J Physiol (2003), 553.3, pp. 967–974 DOI: 10.1113/jphysiol.2003.

047597
© The Physiological Society 2003 www.jphysiol.org
Physiology in Press

A learned component of the ventilatory response to exercise

in man
Helen E. Wood, Marzieh Fatemian and Peter A. Robbins
University Laboratory of Physiology, University of Oxford, Parks Road, Oxford OX1 3PT, UK

The ventilatory response to mild-to-moderate exercise in humans is isocapnic, or ‘error-free’. It has

been suggested that this response is learned over many repetitions of exercise through the process of
minimising any deviations from normal in the blood gas tensions, as sensed by the chemoreceptors.
However, relatively limited training programmes have failed to produce any convincing evidence in
humans that forcibly altering the blood gas tensions during repeated periods of exercise alters the
subsequent steady-state ventilatory response to exercise. In this study, eight healthy young subjects
were exposed, over a 7 day training period, to a total of 70 repeated bouts of exercise paired with a
simultaneous airway CO2 load to stimulate the chemoreceptors (protocol EX + CO2). The
ventilatory response to exercise was measured before and after training to determine whether it had
been modified. Two further training protocols were undertaken as controls. One employed
repeated exercise without an airway CO2 load, and the other employed repeated airway CO2 loading
without exercise. On the 1st and 2nd days following training with protocol EX + CO2, end-tidal PCJ
was regulated at a lower level during steady-state exercise than following training with the control
protocols and than before training (mean ± S.E.M. reduction in end-tidal PCJ = 1.32 ± 0.36 Torr,
ANOVA, P < 0.05). In contrast to previous studies, this finding demonstrates that the steady-state
ventilatory response to exercise can be modified by a prior period of altered chemoreception during
exercise. This suggests that ventilation is matched to metabolic rate during exercise by a mechanism
that involves learning and memory.
(Resubmitted 19 May 2003; accepted after revision 24 September 2003; first published online 26 September 2003)
Corresponding author P. A. Robbins: University Laboratory of Physiology, University of Oxford, Parks Road, Oxford OX1 3PT,
UK. Email: peter.robbins@physiol.ox.ac.uk

As first demonstrated by Haldane & Priestley (1905), the mechanisms have been calibrated to ensure that ◊E rises in a
increase in metabolism that occurs as a result of muscular manner so precisely matched to ◊CJ.
exercise is matched exactly by an increase in pulmonary
In an attempt to overcome this problem, Somjen (1992)
ventilation (◊E). They proposed that during exercise, an
has hypothesised that feedforward control is a learned
increase in alveolar PCJ (PA,CJ), and hence arterial PCJ
response. He proposed that the brain ‘knows’ exactly how
(Pa,CJ), would stimulate the chemoreceptors, and that this
much O2 is demanded and CO2 produced, by the level of
would increase ◊E, thus providing the link between ◊E and
exercise being undertaken and has learned to anticipate
metabolic CO2 production (◊CJ). However, subsequent
Journal of Physiology

the corresponding increase in ◊E that is necessary to avoid

studies have demonstrated that the matching of ◊E to ◊CJ is
any changes in arterial blood gases. He hypothesised that
so precise that during mild-to-moderate exercise, Pa,CJ
the brain has learned how to do this over a period of many
does not change and hence there is no error signal to drive
years, from early in infancy, by a process of ‘trial and error’.
this feedback mechanism (Wasserman et al. 1967). How
◊E would initially be driven by chemoreceptor feedback
this exact matching of ◊E to ◊CJ occurs is not understood.
signals during increased levels of activity, but gradually the
A variety of mechanisms have been proposed to drive the individual would learn to anticipate these errors in blood
increase in ◊E during exercise, including ‘irradiation’ of gases and thus avoid them. Hence, control of ◊E becomes
signals from the motor cortex (feedforward control), possible without the need for any error signal.
stimulation of neural receptors in the exercising muscles,
Somjen indicated that control of ◊E in the absence of error
stimulation of chemoreceptors by a humoral factor released
signals is only possible while the internal and external
from the exercising muscles, and stimulation of chemo-
environments remain constant, because if these change,
receptors in the lungs by mixed venous PCJ (Zuntz &
error signals will result and a process of re-learning will be
Geppert, 1886). All of these mechanisms may, to a greater or
required. As such, it should be possible to test this theory
lesser extent, serve to increase ◊E during muscular exercise.
by repeatedly generating error signals experimentally (i.e.
However, none provides an explanation of how such
disturbances in arterial blood gases) during exercise to
 968 H. E. Wood, M. Fatemian and P. A. Robbins
Physiology in Press
induce a process of re-learning. Subsequent removal of
these error signals should reveal whether learning has
occurred, because ◊E and ◊CJ will no longer be exactly
matched, the brain having learned to anticipate the level of
◊E required under different conditions.
There is some evidence in support of this theory using just
such an experimental approach in goats (Martin &
Mitchell, 1993). After repeated trials of exercise paired
with an added external dead space to induce hypercapnia,
steady-state ◊E was increased during subsequent trials of
exercise without added dead space. However, similar
experiments in human subjects have failed to demonstrate
convincing evidence in favour of Somjen’s theory (Helbling
et al. 1997; Moosavi et al. 2002; Turner & Sumners, 2002).
With one exception, a potential problem with the design of
these previous studies is that the overall period within
which training has taken place has been relatively short.
The exception is the study by Helbling et al. (1997), where
an 8 day training programme was employed. However, in
their training programme there were only two rest-to-
exercise transitions on each training day. Should it be the
case that the change in chemoreceptor feedback occurring
from rest to exercise is important in the learning process,
then it is possible that the total number of transitions
employed by Helbling et al was too few for effective
modification of the steady-state ventilatory response to
exercise to occur. In general, it seems unlikely that a
control system that has been calibrated over years would
alter its properties markedly over a period lasting only a
few hours or perhaps with a training protocol involving
relatively few rest-to-exercise transitions. The present
study sought to address these issues by employing a
training protocol lasting for 7 consecutive days, with 10
rest-to-exercise transitions on each day.
Journal of Physiology
J Physiol 553.3
METHODS
Subjects
The subjects were eight young healthy males with no history of
respiratory or cardiovascular disease. All subjects were non-
smokers. All experiments conformed to the Declaration of
Helsinki, and received the approval of the local ethics committee
(COREC). The nature and requirements of the experiments were
explained to the subjects without revealing the purpose of the
study, and subjects gave their informed written consent prior to
each experiment.
Protocols
Prior to the main experiments, a set of preliminary measurements
was made. These included measurements of end-tidal PCJ
(PET,CJ) and PJ (PET,J) with the subject at rest, determination of
maximal work rate using an incremental exercise test, and
measurements of PET,CJ and PET,J at a work rate equivalent to
50 % of maximal (chosen to be below the anaerobic threshold but
above a level associated with slow walking/cycling on level
ground). This subject-specific work rate was used throughout the
remainder of the study.
For the main experiments, the subjects undertook three different
protocols in a random order. The randomisation was undertaken
by noting that there were six possible orders in which these
protocols could be undertaken; these were chosen at random to
provide the order for subjects 1–6, with subject 7 and 8 repeating
the order used for subjects 1 and 2. Each protocol comprised a
7 day training period, which was separated from the training
period of any other protocol by a minimum of 4 weeks (see Fig. 1).
Measurements of the ventilatory response to exercise were made
before and after these training periods to determine whether the
response had been modified by training. In protocol EX + CO2,
training involved repeated bouts of exercise paired with a
simultaneous airway CO2 load to stimulate the chemoreceptors;
in protocol EX, training involved repeated bouts of air-breathing
exercise; and in protocol CO2, training involved repeated bouts of
airway CO2 loading at rest. During each 7 day training period
subjects came to the laboratory twice a day, and on each occasion
undertook five bouts of training, each lasting 4 min. These bouts
were separated from one another by 4 min periods of air-
Figure 1. Summary of protocols and
measurements
Subjects undertook three different 7 day training
protocols with identical measurements of the
ventilatory response to exercise, under closed-
loop and open-loop conditions, made before and
after each training period.
 J Physiol 553.3 Learned ventilatory response to exercise
Physiology in Press
breathing rest. Outside the laboratory, subjects were requested to
refrain from taking exercise other than the minimum required to
travel around (slow walking and cycling on level ground). Subjects
were equipped with a pulse meter to warn them if they were
exerting themselves to too great a degree. Subjects tended to only
wear the monitor for the first couple of days of each protocol, until
they became accustomed to maintaining this minimal level of
exertion.
In order to determine whether the subjects’ perception of
breathlessness differed between the three training protocols they
were asked to rate their sensations of breathlessness during the
final minute of each bout of training, according to a modified
Borg scale (Borg, 1982). This scale associates numerical ‘scores’
with verbal expressions; in this case, descriptions of the strength of
sensations of breathlessness, which ranged from zero (‘none at
all’) to 10 (‘very, very heavy’). A card displaying the modified Borg
scale was held in front of the subject, who was asked to point at the
score associated with the expression that best described their
sensations of breathlessness at that moment.
The respiratory response to exercise before and after training was
assessed in two ways. In the first, subjects undertook an 8 min
period of exercise breathing air, which leaves the biological
feedback loop between CO2 and ventilation intact (closed-loop
measurements). In the second, subjects undertook an identical
period of exercise, but with their PET,CJ regulated at a fixed level,
which opens the biological feedback loop to allow measurement
of ◊E at a fixed level of PCJ (open-loop measurements). Measure-
ments were undertaken the day before training (day _1), on the
1st and 2nd days after training (days +1 and +2) and 2 weeks after
training (day +14).
Experimental technique
Subjects sat upright in a chair for the procedures exclusively at
rest, and on a cycle ergometer for those involving any exercise. For
the preliminary measurements of the end-tidal gases at rest, gas
was sampled from a catheter taped just below the subject’s nostril
and analysed by mass spectrometry (Airspec MGA300, UK). For
all other experiments, subjects breathed through a mouthpiece
with the nose occluded by a clip. Gas was sampled from a port in
the mouthpiece.
All exercise in this study was performed on the same cycle
ergometer (Mijnhardt KEM-3, Cardiokinetics, Salford, UK). This
ergometer was electromagnetically braked and provided a
constant work rate, independent of pedal frequency. A coloured
Journal of Physiology
light display mounted on the handlebars indicated pedal rate, and
subjects were instructed to maintain a rate of 60 revs min_1 (the
‘green range’) at all times. Subjects were assisted by verbal
instructions whenever they had problems maintaining this rate
(‘slow down’ or ‘speed up’, as required).
The procedure used for the incremental exercise test was as
follows: subjects pedalled at 0 W for 4 min, after which the load
was increased by 25–30 W (the chosen increment depended on
how fit the subject reported himself to be) every minute until
exhaustion. Subjects were instructed to maintain a pedal speed of
60 revs min_1. Exhaustion was taken as the point when either the
subject stopped voluntarily or was unable to maintain a pedal rate
of 60 revs min_1 following an increment, and was told to stop.
Verbal encouragement was given throughout the test to ensure the
subject reached exhaustion. Maximal O2 uptake capacity was
taken as the maximal single-breath value achieved during the test
and was calculated using the method of Pandit & Robbins (1992).
Maximal work rate was taken as the highest load that the subject
969
was able to maintain for a full minute. Heart rate was monitored
throughout the test to check that the expected maximal value was
reached, and plots of PET,CJ vs. work rate were inspected visually
to check that anaerobic threshold had been achieved several
minutes prior to the end of the test (i.e. plots became alinear).
During training, the inspired gas composition was controlled
manually using rotameters (Roxspur Measurement & Control,
Bramley, UK). For protocol EX + CO2, values for inspiratory PCJ
and PJ were chosen that would raise PET,CJ by 8 Torr above the
normal level during exercise and lower PET,J to 8 Torr below the
normal level during exercise. PET,J was lowered in addition to
raising PET,CJ in order that the stimulus would mimic the effects of
hypoventilation as closely as possible. With a background flow of
air, the flows of CO2 and N2 were adjusted until the desired end-
tidal gas values were achieved. For protocol EX, subjects breathed
air throughout the training periods. For protocol CO2, values for
inspiratory PCJ and PJ were chosen that would raise PET,CJ by
8 Torr above the normal level at rest and lower PET,J to 8 Torr
below the normal level at rest.
Measurements of the ventilatory response to exercise on days
before and after the training periods were made using a turbine
volume transducer (Cardiokinetics) to measure respiratory
volumes (Howson et al. 1986). All data were logged to a personal
computer. Two sets of measurements were made under closed-
loop conditions followed by two sets of measurements under
open-loop conditions. For each measurement, there was an initial
period of 5 min at rest, followed by 8 min of exercise, and then a
final 5 min of rest, throughout which the subject was seated on the
cycle ergometer. For the closed-loop measurements, subjects
breathed air throughout. For the open-loop measurements, the
end-tidal gases were regulated using an end-tidal forcing system
(Robbins et al. 1982). PET,CJ was held constant at 2 Torr above the
subject’s normal air-breathing value in exercise during the 8 min
of exercise and at 2 Torr above the subject’s normal air-breathing
value at rest during the 5 min periods of rest before and after
exercise. PET,J was held at the subject’s normal level during
exercise for the 8 min of exercise, and at the subject’s normal level
at rest for the 5 min periods of rest before and after exercise.
Data analysis
In order to assess visually the effects of the different protocols,
breath-by-breath data from the pre- and post-training measure-
ments were first averaged over 20 s intervals. This enabled the
responses to be averaged across subjects for both the closed- and
open-loop measurements. These average responses were then
plotted.
To provide a statistical analysis of the significance of any changes
observed, rest-to-exercise differences were calculated for PET,CJ
and ◊E for each exercise response. These were obtained by
subtracting the average ◊E or PET,CJ for the last 3 min of rest prior
to the onset of exercise from the average ◊E or PET,CJ for the final
3 min of exercise. For each subject, the pairs of values obtained on
the same day were averaged. Differences between these responses
for days _1, +1 and +2 for the different protocols were then
assessed for statistical significance using ANOVA. In the ANOVA,
subjects were treated as a random factor, and the fixed factors were
set in one of the two ways, depending on the hypothesis under test.
To determine whether the different protocols had different
effects, the data for days +1 and +2 were compared between
protocols and with the control (day _1) data. To determine
specifically whether the effects of protocol EX + CO2 for example,
differed from all else, the days +1 and +2 data for protocol
 970 H. E. Wood, M. Fatemian and P. A. Robbins
Physiology in Press
EX + CO2 were compared with pooled data from the day _1
measurements and the days +1 and +2 data from the other two
protocols.
Daily average ratings of breathlessness (Borg scores) were calculated
for each subject and these were averaged overall to give a mean
score for each protocol. Differences between these scores were
assessed statistically using ANOVA.
All statistical analysis was performed using the SPSS statistical
software package. Significance was accepted at P < 0.05 and unless
indicated otherwise, data are presented as the mean ± S.E.M.
Journal of Physiology
Figure 2
PET,CJ measured in normal closed-loop (air-breathing) conditions
during exercise (0–8 min) before training (day _1) and after
training (days +1, +2 and +14). Pre-training (day _1)
measurements (also shown in post-training panels for
comparison), open symbols; post-training measurements, filled
symbols. Values are breath-by-breath data averaged over 20 s
intervals, averaged across subjects.
J Physiol 553.3
RESULTS
Subjects
The individual physical characteristics of the subjects are
given in Table 1, along with values for maximal O2 uptake
(◊O2,max) and the work rate equivalent to 50 % of maximal.
There may have been some bias away from regular
sportsmen in the selection of subjects due to the
limitations that the protocol placed on sporting activities.
However, of the eight subjects selected, only one usually
took no regular exercise.
Closed-loop responses
The closed-loop responses to (air-breathing) exercise
before and after training with the three protocols are
shown in Figs 2 and 3. Average values for PET,CJ, ◊E,
respiratory frequency (fR) and tidal volume (VT) over the
final 3 min of both rest and exercise are given in Table 2.
Inspection of the figures suggests that there was no
training effect of the repeated inspiratory CO2 load at rest
(protocol CO2) in the sense that the regulation neither of
PET,CJ during exercise nor ◊E during exercise was affected
by the training. Following training with repeated exercise
(protocol EX), there was again no change in the level at
which PET,CJ was regulated during exercise compared with
before training. However, ◊E during exercise was lower
after the 70 training bouts of exercise than before,
suggesting a physical training effect. In contrast to the
other two training protocols, training with paired exercise
and inspiratory CO2 load (protocol EX + CO2) resulted in
the PET,CJ during air-breathing exercise being regulated at
a lower level than before training. ◊E during exercise
following protocol EX + CO2 training was maintained at
pre-training levels, instead of falling, as occurred in
response to the physical training effect of protocol EX.
These observations were confirmed by the statistical
analysis. Following training with protocol EX, ◊E increased
less with exercise on days +1 and +2 compared with the
other two protocols and with pre-training responses
(reduction in ◊E = 4.1 ± 1.3 l min_1, ANOVA, P < 0.05).
 J Physiol 553.3 Learned ventilatory response to exercise
Physiology in Press
Following training with protocol EX + CO2, the increase
in PET,CJ with exercise was less on days +1 and +2
compared with the two control protocols and with pre-
training responses (reduction in PET,CJ = 1.3 ± 0.4 Torr,
ANOVA, P < 0.05). By day +14 the responses of both
PET,CJ and ◊E to exercise had returned to normal.
Examining the pattern of breathing during the closed-loop
response (see Table 2), there was no significant difference
in changes in fR from rest to exercise between protocols.
However, after training with protocol EX, VT increased less
with exercise on days +1 and +2 compared with the other
two protocols and with pre-training responses (P < 0.05).
The response of VT had returned to normal by day +14.
Open-loop responses
The open-loop responses to exercise at a regulated PET,CJ
before and after training are shown in Fig. 4. Average
values for PET,CJ, ◊E, fR and VT over the final 3 min of both
rest and exercise are given in Table 2. Consistent with the
expectations from the closed-loop responses, ◊E during
exercise was higher after training with protocol EX + CO2
(increase in ◊E = 11.5 ± 3.8 l min_1), lower after training
with protocol EX (reduction in ◊E = 13.2 ± 4.5 l min_1)
and unchanged after training with protocol CO2. The
increases in ◊E from rest to exercise were significantly
different between day _1 and days +1 and +2 between
protocols (ANOVA, P < 0.05). By day +14 the responses
had returned to normal.
Journal of Physiology
Figure 3
◊E measured in normal closed-loop (air-breathing) conditions
during exercise (0–8 min) before training (day _1) and after
training (days +1, +2 and +14). Pre-training (day _1)
measurements (also shown in post-training panels for
comparison), open symbols; post-training measurements, filled
symbols. Values are breath-by-breath data averaged over 20 s
intervals, averaged across subjects.
971
No significant difference was detected between protocols
in the changes in VT from rest to exercise. ANOVA
conducted on the changes in fR from rest to exercise did not
quite reach significance (P = 0.07).
Sensations of breathlessness
The mean ± S.D. ratings of breathlessness for each of the
training protocols were 1.7 ± 1.1 for protocol EX + CO2,
1.6 ± 1.0 for protocol EX and 1.3 ± 1.1 for protocol CO2.
ANOVA revealed no significant difference between these
values.
DISCUSSION
The major finding of this study is that repeated
disturbances in chemoreception during exercise in
humans modify the normal ventilatory response to
exercise. In particular, repetitive occurrences of increased
chemoreceptor activity during exercise result in an
augmentation of subsequent ventilatory responses to
exercise, which in a naturally occurring situation would
act to strengthen the proportionality between ◊E and ◊CJ
and tighten control over Pa,CJ.
Critique of the study
In this study, PET,CJ has been used as a proxy measurement
for Pa,CJ, whereas ideally, direct measurements of Pa,CJ
would have been made. However, with a study design where
the same subjects undertook all three protocols, this would
Figure 4
◊E measured in open-loop conditions (at regulated PET,CJ) during
exercise (0–8 min) before training (day _1) and after training (days
+1, +2 and +14). Pre-training (day _1) measurements (also shown
in post-training panels for comparison), open symbols; post-
training measurements, filled symbols. Values are breath-by-
breath data averaged over 20 s intervals, averaged across subjects.
 972 H. E. Wood, M. Fatemian and P. A. Robbins
Physiology in Press
have required arterial catheterisation of our volunteers on at
least six occasions, which we felt was difficult to justify.
Although PET,CJ is a fairly good approximation of Pa,CJ,
there is nevertheless a difference between the two variables,
and this difference changes with the level of exercise
(Robbins et al. 1990). At rest, PET,CJ is lower than Pa,CJ, but
during exercise PET,CJ rises to a value above Pa,CJ. Thus, if
Pa,CJ remains constant with exercise, PET,CJ will rise.
Robbins et al. (1990) reported that the difference between
Journal of Physiology
PET,CJ and Pa,CJ changed on average by ~ 4 Torr from rest
to 100 W exercise, which would seem to be in keeping with
the average difference of ~ 6 Torr from rest to the average
work rate of 134 W in the present study.
A second complication of the present study was the finding
that repeated bouts of exercise without an airway CO2 load
(protocol EX) resulted in a reduction in the increment in ◊E
with exercise in the days immediately following training.
This was the result of a significant reduction in the
increment of VT from rest to exercise after protocol EX.
Although we did not expect this result, previous studies of
exercise training, somewhat dissimilar from our own, have
also reported a reduction in ◊E (Rasmussen et al. 1975;
Casaburi et al. 1987). Theoretically, this could result from
an increase in efficiency with which the exercise is
undertaken, an alteration of metabolic substrate employed
J Physiol 553.3
or a reduction in the respiratory dead space. The latter
would seem less likely given that there were no significant
changes in fR. Importantly, from our perspective the
change that occurred with training was a change in ◊E
without a change in PET,CJ. Such a change would be
entirely in keeping with the notion that the respiratory
response to exercise slowly adapts to ensure isocapnia
when internal factors change.
In contrast to protocol EX, protocol CO2 had no effects on
the ventilatory response to exercise. Thus, if the null
hypothesis of this study were to hold true (i.e. that there is no
learning associated with repeated episodes of chemoreceptor
stimulation paired with exercise), then the effects observed
with protocol EX + CO2 would need to be the same as those
for protocol EX. This is clearly not the case. First, following
training with exercise and CO2, the normal response to
exercise has become hypocapnic, which is not the case after
training with exercise alone. Secondly, at regulated PET,CJ
(open-loop responses), the ventilatory response to exercise
following training with exercise and CO2 is increased,
whereas it is decreased following training with exercise alone.
Comparison with other studies
Long-lasting changes in the control of ◊E during exercise,
which are indicative of mechanisms involving learning,
 J Physiol 553.3 Learned ventilatory response to exercise
Physiology in Press
have been demonstrated in goats following surgery to
denervate proprioceptors in the chest wall (Mitchell et al.
1988). After surgery, the normal ventilatory response to
exercise was abolished, with goats becoming severely
hypercapnic during exercise. Over repeated trials of
exercise, a normal response was re-established. This can
not be explained by functional recovery, and hence the
authors concluded that it was due to adaptive control
mechanisms that had modified components of the
respiratory control system (Mitchell et al. 1990). They
proposed that this mechanism was elicited by repeated
associations of chemoreceptor feedback with exercise, and
indeed, subsequently demonstrated that repeated exercise
paired with hypercapnia (induced by increasing the
respiratory dead space) augmented the subsequent
ventilatory response to exercise alone (Martin et al. 1990).
In humans, results from similar studies pairing exercise
with dead space have been far less convincing. It does
appear that pairing exercise with dead space may have
some effect on the time course of the rapid transient in ◊E at
the start of exercise (Helbling et al. 1997; Turner &
Sumners, 2002). Furthermore, there are two preliminary
reports (Adams et al. 1992; Turner et al. 1996) that
repeated pairings of dead space and exercise alter the
subsequent steady-state ventilatory response to exercise.
However, neither of these findings has been substantiated
within the context of a full publication, and furthermore
the preliminary findings of Adams et al. (1992) have been
attributed to habituation to the experience of performing
exercise in the laboratory in a later full publication by the
same group of authors (Moosavi et al. 2002).
Three full publications and one preliminary publication
have reported no effect of repeated pairings of dead space
and exercise on the subsequent steady-state response to
exercise (Helbling et al. 1997; Cathcart et al. 2000; Moosavi
et al. 2002; Turner & Sumners, 2002). In all but one of
these studies (Helbling et al. 1997), the period of
conditioning has been undertaken within a single day. In
the study by Helbling et al. (1997), the conditioning
Journal of Physiology
consisted of 16 sessions of arm-cranking exercise paired
with added dead space over an 8 day period. In this study
there was a 2 day gap in the middle of the training period,
whereas the present study employed a training protocol of
7 consecutive days.
Unlike the studies by Helbling et al. (1997) and Turner &
Sumners (2002), our primary focus was on the steady-state
response to exercise. As such, a detailed analysis of the
transient in ventilation before a steady state was achieved
has not been undertaken. For this reason, we are unable to
comment on how the transient might have been modified
after the training protocols.
We consider that the principal difference between the
present study and previous studies investigating a learned
973
component to the ventilatory response to exercise in
humans relates to the training protocol employed. In the
present study there were 70 rest-to-exercise transitions in
the training period, whereas for previous studies the
maximum number has been 16. In general, it is well-
recognised that the learning of a motor skill often requires
many repetitions over several training sessions, and in
addition a period of consolidation may be required in
order for performance gains to be fully expressed (Karni et
al. 1998). There is little reason to suppose that learning the
respiratory response to exercise should be any different in
this respect. Indeed, given the length of time over which
learning has occurred, it may well be the case that longer
protocols than that employed in the present study would
have greater effects on the ventilatory response to exercise.
Clearly, much more experimental work is required before
the components that are important for learning to occur
are properly identified.
A further difference between our study and those
conducted previously lies in the nature of the respiratory
stimulus that was paired with exercise. Previous studies
(Helbling et al. 1997; Cathcart et al. 2000; Moosavi et al.
2002; Turner & Sumners, 2002) have all paired added dead
space with exercise. However, it has been observed that
dead space may have mechanical as well as chemical
influences on ◊E, such as changes in the endogenous
resistance that may affect the proprioceptors (Martin &
Mitchell, 1993). We have avoided any possible mechanical
influence on ◊E by inducing hypercapnia by adding CO2 to
the inspired air. The dead space used by Turner & Sumners
(2002) induced hypercapnia of 6–8 Torr, which is similar
to the level used in the present study. We can assume that
the degree of hypercapnia would have been similar in the
study by Helbling et al. (1997) as they used a very similar
dead space volume (1.5 l) to Turner & Sumners (2002).
Moosavi et al. (2002) have stated that their protocol may
have been adversely affected by using a small dead space
volume (0.6 l), which induced a lesser degree of
hypercapnia.
Congenital central hypoventilation syndrome
Congenital central hypoventilation syndrome (CCHS) is a
syndrome in which patients have ineffective chemoreceptor
regulation of breathing and severe hypoventilation during
sleep. If Somjen’s (1992) hypothesis is correct, such patients
might be expected to have a ventilatory response to exercise
that is poorly controlled in relation to metabolism because
they may not have the chemoreceptor feedback necessary
with which to learn the calibration of their exercise
response. Shea et al. (1993) investigated the respiratory
response to exercise in five children with CCHS together
with five controls. On average, they found that there was a
similar small increase in PET,CJ in both groups. They
concluded that chemoreceptors are not necessary for an
appropriate ventilatory response to aerobic exercise.
 974 H. E. Wood, M. Fatemian and P. A. Robbins
Physiology in Press
However, we do not consider that their data really support
this conclusion. In particular, from the individual data
plotted in their figures, we estimate that the variance of the
change in PET,CJ from rest to exercise is some five- to sixfold
greater in the children with CCHS than in their normal
controls. Finally, although it is clear that patients with
CCHS lack a reflex stimulation of ◊E by CO2, it is not
necessarily clear that the defect is in the afferent limb of the
reflex loop and that these patients also lack chemoreception
through which the ventilatory response to exercise could be
calibrated.
Concluding remarks
In conclusion, the results of the present study demonstrate
that humans, like goats, can learn the appropriate
calibration of the feedforward mechanisms that regulate
breathing in exercise, with the chemoreceptors providing
the sensory feedback that is necessary for such learning to
occur. Such a mechanism provides a solution to the long-
standing problem of how, during exercise, feedforward
stimuli can provide a respiratory response that is so tightly
coupled to metabolism.
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Acknowledgements
We thank Mr David O’Connor for his skilled technical assistance.
This study was supported by the Wellcome Trust. Helen E. Wood
held a Wellcome Prize Studentship.