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POINT-COUNTERPOINT COMMENTS
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
e-mail: feldrid{at}msn.com
The following letters are in response to the Point:Counterpoint series "Supraspinal locomotor centers do/do not contribute significantly to the hyperpnea of dynamic exercise in humans" that appeared in the March issue (vol. 100: 1077–1083, 2006; http://jap.physiology.org/content/vol100/issue3).
To the Editor: This is regarding the recent Point:Counterpoint series on supraspinal mechanisms involved in exercise hyperpnea (5). I will not repeat the arguments of the "Point" article for the central command mechanism, but suggest that a perusal of several extensive reviews might be rewarding [Eldridge and Waldrop (3), Waldrop and Iwamoto ("Point" Ref. 24]
Houazi (5) bases his criticism of central command on what he calls "spectacular" findings in humans and sheep during oscillatory changes of work rates where a good correlation was found between gas exchange and ventilation. In this regard, the comments of Dempsey et al. (2) are pertinent: that such studies yield only correlative data, which clearly fail to separate cause and effect. Houazi nevertheless dismisses the central command mechanism as well as other probable neural and chemical [K+] signals (3), and ends up contending that ventilation is constrained to follow information related to gas exchange rate, albeit "through unclear mechanisms," to "neglect" other information and that CO2 homeostasis is the main "goal" of the ventilatory response to exercise. This kind of approach is both teleological and antidiluvian.
Other points follow. First, Houazi avoids discussion of cardiovascular responses. These are fast and probably related to central command. Does he believe that these are also due to the mysterious CO2 mechanism he postulates?
Second, he says no real attempt to test the CC mechanism in humans has been made. What about the study with static exercise [Goodwin et al. ("Point" Ref. 24)] that demonstrated the CC mechanism for respiratory and circulatory changes and the study by Asmussen et al. (1) in curarized humans?
Third, although he dismisses short-term potentiation (STP), which has, by the way, been demonstrated in humans (4), it could affect interpretation of his sheep studies. TP's onset is relatively fast, but it has a decay time constant of 40–50 s ("Counterpoint" Ref. 25) so this afterdischarge would still be present during the shorter periods of work oscillation in his studies and would affect ventilation.
REFERENCES
Université Victor Segalen Bordeaux 2
UMR CNRS 5543
Laboratoire Physiologie et Physiopathologie de la Signalisation Cellulaire
Bordeaux Cedex, France
e-mail: didier.morin{at}umr5543.u-bordeaux2.fr
To the Editor: That supraspinal locomotor centers (namely the subthalamic and mesencephalic locomotor regions) contribute directly to hyperpnea during dynamic exercise is now generally accepted (although supporting evidence in humans remains elusive). However, whether this constitutes a significant contribution, remains more questionable. Clearly, hyperpnea is necessary to increase gas exchange during fast locomotion, and therefore the critical parameter during sustained exercise may be locomotor-respiratory coupling (1). Coordination between locomotion and respiration, which occurs throughout the animal kingdom, is necessary to reduce mechanical conflict between breathing and locomotor movements, especially during a sustained effort. In the adult rabbit, electrical stimulation of the mesencephalic locomotor regions (MLR) rapidly enhances respiratory frequency and locomotor-respiratory coupling is observed. Crucially, however, these effects of MLR stimulation are no longer observed after lower cervical cord transection that removes the lumbar locomotor generators (3). Furthermore, we have shown in neonatal rat that respiratory entrainment-induced hyperpnea can be achieved by lumbar proprioceptive input stimulation in an isolated brain stem-spinal cord preparation in which the supraspinal locomotor centers are absent (2). Together these observations strongly suggest that spinal (rather than supraspinal) structures play the crucial role in locomotor-respiratory coupling and hyperpnea and that the latter occurs strictly as a consequence of the former. My opinion, therefore, is that although supraspinal locomotor centers may directly excite the respiratory centers by feedforward pathways (4), these serve more to "prepare" the respiratory networks to react adequately to changes in locomotor effort to facilitate the appropriate coordination between these two functions.
REFERENCES
Louis Stokes Cleveland Department of Veterans Affairs Medical Center
Brecksville, Ohio
e-mail: jaroslaw.romaniuk{at}med.va.gov
To the Editor: Studies of cardiorespiratory responses during exercise must identify the impulse for exercise, whether peripheral or central. If from the center, we study afferent modulation of central command; if from the periphery ("treadmill on"), we study how afferent signals trigger locomotory action and cardiorespiratory responses. Any "corticated" preparation may have a central motor/behavioral/emotional response to "treadmill on." Experiments performed with motor imagery show that no signal from the periphery is necessary for the complex cardiorespiratory responses to perceived exercise (3). Documenting that the stimulation of specific central areas responsible for inducing locomotion also might adjust breathing and circulation to anticipated muscular effort is therefore very interesting. Unanswered questions remain. How is central command organized (2)? How does it affect motor outputs (1), including subpopulations of pattern generators (see Ref. 5 and this author's other papers on locomotion)? How does training affect central regulation (3)? How are afferent signals processed, by creating an error signal with the descending command or by integrating exercise effects in "the plethysmometric" signal (4), directly affecting cardiorespiratory reflexes? What is the time factor of studied responses?
Regarding Haouzi's paper (4), Fig. 1, three segments with different time scales recalibrated to the same lengths, is misleading: in a 30-s interval of high frequency walking for a longer cycle, the maximal effort lasts longer than during the same interval for the shorter cycle. Ventilation is higher with longer effort (for T = 5 min). Also, ventilatory response is delayed by a comparable time in all presented runs.
REFERENCES
Biomedical Engineering Department
University of Southern California
Los Angeles, California
e-mail: syamash{at}usc.edu
To the Editor: The current controversy (4) regarding the contribution of supraspinal locomotor centers to human exercise appears to center on different dynamic components of exercise hyperpnea. According to the neurohumoral theory of Dejours (2), the fast (neural) component occurs within a few seconds and the slow (humoral) component requires minutes to develop. Dejours recognized that the "humoral" component could involve peripheral mechanoreceptive sensors (3). Haouzi (4) in using sinusoidally changing treadmill speed of up to 1 cpm frequency can only measure the slow component (1), whereas Waldrop and Iwamoto's (4) stimulation methods focus on the fast component. Sinusoidal forcing at 1 cpm is incapable of resolving the fast "neural" component, which is most likely connected with central command and supraspinal locomotor centers. However, the slow component still represents about one-half of the overall response (2).
Species differences cloud interpretation, inasmuch as both groups based their conclusions on different animal experiments (sheep and cats). Another methodological issue that can be mentioned is whether sinusoidal locomotor forcing at different frequencies can be considered the same in view of different input locomotor power levels (frequency x cycle kinetic energy change). The cycle kinetic energy change is the same if treadmill speed excursions are kept the same, but power varies with sinusoidal frequency. At least in the steady state, metabolic rate correlates better with locomotor power rather than just speed.
Both central command and peripheral mechanoreceptors seem to play equally important roles in human exercise hyperpnea.
REFERENCES
University of Missouri
Columbia, Missouri
e-mail: pottsjt{at}missouri.edu
To the Editor: The exact nature of the "signal" capable of coupling ventilation to locomotor activity remains elusive. Despite the ongoing controversy (6) regarding the importance and contribution of supraspinal locomotor centers to exercise hyperpnea, it is clear that there are multiple sources of neural input to central respiratory neurons during exercise. So perhaps we should instead shift attention to the central pathways and cellular mechanisms that mediate ventilatory responses during dynamic exercise. There is a growing body of evidence that phasic input to medullary respiratory centers is required to couple respiratory and locomotor rhythms. These rhythms are produced over a wide frequency range in mammalian species, including birds, by neurogenic feedback from limbs (1, 3). One source of phasic input during rhythmic exercise is slowly conducting group III and IV somatic afferents that rapidly respond to mechanical stimulation of skeletal muscle (4). Recent work by Haouzi and Chenuel (2) demonstrated that neural feedback from skeletal muscle provides a respiratory stimulus proportional to the rate of gas exchange in active muscle and independent of changes in PaCO2. This suggests that the respiratory "signal" is sensed by skeletal muscle and is then transmitted through a yet undefined pathway to central respiratory centers. Recently, we reported that stimulation of somatic afferents activated central respiratory neurons indirectly via a polysynaptic pathway from the spinal dorsal horn to the medullary ventral respiratory group via the lateral parabrachial nucleus (5). Whether supraspinal locomotor centers use a similar mechanism to couple respiration to locomotor activity remains to be determined.
REFERENCES
University of California, Los Angeles
Los Angeles, California
e-mail: ichiyama{at}ucla.edu
To the Editor: The role of supraspinal centers in the control of cardiorespiratory function in exercise has long been demonstrated (3). The supporters (4) have shown overwhelming evidence for the role that specific CNS areas (such as posterior hypothalamus and mesencephalic locomotor region) play in both motor and cardiorespiratory regulation. Haouzi (4) argues that the evidence accumulated in reduced animal models does not apply to humans, citing, for example, studies by Gerasimenko et al. (2). Those studies demonstrated that humans with spinal cord injuries can produce locomotor-like EMG activity when stimulated epidurally. They did not, however, monitor cardiorespiratory function. The fact that humans, like animals, can produce locomotion without supraspinal input is well documented (1). But this does not rule out the importance of supraspinal centers. Spinal cord-injured patients are prone to autonomic dysreflexia, which can be triggered by peripheral stimulation. In this condition, spinal reflexes are free of their normal descending inhibition and become hyperactive (5), which illustrates the importance of supraspinal regulation.
It is very important to realize that the evidence presented by both groups points to a built-in redundancy in the system, which regulates cardiorespiratory function in response to any stressor, be it peripheral or central in origin. In the end, both feedback and central command are involved in the regulation and fine tuning of cardiorespiratory function in exercise. I strongly agree with Dr. Haouzi's advice to keep searching for the "primary mechanisms regulating breathing in exercise." The definitive answer is still unclear.
REFERENCES
Department of Cell Biology and Anatomy
University of Calgary
Calgary, Alberta, Canada
e-mail: harold.bell{at}ucalgary.ca
To the Editor: A recent Point:Counterpoint debate (5) has demonstrated the importance of context when discussing mechanisms of putative importance in the control of breathing during exercise. Several mechanisms that could provide a drive to breathing during exercise have been described and characterized in animal models, and this research has undoubtedly been fundamental to our progress in this field. However, it is essential for us to take such research forward to confirm a physiological role for these putative control mechanisms in the whole system response. In this sense, Haouzi (the Counterpoint author) has appropriately identified a lack of firm evidence for a drive to breathe from what Waldrop and Iwamoto (the Point authors) refer to as "central command" in humans. Indeed, the Point authors (5) incongruously refer to human research where respiratory variables were neither the focus of, nor monitored in, the study (3) and where study results clearly lack support for involvement of a hypothalamic locomotor region in exercise hyperpnea (4). The Point article authors' reference to Thornton et al. (4) illustrates an issue no less important in this debate, concerning the interpretation of the phrase "supraspinal." Specifically, this Point:Counterpoint debate was intended to provide a forum for discourse on "supraspinal centers," so I am perplexed as to why focus was placed almost solely on the putative hypothalamic "locomotor" centers. Given the increasing body of evidence that behavior and arousal are important in this hyperpnea (1, 2, 4), perhaps other neuroanatomical regions outside the hypothalamus warranted greater discussion.
REFERENCES
Department of Medicine
University of Toronto
Toronto, Ontario, Canada
e-mail: eliot.phillipson{at}utoronto.ca
To the Editor: Julius Comroe once remarked that almost every respiratory physiologist feels compelled to explain the hyperpnea of muscular exercise—before moving on to other pursuits! This comment appears to be as relevant today as it was over 35 years ago (3).
My own (transient) foray into this field was facilitated by the generosity of my colleague Joel Cooper, who was using an awake sheep preparation to study the effects of a veno-venous, extracorporeal membrane lung on platelet function; part of the research program that led to the first successful human lung transplant (1). The Cooper lab and sheep preparation were put at my disposal for a series of studies in which we compared (in the same animal) the ventilatory response to moderate steady-state exercise (treadmill walking) and the response to venous infusions of CO2 at rest (through the membrane lung).
Somewhat to our surprise, we found that the relationship between ventilation and the rate of CO2 production (at the lungs of the sheep) could be described by a single linear function, regardless of whether CO2 production was increased by exercise, venous infusions of CO2, or combinations of both procedures (2). We therefore concluded that, in this intact preparation, the hyperpnea of moderate exercise could be attributed entirely to the associated increase in rate of CO2 production. Although these findings do not exclude the participation of neural mechanisms in exercise hyperpnea in other settings, they suggest that there is no need to invoke obligatory nonmetabolic stimuli to account for the ventilatory response to steady-state exercise.
REFERENCES
McMaster University
Hamilton, Ontario, Canada
e-mail: killiank{at}mcmaster.ca
To the Editor: Mathematical equations, introduced by the pioneers of respiratory physiology, were exploited in this debate (2). However, understanding requires a broader point of view.
Neurophysiologists, biochemists, and respiratory physiologists view limitation from different points of view. Any explanation should be satisfactory to all. That limitation is ultimately a neural event, with activation and termination arising within the brain, is a logical and defensible explanation.
A central motor command activates the motor units in the spinal cord, leading to depolarization, calcium release, and muscle shortening. The motor command, accompanied by a sense of exertional discomfort intensifies with power and time (effort = k·power2.0·time0.3). When the subject can no longer tolerate the exertional discomfort with the limb or respiratory muscles, exercise is terminated. Breathlessness is distinct from exertional effort arising with respiratory failure (hypercapnia and hypoxemia) when the capacity of the lungs to exchange gas is exceeded. Breathlessness is easily demonstrated by holding one's breath. The responsiveness of the muscle to the motor command depends on its physiological support. Hence, more effort is required to generate and sustain power with reduced perfusion, hypoxemia, acidemia, carbohydrate depletion, and/or any breakdown in the physicochemical equilibrium.
The Henderson's equation ([H+] = 24 PCO2/[HCO3–]) is a valid description of a physicochemical relationship. However, the late Peter Steward (1) elegantly demonstrated that understanding acid-base control requires consideration of the several other equally valid physicochemical relationships obeyed. These same limitations apply to the equations used in this debate.
REFERENCES
Department of Physiology
Dartmouth Medical School
Lebanon, New Hampshire
e-mail: eugene.nattie{at}dartmouth.edu
To the Editor: In moderate aerobic exercise, both metabolism and breathing increase in proportion. How this "match" takes place is a mystery. Waldrop and Iwamoto argue (4) that the similar increases in both locomotor activity and breathing produced by stimulation of hypothalamic regions shows "central command" to be the prime mover. However, these experiments cause hypocapnia (there is no match) and are arguably non-specific, e.g., the injection volumes were large (picrotoxin; 5–25 µl), possibly affecting simultaneous disinhibition of motor activity and breathing at different locations. To prove a link between neurons causing locomotion and breathing requires more discrete experimental paradigms. For example, smaller hypothalamic injections in conscious rats (bicuculline; 100 nl) produce specific autonomic responses but no motor activity (3). Perhaps central command originates higher in the brain with parallel activation of hypothalamic/midbrain sites.
Haouzi argues that with sinusoidal exercise in sheep (4) and humans (1) there is a tight match of ventilation and CO2 production (metabolism), with both being dissociated from work rate. Breathing tracks metabolism, not somatic motor activity. How this occurs is uncertain but there are peripheral sensing mechanisms for local metabolism that could participate, including a putative muscle blood flow detector (2). However, no direct evidence shows how peripheral mechanisms alone can fully account for the match.
It seems prudent to conclude that the match likely requires both a source of central stimulation or "drive" as well as continuous modulation by afferent information from a variety of sources.
REFERENCES
This article has been cited by other articles:
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  P. Haouzi The Last Word: Point:Counterpoint authors respond to commentaries on "Supraspinal locomotor centers do/do not contribute significantly to the hyperpnea of dynamic exercise in humans" J Appl Physiol, July 1, 2006; 101(1): 371 - 371. [Full Text] [PDF]
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