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Department of Physiology, University of Kentucky, Lexington, Kentucky 40536; and Department of Physiology and Biophysics, College of Medicine, University of South Florida, Tampa, Florida 33612
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Xu, Fadi, Donald T. Frazier, Zhong Zhang, David M. Baekey,
and Roger Shannon. Cerebellar modulation of cough motor pattern in
cats. J. Appl. Physiol. 83(2):
391-397, 1997.
The cerebellum modulates respiratory muscle
activity in part via its influence on the central respiratory pattern
generator. Because coughing requires well-coordinated respiratory
muscle activity, studies were conducted to determine whether the
cerebellum influences the centrally generated cough motor pattern.
Integrated phrenic and lumbar efferent neurograms
(
PN and LN, respectively)
were monitored in decerebrated, paralyzed, and ventilated cats.
Mechanical probing of the intrathoracic trachea was used to evoke
fictive coughs; i.e., large increases in
PN and LN amplitudes.
Cerebellectomy resulted in a decrease in the number of coughs
per trial (cough frequency) and LN peak
amplitudes without any consistent change in
PN peak amplitudes. Cerebellar nuclei [the
rostral interposed nucleus (INr) and the rostral fastigial nucleus
(FNr)] known to be involved in respiratory control were ablated
to determine their potential role in the cough response. Control
(eupneic) respiratory frequency was not affected by cerebellectomy or
INr/FNr lesions. Cough frequency was depressed by lesion of the INr but
not by ablation of the FNr. No significant changes in
PN and LN amplitudes were
observed after lesion of either the INr or FNr. These results suggest
that the cerebellum, specifically the INr, is involved in modulation of
the frequency of centrally generated coughing.
fastigial nucleus; interposed nucleus; lumbar nerve motor activity; respiratory control; tracheal probing; thermal lesions
INTRODUCTION COUGH IS ELICITED by airway cough receptors (via vagal
afferents) and moves mucus and foreign irritants out of the respiratory tract. It is characterized generally by enhanced inspiratory, compressive and expulsive phases. Recent reports concluded that neurons
of the Bötzinger complex (BötC) and rostral ventral respiratory group (VRG) that generate the eupneic pattern
of breathing are also involved in producing the cough motor pattern
(13, 15). Modulation of the cough pattern by other regions of the brain
has not been studied.
Several reports have indicated that the cerebellum modulates
respiratory muscle activity during stressed breathing, in part, via its
influence on the central respiratory pattern generator. First,
cerebellar ablation or lesions were shown to alter vagally mediated respiratory responses (21, 25). Second, electrical stimulation
(5) and ablation/lesion (24, 27) of the cerebellum revealed that the expiratory muscle response to respiratory resistive loading was affected more than the inspiratory muscle response. Third,
discrete electrical stimulation within the rostral fastigial nucleus
(FNr) of the cerebellum produced increases in respiratory rate (20,
22), as well as premature termination of VRG inspiratory or expiratory
neuronal activity (22). These effects disappeared after microinjection
of kainic acid (destroying neuronal cell bodies while sparing fibers)
into FNr, indicating that VRG neuronal activity is modulated by
activation of the FNr neurons (22). In a subsequent study, it was found
that changes in phrenic efferent activity induced by FNr stimulation
were abolished after electrolytic lesions of bilateral BötC,
suggesting that cerebellar modulation of respiratory motor output
(phrenic) depends on the integrity of the BötC (28).
It appears that the cerebellum modulates neural activities essential
for cough. Therefore, experiments were conducted to determine whether
the cerebellum influences the centrally generated cough motor pattern.
Phrenic and cranial iliohypogastric (L1) efferent neurograms were
monitored as indexes of a fictive cough response in decerebrated,
paralyzed, and ventilated cats. Coughlike patterns were produced by
probing the intrathoracic trachea. The results showed that
cerebellectomy attenuated the coughing response. Because the FNr and
interposed nuclei are known to influence respiration (5,
7, 9, 12, 21-23, 26), the effects of their individual ablations on
fictive cough were also examined.
METHODS
1 · h1)
and were artificially ventilated through a tracheal cannula by either a
phrenic nerve (PN)-driven pressure respirator or conventional volume
ventilator. End-tidal PO2 and
PCO2 were maintained at >100 Torr
(by inhalation of either room air or an appropriate
O2 mixture) and 30-35 Torr,
respectively. Arterial blood samples were periodically
analyzed for PO2,
PCO2, pH, and
HCO3 as an indication of the adequacy of gas exchange and acid-base balance of the animal. Base deficits, if
present, were corrected by infusion of 0.5 M sodium bicarbonate. Lactated Ringer solution was administered intravenously as needed to
maintain a mean blood pressure of at least 100 mmHg. Nerve recording
electrode movement produced by mechanical ventilation and chest wall
movement was minimized by a bilateral pneumothorax. The functional
residual capacity of the lungs was maintained within a normal range by
adjustment of the end-expiratory pressure. The animals were placed
prone in a stereotaxic frame.
For decerebration, the cerebrum was exposed through a posterolateral
opening in the skull, and the dura was removed. Decerebration was
performed at the intercollicular level with a blunt spatula. After
aspiration of suprapontine tissue rostral to the intercollicular section was performed, the exposed surface was gently packed with an
absorbable hemostat (Surgicel and Gelfoam). The exposure of the
cerebellum was made via an occipital craniotomy, the dura was removed,
and the underlying tissue was covered with mineral oil.
Recording nerve activity.
The right cranial iliohypogastric (L1) nerves and PN (C5) were
desheathed and cut, and their efferent activity was recorded with
bipolar silver electrodes in pools of mineral oil. Nerve signals were
amplified and filtered (band pass 0.1-5 kHz). PN and lumbar nerve
(LN) discharges were integrated [integrated PN neurogram
(PN) and integrated LN neurogram LN, respectively] with a leaky R-C
circuit (0.1 s time constant) and monitored on a storage
oscilloscope and polygraph.
Evoking fictive cough.
A coughlike pattern of activity in the PN and LN neurograms was
elicited by rubbing sections of the intrathoracic trachea (midcervical
to the carinal region) with loops of polyethylene tubing attached to a
thin wire inserted through a port in the tracheal cannula. Two flexible
tubing loops were configured as ellipsoids (diameter = 1 cm). The
pattern of fictive cough was characterized usually by an increased
PN amplitude immediately followed by an enhanced
LN amplitude.
The first series of experiments (n = 5), in which the cerebellum was removed completely, was conducted in
Tampa, FL. The second series involving lesioning of specific cerebellum
nuclei [FNr, rostral interposed nucleus (INr)] was
performed in Lexington, KY. The methods for eliciting fictive cough
were slightly different in the two laboratories. In the first series,
the tracheal probe was motor controlled, which allowed control of the
rotation rate, duration of stimulus, and length of trachea that was
stimulated. The parameters were adjusted initially in each
animal to produce approximately five to six coughs per stimulus period
(rotation rate = 1-2 Hz, duration = 5-10 s, with variable
distances between the tracheal tube and carina). The parameters varied
slightly among animals, but those chosen for a given animal were used
throughout the experiment. The polyethylene tubing was retracted into
the tracheal cannula between stimulus trials to prevent continuous stimulation of the trachea. A recovery period of at least 2 min was
allowed for the LN and PN burst patterns to return to control levels.
Periods of fictive cough were repeated five times before and after
cerebellectomy or nuclei lesions.
In the second series of experiments (n = 10), the tracheal probe was inserted, then rotated (~1 Hz) and
withdrawn manually. A more intense and longer stimulus period was used
in these experiments to elicit more coughs per trial. The probe was
inserted to the carina and withdrawn six times over a period of
18-20 s. In each animal, the stimulus parameters were
qualitatively and quantitatively similar before and after cerebellar
ablations.
Cerebellectomy.
Cerebellectomy was performed by transection of the cerebellar peduncles
with a blunt spatula followed by aspiration of cerebellar tissue (see
details in Ref. 27). The exposed cut surface was gently packed with
absorbable hemostatic agent (Surgicel) and covered with mineral oil.
FNr and/or INr lesions.
Bilateral lesions of the FNr or INr were performed by using stereotaxic
coordinates (16) to position a radio-frequency electrode; a tip (1-mm
diameter, Radionics) temperature of 70°C was maintained for 2 min.
The sites of lesions were histologically examined after completion of
the experiment. After cerebellectomy or lesions, 1 h was allowed to
elapse before the effects on cough were tested.
Histological examination.
The animals were killed by administration of additional anesthetic, and
the brainstem and cerebellum were then removed and placed in 10%
Formalin. After at least 3 days of immersion fixation, the brainstem
and the cerebellum were frozen, and 50-µm-thick sections were cut and
mounted. The placement of the lesions was drawn with a camera lucida.
Data acquisition and analysis.
PN and LN efferent signals, arterial blood pressure, tracheal pressure,
and stimulus information were recorded on analog or videotape for
off-line analysis. During the experiments, appropriate signals were
monitored on an oscilloscope, polygraph, and audio monitor.
The eupneic respiratory frequency (PN bursts/time) was determined
before and after cerebellectomy and lesions as an indicator of changes
in respiratory drive. The magnitude of the cough response before and
after cerebellar ablations was determined by measuring the changes of
PN and LN peak amplitudes
and the number of coughs per stimulus period (cough frequency) compared
with control. Control values were averaged over a 15-s
period before the tracheal stimulus. The measured parameters in
response to the mechanical pertubations were collected from the five
stimulus periods and then averaged before and after cerebellectomy or
cerebellar nuclear lesioning. Group data are presented as means ± SE. A paired t-test was used to
examine the significance of the difference between the data obtained in
the intact and cerebellectomized preparation (series
1). A one-way analysis of variance with repeated
measurement and the Student-Newman-Keuls post hoc test were used to
identify significance of the difference between the control and
coughing responses obtained from the intact, FNr-, and INr-lesioned
preparations (series 2). The
P < 0.05 level of significance was
used to evaluate all statistical tests.
RESULTS
Mechanical stimulation of the intrathoracic trachea
(n = 15) elicited changes in PN and LN
motor discharge patterns that were qualitatively similar to those
reported previously in unanesthetized or anesthetized spontaneously
breathing animals and in anesthetized or decerebrate paralyzed animals
(3, 19). There were a variety of associated responses of PN and LN
activities during tracheal stimulation in intact animals. The most
common discharge patterns included a large increase in PN activity
coincident with or immediately followed by a large increase in LN
activity (Fig. 1). In some animals, there
was no significant change (n = 2) or a
slight decrease (n = 1) in peak PN
activity before the increase in LN activity. During some stimulus
periods, the number of enhanced phrenic responses was
greater than the number of enhanced LN responses. Because of the
variation in peak and number of enhanced phrenic responses, coughlike
patterns were considered to occur only when peak LN activity was
increased substantially above control activity (i.e., at least 500%
greater than control).
PN), integrated LN activity
(LN), and tracheal pressure (Ptr). Animals in
this series were ventilated by PN-driven respirator; thus lung
inflation is in phase with PN activity. Coughs during each stimulus
period (cough frequency) are indicated by the dots above
LN. No. of enhanced PN responses (PN frequency)
is noted by dots above PN.
A typical recording of two episodes of fictive coughing in the intact
cat is shown in Fig. 1A. Both
LN and PN amplitudes were
enhanced dramatically. Coughs during each stimulus period can be
clearly identified from the signals of the LN.
The number of enhanced PN and LN responses above control during
tracheal stimulation was determined to evaluate the potential selective
effect of the cerebellum on inspiratory and expiratory activity (5, 9, 11, 24, 27). After cerebellectomy (Fig.
1B), the tracheal stimulation-induced responses in both PN and LN were significantly attenuated. Figure 1C shows the timing
relationship between PN and LN activity during cough that is
characterized by enhanced inspiration (PN activity) followed by
strengthened expiratory effort (LN activity).
LN amplitude (Fig. 2A) but not
PN amplitude (Fig.
2B) was also markedly attenuated by
cerebellectomy.
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Because of more intense and longer duration of tracheal stimulation, changes in the control (intact) cough parameters were greater (average: 9.9 vs. 5.5) in this series of experiments than in the first cerebellectomy series (Table 1). In several of these experiments, the phase of PN activity was entrained with lung inflation (positive tracheal pressure produced by the conventional ventilator) during the control respiratory period. However, this relationship was disrupted during coughing, i.e., PN activity and lung inflation were out of phase. The effects of FNr and INr lesions on fictive coughing are shown in Figs. 4 and 5 and Table 1. Bilateral FNr lesions (n = 7) had no significant effect on any of the measured cough parameters. INr lesions were performed subsequent to FNr lesions in four animals. To test for possible interactions between the nuclei, INr lesions were done in three intact animals. After INr lesions (n = 7), there was a significant reduction in cough frequency (Fig. 4A) but not in the other parameters. However, there was a tendency for the PN frequency to be lower after INr lesions. Also, both the LN and PN amplitudes during cough were smaller after FNr lesions in five of the seven cats tested and after INr lesions in six of the seven cats tested.
The effects of cerebellectomy and lesions of FNr and/or INr on the eupneic respiratory rate are shown in Fig. 6. Respiratory rate was not significantly altered by the cerebellar ablations.
DISCUSSION
A cough usually starts with a deep inspiration due to increased contraction of the diaphragm and other inspiratory muscles acting in concert with muscles that enlarge the upper airways (abductors). The next compressive phase is brief and is distinguished by continued tone in the diaphragm and concurrent activation of the rib cage and abdominal expiratory muscles and the muscles that close the laryngeal folds (adductors). In the subsequent expulsive phase, the diaphragm ceases activity and the glottis is opened as the adducting muscles relax and the abductors contract. The continued strong expiratory muscle activity results in high airflow velocities (11, 14, 19). In this study, we monitored only PN and LN efferent activities as indicators of the presence of coughlike patterns. Thus, the effects of the cerebellum on the complex upper airway (laryngeal) motor discharge patterns remain unknown.
The major finding of this study was that fictive coughing, elicited by
probing the intrathoracic trachea, was attenuated significantly by
removal of the cerebellum. There was a reduction in the number of
occurrences of enhanced LN (cough frequency) and PN activities (PN
frequency). The percent change in the peak amplitudes of the LN but not PN in response
to tracheal stimulation (in the reduced number of coughs) was
significantly attenuated after cerebellectomy. Ablation of the INr but not the FNr produced similar results. These data strongly suggest that the cerebellum influences primarily the number of
coughs generated in response to a given stimulus.
It is generally accepted that the cough motor pattern is generated in the medulla (14, 19). The medullary BötC/VRG produces the eupneic pattern of breathing (2, 6), and recent evidence is consistent with the participation of this network in configuring the cough pattern (15). The simultaneous recording of many single neurons in this network showed that their activity was altered in an appropriate manner to be involved in generating the cough motor pattern (15). The effects of the cerebellum on coughing is likely due, in part, to the influence of the cerebellum on the BötC/VRG network.
Several studies have shown anatomic projections and functional connections from the cerebellum to the BötC/VRG. Autoradiographic studies demonstrated that the medullary dorsal and ventral respiratory groups were heavily labeled when tritiated amino acids were injected into the vicinity of the cerebellar FN (1). Using extracellular recording techniques, we found that electrical stimulation of the FN significantly altered the firing rates of inspiratory and expiratory modulated neurons in the region of the VRG and dorsal respiratory group concomitant with PN activity (22). In a subsequent study, this cerebellar effect on respiratory output (PN activity) disappeared after bilateral lesions in the BötC/VRG region (28).
There is evidence to support in varying degrees the involvement of
three cerebellar deep nuclei, i.e., FN (4, 5, 21-23, 25, 26), IN
(5, 7, 29), and infracerebellar nucleus (9), in respiratory regulation.
The results of this study imply that the INr plays a major role in
modulating the cough motor pattern. INr lesions dramatically diminished
cough frequency and tended to decrease the number of enhanced PN
responses (PN frequency) without evident changes in the
PN and LN amplitudes.
Respiratory modulated neurons, predominantly expiratory (76%), have
been recorded within the INr (7). Some of these neurons were
antidromically activated from the red nucleus, while others responded
to electrical stimulation of the inferior olive. It was proposed that
the INr was involved in locomotor readjustments of the respiratory
muscles. This assumption was supported by experiments in which
stimulation of cerebellar deep nuclei in opossums (5) or selective
activation of the IN in the cat (9) produced an alteration in
expiratory activity. Our finding that cerebellectomy or INr lesions
reduced expiratory motor drive during fictive cough is consistent with
these observations (5, 7, 9). No attempt was made in the present study
to identify whether the INr modulation of the cough motor pattern involved cell bodies or fibers of passage. It has been reported that
microinjection of glutamate or kainic acid into the IN in the cat
failed to alter eupneic respiration (10) although there were
respiratory-modulated neurons within the IN (7). The finding that FNr
lesions failed to significantly affect fictive cough was somewhat
surprising, because previous studies have shown the importance of this
region in the regulation of respiration (2, 21-23), specifically
during stressed breathing (5, 25, 26). Coughing is clearly a very
complex motor pattern, and other cerebellar nuclei may also be involved
in the modulation of the cough motor pattern. For example, the
infracerebellar nucleus has been shown to control medullary expiratory
neuron and spinal nerve expiratory activities and to influence the
respiratory frequency (9). To date, we have no information on the
involvement of any other nuclei in fictive cough.
The effects of the cerebellum on cough may include modulation of airway receptor afferent information. Rapidly adapting receptors and C fibers have been implicated as "cough" receptors, and pulmonary stretch receptors and slowly adapting receptors appear to play a significant, but permissive, role in the production of cough, probably by the central facilitation of expiration (14, 18). There is evidence for a functional link between vagal afferents and the cerebellum. Studies in anesthetized cats have shown that electrical stimulation of the cervical vagus afferents produced evoked potentials in the cerebellar cortex and its deep structures (8). Autoradiographic studies demonstrated that dorsal vagal nuclei were labeled after injection of horseradish peroxidase into the cerebellar anterior lobe and the IN and FN, indicating that some vagal fibers project directly to these cerebellar nuclei (29). Injection of capsaicin into the pulmonary circulation induced an apnea, the duration of which was prolonged after removal of the whole cerebellum, suggesting that the cerebellum modulates vagal afferent C fiber reflexes (25). There is also evidence that the cerebellum modulates the pulmonary stretch receptor effect on the expiratory muscle response to expiratory threshold loading or tracheal occlusion (24). However, this experiment suggested that the cerebellum has an inhibitory effect on expiratory muscle activity. The phasic activity of the transversus abdominis muscle elicited by a continuous expiratory threshold load or single expiratory tracheal occlusion was increased after cerebellectomy.
The data further support the conclusion that the decrement in cough responses after cerebellectomy or lesions is not the result of alterations in respiratory drive or adaptation of the reflex over time. There were no significant changes in control LN and PN activities (cycling frequency) after cerebellectomy and specific nuclear lesions, in agreement with previous reports in spontaneously breathing (21, 26) and paralyzed cats (17). The series of experiments in which lesions of the FNr had no effect on cough is evidence that the attenuated cough responses after cerebellectomy and INr lesions are not due to adaptation. These separate series of experiments extended over a similar time period.
As shown in this and previous experiments (3, 15, 19), coughlike motor patterns can be produced in paralyzed animals, indicating that feedback from mechanoreceptors in contracting respiratory muscles or postural muscle is not essential for cough. The cough pattern in intact, awake, spontaneously breathing animals may be further influenced by the cerebellum, because of its well-known function of processing and modulation of muscle mechanoreceptor reflexes. During coughing, there would be substantial alteration in mechanoreceptor activity in both respiratory and thoracic cage postural muscles.
ACKNOWLEDGEMENTS
The authors are grateful to members of the University of Kentucky Respiratory Group for helpful comments and critiques and to Donna Painter for data analysis. The technical support of Jan Gilliland and Zhongzeng Li and advice from Bruce Lindsey and Kendall Morris at the University of South Florida are also appreciated.
FOOTNOTES
Address for reprint requests: F. Xu, Dept. of Physiology, Univ. of Kentucky, Lexington, KY 40536.
Received 29 January 1997; accepted in final form 28 March 1997.
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