that would have been included in the analysis of the {delta}2 statistic. The amplitude of the action potentials (first trace) did not vary systematically with pulse (fourth trace). B: the amplitudes of the largest unit (solid black line) and small units in the background (light gray line) were stable across the cardiac and respiratory cycles. The waveforms in both A and B indicate that the modulation of the unit, which is most apparent as the discharge frequency decreases, did result from systematic changes in the orientation of the neuron with the recording electrode. C: the ACH for the large unit contained a period of quiescence, indicating that the largest unit was discriminated without false positive errors. A/D, analog to digital.

 
Data entry.   Action potentials of single-unit recordings were identified on the basis of 11 characteristics of the waveform and converted to times of occurrence with spike-sorting software (Datawave Technology) (Fig. 1). The motor nerve signals were high-pass filtered (40 Hz, 3 dB cutoff) and digitized (5 kHz) with a 16-bit ADC488/16 analog-to-digital converter hosted by a Hewlett-Packard 9000/380 computer. Data files were transferred to Hewlett-Packard 9000/735 and c160 computers and synchronized. The action potentials and other digital and analog signals were displayed graphically using XSCOPE (24), a program that allowed event codes to be added and data segments to be selected for later analysis.

Analysis methods for single neurons.   The following analyses were performed on brain stem unit activity recorded during a 5- to 10-min period: 1) autocorrelation histograms (Fig. 1C), 2) respiratory cycle-triggered histograms (rCTHs; Figs. 2–4), and 3) cardiac cycle-triggered histograms (cCTHs; Figs. 2–4). These analyses were limited to the activities of motoneurons or premotoneurons, as determined by positive identification of axonal projections using either spike-triggered averaging (STA; Figs. 2 and 3) or antidromic activation (Fig. 4).



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  		Fig. 2. Respiratory and pulse modulated activity of a recurrent laryngeal motoneuron (RLmn; A) and an excitatory premotor input to the recurrent laryngeal motoneuronal pool [B; premotor recurrent laryngeal nerve (RLN)]. A1 and B1: rCTHs (solid line) of activity recorded from a RLmn and a premotor RLN, respectively, and from the integrated phrenic nerve (dashed line). The RLmn was classified as an expiratory (E)-augmenting (Aug) type and had an {eta}2 value of 0.33. The premotor RLN was classified as an inspiratory (I)-Aug type and had an {eta}2 value of 0.80. In all rCTHs, averaging was triggered with the transition from inspiration to expiration. A2 and B2: pCTHs (solid line) of a RLmn and a premotor RLN, respectively, and integrated heart beat (dashed line). Both neurons had activity modulated by pulse: the RLmn had a {delta}2 value of 0.49, and the premotor RLN had a {delta}2 value of 0.13. In all pCTHs, averaging was triggered with sharp rise in arterial blood pressure. A3 and B3: spike-triggered averages (STAs) to the full-wave-rectified RLN activity. The narrow positive waveform (A3) displaced from the reference event (vertical dashed line) represented a time-locked potential recorded peripherally from the efferent vagus nerve. In contrast, the broad positive wave (B3) was indicative of dispersed excitatory drive. A4 and B4: the STAs to the unrectified RLN activity. The waveform (A4) resulted from the axonal action potential of a single RLmn recorded peripherally from the central cut end or "efferent" vagus nerve. The difference between the reference event (vertical dashed line) and the waveform was proportional to the conduction time, which varied little. In contrast, absence of a feature in the STA of the unrectified RLN activity (B4) was due to the variance in action potential hypothetical due to synaptic delays.

 


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  		Fig. 4. "Premotor" bulbospinal neurons activated antidromically from the spinal cord for E-decrementing (Dec) neurons: one nonmodulated (A) and the other pulse modulated (B). A: the rCTH and pCTH of a bulbospinal neuron (bold solid line). This bulbospinal neuron was classified as an E-Dec type and had an {eta}2 value of 0.79, but its activity was not pulse modulated. The left panel shows the collision test. In the top trace when the stimulus pulse (stimulus artifact noted by arrow head) was delayed ~4 ms after the spontaneous action potential, an evoked action potential was recorded consistently. In the bottom trace, the delay was decreased, and the evoked AP was not recorded. B: the rCTH and pCTH of a bulbospinal neuron (bold solid line) recorded simultaneously with A. This bulbospinal neuron was also E-Dec with a comparable {eta}2 value (0.76), but its activity was significantly modulated with pulse and had an {delta}2 value of 0.47. The collision test is as described in A; however, a second unit was recruited at approximately the same latency as the spontaneously active one.

 


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  		Fig. 3. Pulse modulation preferentially expressed in the expiratory activity of a tonically active RLmn (A) and a premotor RLN (B). A1 and B1: as in Fig. 2, rCTHs (solid line) of a RLmn (A) and a premotor RLN (B) and integrated PNA (dashed line). The RLmn was classified as an I-Aug and had an {eta}2 value of 0.24. The premotor RLN was classified as E-Other. A2 and B2: as in Fig. 2, pCTHs (solid line) of RLmn activity and integrated heartbeat (dashed line). Both neurons had activity modulated by pulse with {delta}2 value of 0.13 (A) and 0.21 (B). A, 2-I and 2-E and B, 2-I and 2-E: activity that occurred in inspiration (A, 2-I and B, 2-I) was not modulated with pulse, whereas activity that occurred in expiration (A, 2-E and B, 2-E) was significantly modulated. A3 and A4 and B3 and B4: as in Fig. 2, the full-wave-rectified (A3 and B3) and unrectified (A4 and B4) STAs were consistent with activity of a RLmn (A) and a premotor RLN (B).

 
The interpretation of these analyses depended on a signal profile that did not change with the pulse or ventilation. To ascertain the consistency of the signal, we routinely inspected the action potential waveform in the raw tracing (Fig. 1A), overlaid tracings of the analog-to-digital conversion of spike activity (Fig. 1B), and evaluated the autocorrelogram (Fig. 1C). In the raw data tracing (Fig. 1A, top), activity from more than one neuron was recorded simultaneously on one electrode. Neither the cardiac nor ventilatory cycles were associated with changes in the amplitude of the individual spikes or the relative amplitudes of the large waveform compared with the activity recorded in the background. Autocorrelograms were computed for each spike train to determine whether respective signals could be discriminated from the simultaneously recorded activities and contained no false positives (Fig. 1C). The autocorrelation histogram from an isolated single neuronal recording contains a period without an event after the occurrence of the reference spike. In contrast, in multiunit recordings, spurious activity occurs during the period after the reference spike.

For rCTHs, the triggering or reference event was the point at which the integrated phrenic nerve activity had its steepest negative slope. Each cycle was divided into 20 equal bins, and the number of action potentials that occurred in each 5% of the breath was tabulated for 50 breaths. The significance of the respiratory modulation of activity patterns was determined by the ANOVA (30) and the binary test (27). Activity patterns that were found not to be significantly modulated, as indicated by the ANOVA, were, nonetheless, included among those of respiratory-modulated neurons if identified as such by the binary test (27). We classified each respiratory-modulated activity on the basis of its firing pattern as displayed in its rCTH, with respect to phase of onset and peak firing frequency and to slope of activity.

For cCTHs, the reference event was the sharp rise of arterial blood pressure associated with systole. An algorithm for detecting the rising phase of pulse pressure from the arterial blood pressure tracing was used to discriminate the cardiac cycle. Each cycle was divided into equal quintiles. The number of action potentials that occurred in each quintile was tabulated for 50 composite cardiac cycles. For cardiac modulation, we used only ANOVA to determine significant pulse modulation (12).

Standard physiological criteria were used to identify motor and premotoneurons. Recurrent laryngeal motoneurons were identified by STAs of the RLN activity. Averaging enhances the signal-to-noise ratio of events that are time locked, i.e., correlated, to the reference event. The shape of this waveform depends on whether the RLN activity is rectified or unrectified and on the variability in the delay of the correlated events. If a brain stem neuron's axon was in the RLN, then the conduction time of the action potential would be the only factor determining the delay. This delay is consistent. Consequently, the STA of unrectified RLN activity would reveal the triphasic waveform of the action potential passing the bipolar recording electrodes, whereas STA of rectified activity would be observed as a positive waveform of narrow width. On the other hand, if the brain stem neuron was presynaptic to the recurrent laryngeal motoneuron pool, then additional variability would affect the time interval between the reference and correlated events, due to synaptic delays and conduction times of the various motoneurons that it excites. Consequently, the STA of unrectified RLN activity would not reveal any waveform, whereas STA of rectified activity would reveal a positive waveform with a broad peak. Conduction velocity for recurrent laryngeal motoneurons was determined by dividing the conduction distance by the observed delay to appearance of the action potential in the STA. The conduction distance (~15 cm) was determined by dissecting the RLN and measuring the length of the RLN, using the obex to approximate the point of brain stem origin of the RLN.

Bulbospinal premotoneurons were identified by antidromic activation from the spinal cord stimulation, confirmed by a positive collision test. An array of four stimulating electrodes was placed on the left side of the spinal cord, i.e., contralateral to the medullary recording electrodes. The electrodes were placed in the ventrolateral white matter of the spinal cord in the region of the last cervical/first thoracic segment. At the end of the recording session, we tested for antidromic activation. A constant stimulus latency for evoked activity was the first criterion applied to identify potential premotoneurons. We tested this neuronal activity by triggering the stimulator ~2 ms after a spontaneous action potential recorded in the medulla. If an evoked action potential was not recorded following this stimulus, then the collision test was considered positive. Although we did not determine the "critical delay" per se for each of these recordings, we classified the neurons as bulbospinal because respiratory-modulated neurons recorded in the caudal ventrolateral cell column are known to project to the spinal cord (6, 33).

The distributions of high ({delta}2 ≥ 0.3), low ({delta}2 ≤ 0.2), and nonsignificant {delta}2 values for E and I neurons as well as for recurrent laryngeal motoneurons, premotor excitatory neurons to RLN, and bulbospinal neurons were determined and plotted. The statistical significance of differences in the distributions of {delta}2 values was tested using the {chi}2 test. Values of P < 0.05 were accepted as indicative of significant differences.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
The magnitude of cardiac and respiratory modulation was determined in a total of 581 spike trains from 28 animals, recorded from neurons located in the rostral and caudal ventral respiratory groups. For a subset of these neurons (n = 72), their axonal projections were identified either by the STA to the RLN or by antidromic activation from the spinal cord. Using these criteria, 22 were identified as putative recurrent laryngeal motoneurons (Figs. 2A and 3A), 19 as premotor to recurrent laryngeal motoneurons (Figs. 2B and 3B), and 31 as premotor to spinal cord motoneurons (Fig. 4).

Recurrent laryngeal motoneurons.   Recurrent laryngeal motoneurons (n = 22) were identified by 1) a positive, sharp, narrow peak in the STA of the full-wave-rectified RLN recording (Figs. 2A3 and 3A3) and 2) a waveform in the unrectified RLN recording (Figs. 2A4 and 3A4). These motoneurons had an average conduction velocity of 42 ± 17 m/s. In this group, 8 neurons had I activity [2 I decrementing (I-Dec), 1 I continuous (I-Con), and 5 I augmenting (I-Aug)] and 14 had E activity [11 E decrementing (E-Dec), 1 E augmenting (E-Aug)], and 2 were recruited during E reflexes (E-Recruit). The activity patterns of these neurons were significantly correlated with the respiratory cycle; {eta}2 values ranged from 0.02 to 0.96. Among these subclassifications, E-Recruit motoneurons exhibited the lowest {eta}2 values, indicating their activity had the weakest association with respiration.

A subset (n = 5/22, 23%) of these recurrent laryngeal motoneurons exhibited significant pulse-modulated activity (Figs. 2A2 and 3A2). The significant {delta}2 values ranged from 0.05 to 0.49. The recurrent laryngeal motoneuron that exhibited the highest {delta}2 value (0.49) was the only E-Aug motoneuron ({eta}2 value of 0.33, Fig. 2A2). Although the recurrent laryngeal motoneuron exhibiting the next highest {delta}2 value (0.13) was an I-Aug motoneuron ({eta}2 value of 0.24, Fig. 3A2), after partitioning its tonic activity into the I and E components, the I component was found not to be pulse modulated, whereas the E component exhibited a greater {delta}2 value (0.16, Fig. 3A, 2-I and 2-E). The other three neurons (1 I-Dec and 2 E-Dec) had {delta}2 values between 0.06 and 0.11. These neurons were phasically active, having {eta}2 values of 0.79 (I-Dec) and 0.72 (E-Dec), but one (E-Dec) had a low discharge frequency and an {eta}2 value of 0.12.

Putative premotoneurons to recurrent laryngeal motoneurons.   Excitatory premotor input to recurrent laryngeal motoneurons was identified by a positive, short-latency (<5 ms) but broad (half-width > 2 ms) peak in the STA of the full-wave-rectified RLN recording (Figs. 2B3 and 3B3) and the absence of a feature in the unrectified recording (Figs. 2B4 and 3B4). Using these criteria, 19 neurons were characterized as having excitatory inputs to the recurrent laryngeal motoneuronal pool; 13 neurons were I modulated (7 I-Dec, 2 I-Con, and 4 I-Aug), whereas 6 were most active during the E phase (2 E-Dec, 1 E-Aug, 2 E-Other, and 1 E-Recruit). The {eta}2 values ranged from 0.04 to 0.99. As in the recurrent laryngeal motoneuron activities, patterns exhibiting the lowest discharge frequencies had the lowest {eta}2 values (e.g., the E-Recruit had an {eta}2 value of 0.04).

Approximately 40% (8/19) of these recordings exhibited significant pulse-modulated activity (Figs. 2B2 and 3B2). Within this subset, none of the activity patterns had high {delta}2 values ({delta}2 values ranged between 0.05 and 0.13). Six of the eight observed pulse-modulated patterns were also I modulated and phasic (five I-Dec and one I-Aug), including the recording that exhibited the highest {delta}2 value (Figs. 2B2 and 3B2). These neurons had {eta}2 values between 0.36 and 0.8. Similarly, the E neurons (E-Other and E-Dec) exhibited low {delta}2 values (0.10 and 0.07) and high {eta}2 values (0.4 and 0.67). One E neuron (E-Other, Fig. 3B1) exhibited activity during both I and E phases. Separate analysis of the I and E components indicated that the I component was not pulse modulated. In contrast, the E component had a greater {delta}2 value than that for combined activity (0.21; Fig. 3B, 2-I and 2B, 2-E), as was observed for recurrent laryngeal motoneurons that were active in both I and E phases (Fig. 2A), indicating that pulse modulation occurs preferentially during E-phase activity.

Bulbospinal neurons.   Putative premotoneurons (n = 31) were identified by antidromic activation and collision test from spinal cord stimulation (Fig. 4). These neurons had I activity (n = 18, 1 I-Dec, 2 I-Con, and 15 I-Aug), E activity (n = 11, 5 E-Dec and 6 E-Aug), or phase-spanning (PS) patterns (n = 2, 1 IE PS and 1 EI PS). The {eta}2 values ranged from 0.23 to 0.98, and only four exhibited tonic activity.

In this group, 9 of 31 recordings exhibited significant pulse-modulated activity (Fig. 4B), characterized by {delta}2 values between 0.04 and 0.56. Neither the IE PS nor the EI PS neurons exhibited pulse-modulated activity. Only 4 of the 18 I-modulated patterns were also pulse modulated, and these were all weakly modulated with {delta}2 values of 0.04 for 1 I-Dec, 0.07 for 1 I-Con, and 0.06 and 0.07 for 2 I-Aug neurons. In contrast, 5 of the 11 predominantly E neurons (3 E-Dec and 2 E-Aug) were pulse modulated, and 2 E-Dec neurons, in particular, exhibited high {delta}2 values. These neurons had {eta}2 values between 0.7 and 0.93.

Distributions of {delta}2 values for different types of neurons.   The distribution of high (>0.3) and low (<0.2) {delta}2 values, as well as nonsignificant pulse-modulated activity, was plotted separately for I and E activity (Fig. 5A) and for recurrent laryngeal motoneurons, premotoneurons to the RLN, and bulbospinal neurons (Fig. 5B). Separating {delta}2 values on the basis of the predominant respiratory phase of discharge revealed that the distribution of {delta}2 values for E was significantly different than that for I activity, wherein "high" {delta}2 values were only associated with E activity. In contrast, separating {delta}2 values on the basis of identified axonal projections did not result in a differential distribution of {delta}2 values. In this connection, the absence of "high" {delta}2 values in premotoneurons to the RLN (Fig. 5B) was not significant.



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  		Fig. 5. Distribution of {delta}2 values for E vs. I activities (A) and for RLmn vs. premotoneurons to the recurrent laryngeal motor pool (pre-RLmn) or spinal cord (AA-cord; AA refers to group antidromically activated from the spinal cord) (B). The significance of the differences in the distributions was determined with the {chi}2 test. *The number of high {delta}2 values was significantly greater than expected for expiratory activity. There was no difference in the distribution based on axonal projection.

 
Distribution of {delta}2 values for corecorded activity.   The activity patterns for the recurrent laryngeal motoneurons, premotoneurons to the RLN, and bulbospinal neurons were recorded by using electrode array technology, which permits simultaneous recording of multiple single units. Consequently, the activities of these neurons were recorded along with those of 3–28 other medullary neurons. On average, 13 neurons were recorded simultaneously. The distribution of {delta}2 values for the group of simultaneous neurons was similar to that for the subset of motor and premotoneurons (Fig. 6A). In particular, 29.9% of the overall and 31.9% of motor and premotoneurons were significantly modulated with pulse. Furthermore, in Fig. 6A, the distributions appeared bimodal: a large group of weakly related activity ({delta}2 values ≤ 0.2) and a small group of highly modulated activity ({delta}2 values ≥ 0.3).



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  		Fig. 6. Distribution of {delta}2 values. A: frequency histograms showing the number of occurrences in which a {delta}2 value fell between certain values as defined on the x-axis. The solid bars indicate high {delta}2 values (≥0.3); the open bars, low {delta}2 values (≤0.2). We plotted the {delta}2 values of all of the simultaneously recorded activity patterns (A1) and for only the RLmn, premotor-RLN, and bulbospinal neurons (A2). The distribution patterns were similar and bimodal. B: the mean {delta}2 value was plotted against the percentage of simultaneously recorded neurons that showed significant pulse-modulated activity. As the prevalence of pulse modulated activity within the sample recorded by the multielectrode array increased, the average {delta}2 value for RLmn, premotor-RLN, and bulbospinal spinal neurons increased.

 
Within a recording, the number of neurons that exhibited activity modulated with pulse ranged from 0 to 10 or from 0 to 78% of the simultaneously recorded activity. To determine whether pulse modulation was clustered or prevalent in certain animals, we correlated the average {delta}2 value for motor and premotoneurons against the percentage of simultaneously recorded single units that had significant {delta}2 values in their activity patterns (Fig. 6B). The correlation between these variables was significant for both linear and polynomial regressions (line of polynomial regression is shown in Fig. 6B).

Relationship between respiratory and pulse-modulated activity.   To determine whether the strength and consistency of the pulse and respiratory modulation were related, we plotted {delta}2 values against {eta}2 values (Fig. 7). These variables did not appear either correlated or exclusionary. Arterial pulse-modulated activity was statistically significant even within the subset of respiratory neural activities with {eta}2 values ≥ 0.9 (even within the subset of respiratory neural activities in which almost all of the variance was correlated to respiration). On the other hand, four of five high {delta}2 values (>0.3) occurred at {eta}2 values between 0.7 and 0.8 (Fig. 7), indicating that motor activity can reflect accurately both respiratory and pulse modulation.



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  		Fig. 7. {delta}2 vs. {eta}2 values. Although {delta}2 values were not correlated to {eta}2 values, the greatest concentration of high {delta}2 values in the 72-neuron sample appears as a cluster, exhibiting {eta}2 values lying in a narrow range just below those activity patterns exhibiting the highest {eta}2 values.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
The present findings demonstrate that the activity of medullary respiratory neurons is modulated with arterial pulse. The specific neuronal population studied here included recurrent laryngeal motoneurons, bulbospinal premotoneurons, and putative premotoneurons to RLN, based on their axonal projections and functional correlations of activity with those in the RLN.

In addition, we found that pulse-modulated activity was expressed preferentially during the E phase. Overall, E neurons exhibited a greater frequency of high {delta}2 values than did I neurons. In contrast, phasic I neurons displayed weaker but, nonetheless, significant pulse-modulated activity, whereas tonically active I neurons exhibited pulse-modulated activity only during E, suggesting that respiratory pulse modulation may be a function of phase rather than specific neuronal phenotype.

The results also suggest that pulse modulation of respiratory neuronal activity is expressed preferentially during specific conditions, as we found that significant values of {delta}2 tended to occur within a given recording period. Accordingly, the average {delta}2 value of the premotor and motoneurons was correlated with the observed percentage of simultaneously recorded neurons exhibiting significant pulse modulation. Therefore, pulse modulation became increasingly evident in motor activity as the prevalence of concurrently recorded respiratory-modulated neurons expressing this feature increased. Furthermore, this relationship appeared to be quite robust, as this correlation persisted across a diverse range of recording sites and neuronal types monitored, which suggests that pulse modulation is a common feature of respiratory neurons. Although we have not yet had the opportunity to study this systematically, we speculate that the magnitude and prevalence of pulse-modulated activity may be a function of the magnitude of the pulse pressure, based on our earlier findings that percentage of simultaneously recorded neurons exhibiting pulse-modulated activity or magnitude of {delta}2 values was significantly correlated with pulse pressure (12). However, the variables that influence {delta}2 values remain to be determined.

Origin of pulse-modulated activity.   The mechanisms involved in the origin of the pulse-modulated signal in the respiratory efferent activity are unknown. We hypothesize that respiratory pulse modulation is of sensory, rather than central, origin and, furthermore, that it indicates reciprocal interactions between sympathetic and respiratory control systems. The extent to which the present data support a reciprocal interaction between respiratory and sympathetic control systems relies on correctly identifying efferent activity as eliciting a respiratory motor rather than autonomic function. We characterized brain stem activity as respiratory related if a waveform appeared in the STA of the unrectified RLN.

Even though the RLN innervates airway and esophageal smooth muscles (8, 10, 11) and contains sensory fibers from the larynx as well as sympathetic anastomoses (5, 37), we interpreted this waveform as arising from a motoneuron innervating striated muscle, rather than from a vagal preganglionic neuron, according to the following rationale.

First, the peripheral bipolar electrode was positioned to record from only the distal-most components of the RLN, distal to the points of egress of the majority of vagal neurons that innervate esophageal and tracheal smooth muscle (10, 11).

Second, the calculated conduction velocities (42 m/s) of axons generating the STA waveform indicated that they were myelinated and had an axonal diameter >10 µm. Myelinated axons with smaller diameters (2–3 µm) and slower conduction velocities (10 m/s) innervate the trachea and esophagus (8, 10, 11).

Third, the central microelectrode was positioned in the nucleus ambiguus and nucleus retroambigualis of ventrolateral respiratory column. Neurons in these nuclei as well as in retrofacial nucleus project in the RLN (18, 39). The axons from the retrofacial nucleus are the source for the smaller diameter efferent axons in the RLN (18). Furthermore, the retrofacial nucleus is located more rostral in the medulla than where the recording electrode was placed.

Thus we conclude that the medullary neurons that were recorded with axons in the RLN projected to striated muscle of the larynx and subserved a respiratory rather than autonomic function.

One mechanism that could potentially contribute to pulse modulation of E rather than I activity is gating of primary afferent input from baroreceptors. However, we believe that this is unlikely, based on evidence that baroreceptor input may not be modulated by respiratory phase, at least at its first synapse (20, 26). For instance, Mifflin et al. (26) recorded activities of nucleus tractus solitarii neurons that were shown to be involved in the baroreflex pathway by their responsiveness to increased arterial pressure and found that the postsynaptic potentials evoked by carotid sinus nerve stimulation were not modified by either lung inflation or respiratory phase. Thus the preferential pulse modulation of E activity is probably not due to gating of afferent carotid sinus nerve activity during inspiration.

Alternatively, the expression of pulse modulation in the activity of E neurons may be a function of their differential inputs, because the values of {delta}2, like those of {eta}2 values, reflect the balance of inputs that a neuron receives (30, 31). E neurons have a tendency to exhibit lower {eta}2 values than I neurons. Lower {eta}2 values may reflect an activity pattern resulting from greater synaptic noise and a wider variety of synaptic inputs and indicate that firing pattern is simply not "a slave to the respiratory rhythm." Consequently, the activity of E neurons may be more susceptible to modulation by baroreceptor activity.

Physiological significance of pulse-modulated activity.   The physiological significance of the presently described pulse-modulated activity in respiratory neurons remains to be determined. Nevertheless, we believe that it is instructive to consider the phenomenon in a teleological context. A fundamental organizational precept of cardiorespiratory regulation posits a unitary system devoted to gas exchange (16, 33). Feldman and Ellenberger (16) reasoned that the dualistic concept of parallel, but separate, circuits may have developed primarily as a result of the qualitative differences in end-stage effectors of the respiratory and cardiovascular systems and the predominant focus of researchers on mechanisms involved in their respective neuromotor control. Thus the reductionist nature of research into the physiology and pathophysiology of the airways, lung, heart, and vasculature has led to a predominant focus on the networks of neurons that control each of these respective effectors (16). Nevertheless, even a dualistic model of central cardiorespiratory control can accommodate the existence of reciprocal interactions between respiratory and cardiovascular neurons at the level of the brain stem, which would be reflected in both of the respective effector systems. In this connection, Zhong et al. (41) have promoted a concept of dualistic, but highly coupled, cardiorespiratory control. The present findings, which simply show that the influence of a controlled variable, pulse, is evident in respiratory motor activity, are equally consistent with the concepts of unitary and coupled dualistic cardiorespiratory control systems.

We presume that the appearance of pulse-modulated respiratory activity serves a homeostatic function in gas exchange. In this regard, Lichtwarck-Aschoff et al. (23) reported oscillations in lung volume that are synchronous with the heartbeat, presumably due to the mechanical force of the heartbeat, and that serve to promote gas mixing and gas exchange. The oscillations in lung volume dissipated with prolonged mechanical ventilation, which resulted in progressive declines in both lung compliance and gas exchange (23). It is possible that the presently described pulse-modulated motor activity may promote gas exchange through such a mechanism. It remains to be determined whether this is the case, because the animals in the present study were paralyzed, precluding any analysis of the potential mechanical effects of the pulse-modulated motoneuronal activity.

An influence of the respiratory pattern on sympathetic peripheral nerve activity has been recognized since Adrian and colleagues (1) recorded respiratory-modulated sympathetic nerve activity. On the other hand, the modulatory influence of cardiovascular parameters on respiratory neuronal activity has not been widely recognized, despite numerous reports concerning barorespiratory reflexes (7, 13, 19, 21, 22, 25, 28, 29, 32, 36, 38, 40) and the known modulatory effects of baroreceptor stimulation on medullary respiratory activity (2, 9, 17, 21, 22, 25, 32). The barorespiratory reflex has been described as acute increases in blood pressure leading to decreased respiratory frequency and tidal volume (8, 13, 19, 29). In those studies, the decreases in respiratory frequency resulted from E prolongation (29), and these were attributed to changes in motor activity as well as cycle timing (14). Consequently, our present finding that pulse-modulated activity is manifested in E activity of the bulbospinal premotor population, which may similarly affect cycle timing (6), is consistent with earlier reports that acute increases in blood pressure affect E more than I activity. Nevertheless, to our knowledge, a beat-to-beat expression of the cardiac cycle in respiratory motor activity has not been reported previously, and understanding the functional implications of this phenomenon remain to be determined.

In conclusion, the present findings indicate that the cardiac cycle is represented functionally in the activity of medullary respiratory neurons. This influence is expressed as modulation with arterial pulse and is evident in respiratory premotor activity as well as motor output, predominantly in the activity of neurons involved in expiration. This phenomenon appears to be a fundamental manifestation of central cardiorespiratory coupling and hence an intrinsic property of the cardiorespiratory control system. The functional implications of cardiorespiratory coupling at this level, and particularly its potential adaptive or maladaptive significance in different physiological and pathophysiological circumstances, remains to be determined.


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ACKNOWLEDGMENTS
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This research was supported by National Institutes of Health Grants NS-19814, HL-49813, and HL-63042, and the Chiles Endowment Biomedical Research Program Florida D.O.H. BM037.

Present address of D. M. Baekey: Division of Pulmonary and Critical Care Medicine, Departments of Medicine, Pharmacology, and Neurosciences, University Hospitals Research Institute, Case Western Reserve University, Cleveland, OH 44106–4941.


   ACKNOWLEDGMENTS
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 ACKNOWLEDGMENTS
REFERENCES
 
The authors thank Kim Ruff and Kathryn Ross for expert technical assistance in preparation of this manuscript.


   FOOTNOTES
 

Address for reprint requests and other correspondence: T. E. Dick, Division of Pulmonary and Critical Care Medicine, Dept. of Medicine, Case Western Reserve Univ., Biomedical Research Bldg. BRB B55, 10900 Euclid Ave., Cleveland, OH 44106–4941 (E-mail: thomas.dick{at}case.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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