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The Neural Control of Human Inspiratory Muscles
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The Neural Control of Human Inspiratory Muscles
Jane E. Butler1, Anna L. Hudson, Simon C. Gandevia Neuroscience Research Australia and University of New South Wales, Sydney, Australia 1 Corresponding author: Tel.: þ61-2-9399-1608; Fax: þ61-2-93991005, e-mail address: [email protected]
Abstract The neural control of inspiratory muscles can be assessed in human subjects by measurement of the behavior of populations of single motor unit from the various inspiratory muscles. The discharge frequencies and patterns of firing of the motor units directly reflect the output of the motoneurons that innervate them. With the use of these methods, our work has revealed several features of the way the output of different inspiratory motoneuron pools are controlled. The output of inspiratory motoneurons is nonuniform across pools during quiet breathing and this coordinates the contraction of all the different muscles. This output is geared to the mechanical advantage of the muscles that they innervate. For the intercostal muscles, there is recruitment of the motor units by a principle of neuromechanical matching in which neural drive is higher in the muscles with the greatest mechanical advantage for inspiration, presumably to minimize the metabolic cost of ventilation. We summarize some evidence that this principle is likely to be organized at the spinal cord, although the exact underlying mechanisms are not known. The specific differences in the output from motoneurones innervating parasternal intercostal and diaphragm muscles during trunk rotation suggest that the output of inspiratory motoneurones engaged in a nonrespiratory voluntary task involve integration of corticospinal and bulbospinal drives at the spinal cord. An evolutionary argument is presented to support the importance of a role for spinal integration in ventilatory control.
Keywords human inspiratory muscles, motoneurone, neural drive
1 INTRODUCTION Although we often think of breathing as mostly automatic, we also have voluntary control of the breathing muscles, for example when we take a big breath in, sniff, or make a voluntary but nonrespiratory movement, such as rotation of the trunk. Little is Progress in Brain Research, Volume 209, ISSN 0079-6123, http://dx.doi.org/10.1016/B978-0-444-63274-6.00015-1 © 2014 Elsevier B.V. All rights reserved.
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known about the voluntary control of the respiratory muscles. Inhibitory connections from the cerebral cortex to the medulla exist in cats (Bassal and Bianchi, 1981a,b, 1982) and are active in trained behavioral breath holds (Orem, 1989; Orem and Netick, 1986). However, there is no evidence for excitatory connections between the cortex and medulla in the literature. On the other hand, there is evidence in humans of direct corticospinal projections from the motor cortex to phrenic motoneurons (similar to those described for limb muscles) that “bypass” the medulla (Gandevia and Rothwell, 1987; Maskill et al., 1991; Sharshar et al., 2003, 2005). While several studies that show that the motor cortex is active and helps to generate voluntary breaths (Colebatch et al., 1991; Evans et al., 1999; Macefield and Gandevia, 1991; McKay et al., 2003; Nakayama et al., 2004; Petersen et al., 2011; Ramsay et al., 1993; Raux et al., 2007), it is not known whether the direct corticospinal pathway is used exclusively during voluntary contractions of the inspiratory muscles or whether there is an interaction with the inspiratory networks in the brainstem (Corfield et al., 1998; McKay et al., 2003). The output of the inspiratory motoneurons is dependent on descending and reflex inputs from multiple sources. These inputs must be integrated at some levels to produce a coordinated output from motoneurons innervating the various inspiratory pump muscles along with the upper airway dilator muscles. The two most likely sites of integration are at the medulla with a common output from bulbospinal inspiratory neurones or at the level of the spinal cord with a final common output from spinal motoneurons. In humans, the motor unit discharge patterns from a range of human inspiratory muscles can be measured from selective recordings of intramuscular electromyographic (EMG) activity. The firing of the single motor units directly reflects the activity of the motoneurons in the spinal cord. From these studies and the use of different tasks such as quiet breathing, voluntary breathing, and voluntary nonrespiratory tasks, we have been able to infer that there may be some integration of the voluntary and involuntary input at the level of the spinal cord. In this review, we discuss how the output of motoneurons in quiet breathing is determined, and then how voluntary and involuntary descending inputs to the inspiratory motoneurons interact.
2 HUMAN INSPIRATORY MOTONEURON OUTPUT IN QUIET BREATHING During quiet breathing, the output of the various respiratory motoneuron pools is timed and organized to produce coordinated contractions of a complex threedimensional system of pump muscles that act on the chest wall to draw air into the lungs together with the contraction of a perhaps even more complex group of valve or upper airway muscles that keep the airway open during breathing. The output from these various motoneuron pools to each of these muscles is not uniform in terms of timing, discharge frequency, and patterns of activity (Saboisky et al., 2007c) to achieve efficient ventilation. These differences in motoneuron output cannot all be
3 Neuromechanical Matching of Drive to the Inspiratory Muscles
attributed simply to differences in motoneuron properties or muscle fiber type (see De Troyer et al., 2005, for review). For this reason and others given below, we suggest that there is precise organization of the timing and amount of motoneuron output by premotoneuronal networks. This may act as a “spinal distribution network” for output to respiratory motor nuclei. The time and frequency plots (TAFPLOTs) for five different inspiratory muscles: diaphragm, scalene, dorsal external intercostal (3rd and 5th spaces), and parasternal intercostal (2nd space) muscles are shown in Fig. 1A. These plots summarize the behavior of the sample of motor units recorded for each muscle and give an overall impression of the behavior of each of the motoneuron pools during inspiration (Saboisky et al., 2007b). Across the five inspiratory pump muscles, they depict the nonuniformity of motoneuron behavior across pools. Each colored line represents the firing of a single motor unit during inspiration and they are ordered by time of onset of firing relative to inspiratory flow from bottom to top. The total timing of firing is represented by the length of the line and the peak firing frequency is represented by the color of the line. Motoneurons discharge exclusively phasically for the diaphragm but show variable levels of tonic firing in the other pump muscles. In addition, the recruitment times of motoneurons are earlier for the diaphragm and later for the dorsal external intercostal (5th space) motoneurons. This late onset of inspiratory drive is evident even for those motoneurons innervating the dorsal external intercostal muscle (5th space) that are already tonically active. This indicates a delay in the arrival of the central respiratory drive at these motoneurons that are close to threshold or already firing. Genioglossus is the major upper airway dilator muscle and is innervated by the hypoglossal motoneurons via the hypoglossal nerve and although it is largely active in inspiration, there are even greater differences in the behavior of its motor units compared to the pump muscles (Saboisky et al., 2006). Figure 1B is the same data as in Fig. 1A for the inspiratory pump muscles but now plotted on a compressed frequency scale alongside the data for genioglossus (bottom right panel). The genioglossus motor units are recruited earlier relative to inspiration and discharge at much higher rates. In addition to these differences in timing and rate, although the hypoglossal motoneuron pool overall is increasing its output in inspiration, there are patterns of activity that are not seen in motoneurons innervating the pump muscles. Some hypoglossal motoneurons are driven with purely tonic activity unmodulated by respiration at all and others that increase their discharge in expiration either phasically or from a tonic background discharge (Bailey et al., 2007a,b; Nicholas et al., 2010; Saboisky et al., 2006, 2007a, 2010; Tsuiki et al., 2000; Wilkinson et al., 2008, 2010).
3 NEUROMECHANICAL MATCHING OF DRIVE TO THE INSPIRATORY MUSCLES Across the different intercostal motoneuron pools that innervate both dorsal and parasternal intercostal muscles in humans, the output of the motoneurons depends directly on the mechanical effectiveness of the muscle fibers that they innervate. First
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FIGURE 1
3 Neuromechanical Matching of Drive to the Inspiratory Muscles
described in the dog (De Troyer et al., 2005), we call this “neuromechanical matching” of drive to the inspiratory muscles (Butler, 2007; Butler and Gandevia, 2008; Hudson et al., 2011b) and its effect is to produce the most efficient contraction of the inspiratory muscles to produce inspiratory airflow (for review, see De Troyer et al., 2005). In the dog, the pattern of activity is maintained even after muscle afferent feedback is removed by dorsal rhizotomy and section of the phrenic nerve (De Troyer and Legrand, 1995; De Troyer et al., 1996; Legrand et al., 1996), suggesting a preset component to the activation of the muscles (see also Hudson et al., 2007). This relationship between neural output from motoneurons and the mechanical effect of the muscle fibers that they innervate can account for a large part of the nonuniformity of output from the various motoneuron pools. The inspiratory mechanical advantage or inspiratory effectiveness of the intercostal muscles has been measured in dogs (De Troyer et al., 1996b, 1999; Wilson and De Troyer, 1992, 1993) and in humans (Wilson et al., 2001) and it varies around the chest wall depending on a number of factors and is related to the inspiratory pressure that can be generated by selective electrical stimulation of these muscles (De Troyer et al., 2005). In humans, the inspiratory mechanical advantage of the different portions of the intercostal muscles around the chest wall has been measured with the use of a CT images and measurement of the fractional passive length change of the various intercostal muscles during lung inflation. In humans, there are decreasing rostrocaudal gradients of mechanical advantage across spaces for the external and parasternal intercostals and also a decreasing dorsoventral gradient around a space for the external intercostals (Wilson et al., 2001). So, those portions of intercostal muscles with the greatest mechanical advantage for inspiration are located more Time and frequency plots (TAFPLOTs) of motor units recorded from human inspiratory muscles during quiet breathing. (A) TAFPLOTs from five obligatory inspiratory muscles (diaphragm, scalene, 3rd and 5th dorsal external intercostal, and 2nd parasternal intercostal muscles). Each horizontal line represents the discharge of a single motor unit recorded during quiet breathing. The number of lines indicates the number of motor units recorded. The length of each line indicates the timing of discharge relative to the inspiratory time (% inspiratory time). The lines are stacked from bottom to top according to the onset time of discharge of the motor unit. Thin horizontal lines indicate tonic discharge. The line color represents the peak firing frequency for each unit plotted between 5 and 17 Hz. Black dots indicate the time of peak firing frequency relative to inspiration. Onset and end discharge frequencies are indicated by the color of the dots at the beginning and end of the lines, respectively. (B) The same data as in (A) are plotted for the motor units from five obligatory inspiratory muscles on a different frequency scale (10–30 Hz) along with motor units recorded during quiet breathing from genioglossus (a major upper airway dilator muscle, bottom right panel). The data depicted in (A and B) highlight differences in motor unit patterns of activity, timing of recruitment, and motor unit discharge rates across human inspiratory muscles. Adapted from Saboisky et al. (2006, 2007).
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rostrally and dorsally. In dogs, the gradients of mechanical advantage parallel gradients of neural drive to the different portions of muscle (for review, see De Troyer et al., 1996b, 2005; Legrand et al., 1996) and we have now shown this is also the case in humans (De Troyer et al., 2003; Gandevia et al., 2006; Hudson et al., 2011c). The measurement of intramuscular EMG and single motor unit action potentials from human intercostal muscles allows us to quantify the phasic neural drive to various portions of the muscles around the chest. We have measured neural drive in the 3rd, 5th, and 7th spaces of the external intercostal muscles and all five parasternal intercostal muscle spaces in humans to examine the relationship between neural drive and mechanical advantage (De Troyer et al., 2003; Gandevia et al., 2006). The primary measurements made are recruitment time relative to inspiratory time and peak discharge frequency of single motor units during inspiration. Together, these measures provide an index of neural drive based on the mean number of motor unit spikes in a muscle portion during inspiration. For both parasternal intercostal muscles and the dorsal portions of the external intercostal muscles during normal quiet breathing, motor units in the higher more rostral spaces discharge earlier in the breath and reach higher firing frequencies than those in the lower spaces such that there is a decreasing rostrocaudal gradient of neural drive (De Troyer et al., 2003; Gandevia et al., 2006). For the external intercostal muscles, there was also progressive recruitment of the ventral portions of the muscles (measured in the 3rd space; De Troyer et al., 2003). Thus, here there is also a dorsoventral gradient of neural drive. These gradients in neural drive are similar to the gradients of mechanical advantage around the chest wall in humans (De Troyer et al., 1998; Wilson et al., 2001). When the known measures of mechanical advantage of each intercostal muscle in humans for each space are plotted against the mean number of motor unit spike during inspiration, which takes into account firing rate and time of firing, there is a strong linear relationship between mechanical advantage and neural drive for both the parasternal intercostal muscles (Fig. 2A) and external intercostal muscles (Fig. 2B) that holds for both across the dorsal portions and within a single intercostal space through to ventral portions where the mechanical advantage and corresponding neural drive is significantly lower than the dorsal portions. The difference in neural drive around the 3rd external intercostal muscle from dorsal to ventral is illustrative of a need for premotoneuronal control of the motoneuron output. Here, the muscle fibers across this space are all innervated by motoneurons in the T3 motor nucleus. The muscle fibers in the dorsal portion have a high mechanical advantage for inspiration, whereas the muscle fibers in the ventral portion have a low mechanical advantage. Rather than the whole motoneuron pool being recruited simply in order of cell size, the descending drive is distributed preferentially to motoneurons that innervate dorsal regions with high mechanical advantage for inspiration and then as inspiratory drive increases further, the ventral portions are recruited. This is unlikely to be due to motoneuron threshold or cell size (Zhan et al., 2000). We have proposed that the recruitment of the muscles is governed by a principle of neuromechanical matching, which is superimposed on normal motoneuron recruitment by Henneman’s size principle. Drive is directed to motoneurons
3 Neuromechanical Matching of Drive to the Inspiratory Muscles
FIGURE 2 Relationship between mechanical advantage and inspiratory drive in human intercostal muscles during quiet breathing. The linear relationships for parasternal intercostal muscles and external intercostal muscles, between the inspiratory mechanical advantage (calculated in human subjects from the passive length changes in intercostal muscle fibers during lung inflation) and the inspiratory neural drive (measured in a separate study and indicated by the mean number of motor unit spikes per breath). Higher negative values for inspiratory mechanical advantage indicate larger relative shortening of muscle length during passive inflation and correspond to higher airway opening pressures. For parasternal intercostal muscles, mechanical advantage was measured only for muscles in the 2nd to 5th interspaces and is estimated for the 1st interspace from the motor unit data. For external intercostal muscles, measures were made of inspiratory mechanical advantage and neural drive in the dorsal portions of the 3rd, 5th, and 7th interspaces and the ventral portion of the 3rd interspace. Adapted from Gandevia et al. (2006), De Troyer et al. (2003), and Butler and Gandevia (2008).
depending on the mechanical effectiveness of the muscle they innervate for the task, and this applies to motoneurons that innervate muscle fibers not only around an intercostal space but also across spaces (Butler, 2007; Butler and Gandevia, 2008; Hudson et al., 2011c). Furthermore, during voluntary breaths matched to quiet breaths, the gradient of neural drive across the interspaces are maintained and the active motor units are largely the same ones in each task (Hudson et al., 2011c). Thus, we suggest that the level of organization for their neuromechanically matched outputs may be somewhere at the spinal cord: a common component in the involuntary and voluntary pathways to the motoneurons. Further evidence for spinal organization of the output across inspiratory muscles comes from recent experiments in the dog (DiMarco and Kowalski, 2011, 2012).
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In these experiments, the same patterns of muscle activation seen in spontaneous breathing, that are matched to the gradients of mechanical advantage, are maintained in breathing evoked by high-frequency stimulation of the ventral surface of the spinal cord at T2 in dogs with a C2 spinal section. Not only is the pattern of EMG similar but also the firing rates of motor units are the same in spontaneous and stimulated breathing when the rib cage excursion is matched (DiMarco and Kowalski, 2011). Additionally, in support of a spinal network of respiratory muscle activation, the same type of stimulation at T2 can activate phrenic motor output through spinal connections (DiMarco and Kowalski, 2012). As inspiratory intercostal motoneurons are recruited by a principle of neuromechanical matching where neural output is related to the mechanical advantage of the portion of muscle in (i) quiet breathing, (ii) voluntary breathing, and (iii) stimulated breathing, the evidence is accumulating to suggest that organization of the output may be at the level of the spinal cord. It may be organized through a premotoneuronal network of interneurones or possibly through varying intrinsic properties of motoneurons. However, the exact mechanism is unknown.
4 INTERACTION OF VOLUNTARY AND INVOLUNTARY DRIVES TO HUMAN INSPIRATORY MOTONEURONS It is possible to make nonrespiratory voluntary contractions of the inspiratory muscles, for example, during trunk or neck flexion or rotation (Gandevia et al., 1990; Rimmer et al., 1995; Whitelaw et al., 1992). These voluntary movements are likely controlled by corticospinal projections. In a series of experiments, we have used the task of voluntary trunk rotation combined with quiet breathing to examine how the voluntary and involuntary pathways to the motoneurons might interact (Hudson et al., 2010, 2011a). During voluntary isometric rotation efforts of the trunk against in each direction, we measured the EMG activity of parasternal intercostal muscles (2nd space) and the diaphragm. The trunk rotation was divided into the initial part of the rotation, performed at rest at functional residual capacity, and the maintained rotation where the subjects breathed normally while maintaining the isometric rotational effort. The behavior of the two muscles during initial and maintained trunk rotation was quite different (Hudson et al., 2010, 2011a). For the parasternal intercostal muscles, there are differential bilateral effects of voluntary trunk rotation. During the initial part of ipsilateral (isometric) trunk rotation, about half (45%) of the parasternal intercostal motor units recorded during quiet breathing in the neutral position were active. Then, in the maintained ipsilateral rotation, parasternal intercostal phasic inspiratory activity increased twofold and there was earlier recruitment of the muscles relative to the onset of inspiratory flow. During contralateral trunk rotation efforts, no activity occurred in the initial part of rotation. During maintained contralateral trunk rotation parasternal intercostal phasic inspiratory activity was reduced by 30% and recruitment time was delayed
5 Evolutionary Considerations
relative to the onset of inspiratory flow (Hudson et al., 2010). The increases and decreases in parasternal intercostal activity during maintained trunk rotation efforts were due to both increasing and decreasing firing rates as well as the recruitment and derecruitment of motor units (Hudson et al., 2010). For the diaphragm, during the initial part of ipsilateral trunk rotation, inconsistent small amounts of activity occurred in only a small proportion (10%) of all the diaphragm motor units recorded in quiet breathing in the neutral position, some of which were also active in contralateral rotation efforts. However, voluntary trunk rotation in either direction had no effect on the diaphragm phasic inspiratory activity, the timing of the activity during breathing, or the firing rates of the diaphragm motor units (Hudson et al., 2011a). The differences in behavior of the inspiratory neural drive to the two inspiratory muscles during this voluntary task (Fig. 3) highlight two points. Firstly, that the roles of the two inspiratory muscles in trunk rotation are different presumably because the mechanical effect of parasternal intercostal muscle fibers for trunk rotation is greater than for the costal diaphragm muscle fibers. Secondly, that the interactions of voluntary and involuntary drives differ across the motoneuron pools and importantly for parasternal intercostal muscles across sides. The way that the voluntary drive interacts with the involuntary inspiratory drive for these two muscles suggests that the cortical and pontomedullary drives are integrated at the spinal level rather than at the medulla for a number of reasons: (i) we know that many of the bulbospinal projections to inspiratory muscles are bilateral (e.g., Feldman et al., 1985; Lipski et al., 1994; Merrill and Lipski, 1987; RikardBell et al., 1984; Tian and Duffin, 1996) and yet, for parasternal intercostal muscles during voluntary trunk rotation, inspiratory output changes in a direction specific manner; (ii) because the effects of voluntary rotation are specific to one set of inspiratory muscles (parasternal intercostals) and not a global effect across inspiratory muscles as may be expected (De Troyer, 1991; Feldman et al., 1985; Hilaire and Monteau, 1976; Lipski et al., 1994); and (iii) because as mentioned at the beginning of this review there is little, if any, anatomical or physiological evidence to show any excitatory connections between the cortex and the medulla. Therefore, one explanation for our findings in this task is that the integration of involuntary and voluntary pathways to inspiratory muscles is at the spinal cord.
5 EVOLUTIONARY CONSIDERATIONS In mammals, axial muscles are innervated by multiple descending pathways and these have been imposed at different points in vertebrate evolution to achieve critical respiratory and other functions. Prior to lung respiration, axial muscles were used for swimming and postural movements (Fetcho, 1992), while ventilation was achieved by gill respiration (Hickman et al., 1982) or a buccal pump (Brainerd et al., 1993). Therefore, innervation of axial muscles by reticulospinal pathways was present before descending bulbospinal respiratory pathways from
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FIGURE 3 Motor unit discharge rates during quiet breathing with and without isometric trunk rotation. Motor unit discharge rates during quiet breathing without trunk rotation (y axes, neutral breaths) and quiet breathing during isometric trunk rotation (x axes, with ipsilateral rotation indicated to the right and contralateral rotation indicated to the left) for (A), parasternal intercostal muscles and (B), diaphragm. The peak discharge of motor units active in both conditions are represented by the open circles (mean shown by filled circles) and the peak discharge of motor units active in only one condition (either recruited or derecruited) are shown by open squares (mean shown by filled squares).
the medulla. With the development of lungs, the axial muscles were used first for expiration, as in amphibians (Brainerd et al., 1993), and then were also used for inspiration in birds, reptiles, and mammals (e.g., Carrier, 1989). Given that ventilatory efficiency is likely to have always been crucial for survival, we propose that higher vertebrates retained the spinal networks through which coordinated
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breathing was first achieved. Furthermore, later descending systems which needed “access” to drive the inspiratory muscles (such as for voluntary movement in primates), have done so through the same spinal networks. Such an arrangement is not only parsimonious in terms of neural circuitry but would probably enhance the adaptive capacity of the truncal musculature.
Acknowledgments We wish to acknowledge the important contributions to this work of our colleagues Prof. Andre De Troyer, Assoc. Prof. David McKenzie, Dr. Robert Gorman, and Dr. Julian Saboisky.
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Legrand, A., Brancatisano, A., Decramer, M., De Troyer, A., 1996. Rostrocaudal gradient of electrical activation in the parasternal intercostal muscles of the dog. J. Physiol. 495, 247–254. Lipski, J., Zhang, X., Kruszewska, B., Kanjhan, R., 1994. Morphological study of long axonal projections of ventral medullary inspiratory neurons in the rat. Brain Res. 640, 171–184. Macefield, G., Gandevia, S.C., 1991. The cortical drive to human respiratory muscles in the awake state assessed by premotor cerebral potentials. J. Physiol. 439, 545–558. Maskill, D., Murphy, K., Mier, A., Owen, M., Guz, A., 1991. Motor cortical representation of the diaphragm in man. J. Physiol. 443, 105–121. Merrill, E.G., Lipski, J., 1987. Inputs to intercostal motoneurons from ventrolateral medullary respiratory neurons in the cat. J. Neurophysiol. 57, 1837–1853. McKay, L.C., Evans, K.C., Frackowiak, R.S., Corfield, D.R., 2003. Neural correlates of voluntary breathing in humans. J. Appl. Physiol. 95, 1170–1178. Nakayama, T., Fujii, Y., Suzuki, K., Kanazawa, I., Nakada, T., 2004. The primary motor area for voluntary diaphragmatic motion identified by high field fMRI. J. Neurol. 251, 730–735. Nicholas, C.L., Bei, B., Worsnop, C., Malhotra, A., Jordan, A.S., Saboisky, J.P., Chan, J.K., Duckworth, E., White, D.P., Trinder, J., 2010. Motor unit recruitment in human genioglossus muscle in response to hypercapnia. Sleep 33, 1529–1538. Orem, J., 1989. Behavioral inspiratory inhibition: inactivated and activated respiratory cells. J. Neurophysiol. 62, 1069–1078. Orem, J., Netick, A., 1986. Behavioral control of breathing in the cat. Brain Res. 366, 238–253. Petersen, N.C., Taylor, J.L., Murray, N.P., Gandevia, S.C., Butler, J.E., 2011. Differential effects of low-intensity motor cortical stimulation on the inspiratory activity in scalene muscles during voluntary and involuntary breathing. Respir. Physiol. Neurobiol. 175, 265–271. Ramsay, S.C., Adams, L., Murphy, K., Corfield, D.R., Grootoonk, S., Bailey, D.L., Frackowiak, R.S., Guz, A., 1993. Regional cerebral blood flow during volitional expiration in man: a comparison with volitional inspiration. J. Physiol. 461, 85–101. Raux, M., Straus, C., Redolfi, S., Morelot-Panzini, C., Couturier, A., Hug, F., Similowski, T., 2007. Electroencephalographic evidence for pre-motor cortex activation during inspiratory loading in humans. J. Physiol. 578, 569–578. Rikard-Bell, G.C., Bystrzycka, E.K., Nail, B.S., 1984. Brainstem projections to the phrenic nucleus: a HRP study in the cat. Brain Res. Bull. 12, 469–477. Rimmer, K.P., Ford, G.T., Whitelaw, W.A., 1995. Interaction between postural and respiratory control of human intercostal muscles. J. Appl. Physiol. 79, 1556–1561. Saboisky, J.P., Butler, J.E., Fogel, R.B., Taylor, J.L., Trinder, J.A., White, D.P., Gandevia, S.C., 2006. Tonic and phasic respiratory drives to human genioglossus motoneurons during breathing. J. Neurophysiol. 95, 2213–2221. Saboisky, J.P., Butler, J.E., McKenzie, D.K., Gorman, R.B., Trinder, J.A., White, D.P., Gandevia, S.C., 2007a. Neural drive to human genioglossus in obstructive sleep apnoea. J. Physiol. 585, 135–146. Saboisky, J.P., Butler, J.E., Walsh, L.D., Gandevia, S.C., 2007b. New display of the timing and firing frequency of single motor units. J. Neurosci. Methods 162, 287–292. Saboisky, J.P., Gorman, R.B., De Troyer, A., Gandevia, S.C., Butler, J.E., 2007c. Differential activation among five human inspiratory motoneuron pools during tidal breathing. J. Appl. Physiol. 102, 772–780. Saboisky, J.P., Jordan, A.S., Eckert, D.J., White, D.P., Trinder, J.A., Nicholas, C.L., Gautam, S., Malhotra, A., 2010. Recruitment and rate-coding strategies of the human genioglossus muscle. J. Appl. Physiol. 109, 1939–1949.
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Sharshar, T., Ross, E., Hopkinson, N.S., Dayer, M., Nickol, A., Lofaso, F., Moxham, J., Similowski, T., Polkey, M.I., 2003. Effect of voluntary facilitation on the diaphragmatic response to transcranial magnetic stimulation. J. Appl. Physiol. 95, 26–34. Sharshar, T., Hopkinson, N.S., Ross, E.T., Jonville, S., Dayer, M.J., Nickol, A.H., Lofaso, F., Moxham, J., Polkey, M.I., 2005. Motor control of the costal and crural diaphragm–insights from transcranial magnetic stimulation in man. Respir. Physiol. Neurobiol. 146, 5–19. Tian, G.F., Duffin, J., 1996. Spinal connections of ventral-group bulbospinal inspiratory neurons studied with cross-correlation in the decerebrate rat. Exp. Brain Res. 111, 178–186. Tsuiki, S., Ono, T., Ishiwata, Y., Kuroda, T., 2000. Functional divergence of human genioglossus motor units with respiratory-related activity. Eur. Respir. J. 15, 906–910. Whitelaw, W.A., Ford, G.T., Rimmer, K.P., De Troyer, A., 1992. Intercostal muscles are used during rotation of the thorax in humans. J. Appl. Physiol. 72, 1940–1944. Wilkinson, V., Malhotra, A., Nicholas, C.L., Worsnop, C., Jordan, A.S., Butler, J.E., Saboisky, J.P., Gandevia, S.C., White, D.P., Trinder, J., 2008. Discharge patterns of human genioglossus motor units during sleep onset. Sleep 31, 525–533. Wilkinson, V., Malhotra, A., Nicholas, C.L., Worsnop, C., Jordan, A.S., Butler, J.E., Saboisky, J.P., Gandevia, S.C., White, D.P., Trinder, J., 2010. Discharge patterns of human genioglossus motor units during arousal from sleep. Sleep 33, 379–387. Wilson, T.A., De Troyer, A., 1992. Effect of respiratory muscle tension on lung volume. J. Appl. Physiol. 73, 2283–2288. Wilson, T.A., De Troyer, A., 1993. Respiratory effect of the intercostal muscles in the dog. J. Appl. Physiol. 75, 2636–2645. Wilson, T.A., Legrand, A., Gevenois, P.A., De Troyer, A., 2001. Respiratory effects of the external and internal intercostal muscles in humans. J. Physiol. 530, 319–330. Zhan, W.Z., Mantilla, C.B., Zhan, P., Bitton, A., Prakash, Y.S., de Troyer, A., Sieck, G.C., 2000. Regional differences in serotonergic input to canine parasternal intercostal motoneurons. J. Appl. Physiol. 88, 1581–1589.
15
The Neural Control of Human Inspiratory Muscles
Jane E. Butler1, Anna L. Hudson, Simon C. Gandevia Neuroscience Research Australia and University of New South Wales, Sydney, Australia 1 Corresponding author: Tel.: þ61-2-9399-1608; Fax: þ61-2-93991005, e-mail address: [email protected]
Abstract The neural control of inspiratory muscles can be assessed in human subjects by measurement of the behavior of populations of single motor unit from the various inspiratory muscles. The discharge frequencies and patterns of firing of the motor units directly reflect the output of the motoneurons that innervate them. With the use of these methods, our work has revealed several features of the way the output of different inspiratory motoneuron pools are controlled. The output of inspiratory motoneurons is nonuniform across pools during quiet breathing and this coordinates the contraction of all the different muscles. This output is geared to the mechanical advantage of the muscles that they innervate. For the intercostal muscles, there is recruitment of the motor units by a principle of neuromechanical matching in which neural drive is higher in the muscles with the greatest mechanical advantage for inspiration, presumably to minimize the metabolic cost of ventilation. We summarize some evidence that this principle is likely to be organized at the spinal cord, although the exact underlying mechanisms are not known. The specific differences in the output from motoneurones innervating parasternal intercostal and diaphragm muscles during trunk rotation suggest that the output of inspiratory motoneurones engaged in a nonrespiratory voluntary task involve integration of corticospinal and bulbospinal drives at the spinal cord. An evolutionary argument is presented to support the importance of a role for spinal integration in ventilatory control.
Keywords human inspiratory muscles, motoneurone, neural drive
1 INTRODUCTION Although we often think of breathing as mostly automatic, we also have voluntary control of the breathing muscles, for example when we take a big breath in, sniff, or make a voluntary but nonrespiratory movement, such as rotation of the trunk. Little is Progress in Brain Research, Volume 209, ISSN 0079-6123, http://dx.doi.org/10.1016/B978-0-444-63274-6.00015-1 © 2014 Elsevier B.V. All rights reserved.
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known about the voluntary control of the respiratory muscles. Inhibitory connections from the cerebral cortex to the medulla exist in cats (Bassal and Bianchi, 1981a,b, 1982) and are active in trained behavioral breath holds (Orem, 1989; Orem and Netick, 1986). However, there is no evidence for excitatory connections between the cortex and medulla in the literature. On the other hand, there is evidence in humans of direct corticospinal projections from the motor cortex to phrenic motoneurons (similar to those described for limb muscles) that “bypass” the medulla (Gandevia and Rothwell, 1987; Maskill et al., 1991; Sharshar et al., 2003, 2005). While several studies that show that the motor cortex is active and helps to generate voluntary breaths (Colebatch et al., 1991; Evans et al., 1999; Macefield and Gandevia, 1991; McKay et al., 2003; Nakayama et al., 2004; Petersen et al., 2011; Ramsay et al., 1993; Raux et al., 2007), it is not known whether the direct corticospinal pathway is used exclusively during voluntary contractions of the inspiratory muscles or whether there is an interaction with the inspiratory networks in the brainstem (Corfield et al., 1998; McKay et al., 2003). The output of the inspiratory motoneurons is dependent on descending and reflex inputs from multiple sources. These inputs must be integrated at some levels to produce a coordinated output from motoneurons innervating the various inspiratory pump muscles along with the upper airway dilator muscles. The two most likely sites of integration are at the medulla with a common output from bulbospinal inspiratory neurones or at the level of the spinal cord with a final common output from spinal motoneurons. In humans, the motor unit discharge patterns from a range of human inspiratory muscles can be measured from selective recordings of intramuscular electromyographic (EMG) activity. The firing of the single motor units directly reflects the activity of the motoneurons in the spinal cord. From these studies and the use of different tasks such as quiet breathing, voluntary breathing, and voluntary nonrespiratory tasks, we have been able to infer that there may be some integration of the voluntary and involuntary input at the level of the spinal cord. In this review, we discuss how the output of motoneurons in quiet breathing is determined, and then how voluntary and involuntary descending inputs to the inspiratory motoneurons interact.
2 HUMAN INSPIRATORY MOTONEURON OUTPUT IN QUIET BREATHING During quiet breathing, the output of the various respiratory motoneuron pools is timed and organized to produce coordinated contractions of a complex threedimensional system of pump muscles that act on the chest wall to draw air into the lungs together with the contraction of a perhaps even more complex group of valve or upper airway muscles that keep the airway open during breathing. The output from these various motoneuron pools to each of these muscles is not uniform in terms of timing, discharge frequency, and patterns of activity (Saboisky et al., 2007c) to achieve efficient ventilation. These differences in motoneuron output cannot all be
3 Neuromechanical Matching of Drive to the Inspiratory Muscles
attributed simply to differences in motoneuron properties or muscle fiber type (see De Troyer et al., 2005, for review). For this reason and others given below, we suggest that there is precise organization of the timing and amount of motoneuron output by premotoneuronal networks. This may act as a “spinal distribution network” for output to respiratory motor nuclei. The time and frequency plots (TAFPLOTs) for five different inspiratory muscles: diaphragm, scalene, dorsal external intercostal (3rd and 5th spaces), and parasternal intercostal (2nd space) muscles are shown in Fig. 1A. These plots summarize the behavior of the sample of motor units recorded for each muscle and give an overall impression of the behavior of each of the motoneuron pools during inspiration (Saboisky et al., 2007b). Across the five inspiratory pump muscles, they depict the nonuniformity of motoneuron behavior across pools. Each colored line represents the firing of a single motor unit during inspiration and they are ordered by time of onset of firing relative to inspiratory flow from bottom to top. The total timing of firing is represented by the length of the line and the peak firing frequency is represented by the color of the line. Motoneurons discharge exclusively phasically for the diaphragm but show variable levels of tonic firing in the other pump muscles. In addition, the recruitment times of motoneurons are earlier for the diaphragm and later for the dorsal external intercostal (5th space) motoneurons. This late onset of inspiratory drive is evident even for those motoneurons innervating the dorsal external intercostal muscle (5th space) that are already tonically active. This indicates a delay in the arrival of the central respiratory drive at these motoneurons that are close to threshold or already firing. Genioglossus is the major upper airway dilator muscle and is innervated by the hypoglossal motoneurons via the hypoglossal nerve and although it is largely active in inspiration, there are even greater differences in the behavior of its motor units compared to the pump muscles (Saboisky et al., 2006). Figure 1B is the same data as in Fig. 1A for the inspiratory pump muscles but now plotted on a compressed frequency scale alongside the data for genioglossus (bottom right panel). The genioglossus motor units are recruited earlier relative to inspiration and discharge at much higher rates. In addition to these differences in timing and rate, although the hypoglossal motoneuron pool overall is increasing its output in inspiration, there are patterns of activity that are not seen in motoneurons innervating the pump muscles. Some hypoglossal motoneurons are driven with purely tonic activity unmodulated by respiration at all and others that increase their discharge in expiration either phasically or from a tonic background discharge (Bailey et al., 2007a,b; Nicholas et al., 2010; Saboisky et al., 2006, 2007a, 2010; Tsuiki et al., 2000; Wilkinson et al., 2008, 2010).
3 NEUROMECHANICAL MATCHING OF DRIVE TO THE INSPIRATORY MUSCLES Across the different intercostal motoneuron pools that innervate both dorsal and parasternal intercostal muscles in humans, the output of the motoneurons depends directly on the mechanical effectiveness of the muscle fibers that they innervate. First
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FIGURE 1
3 Neuromechanical Matching of Drive to the Inspiratory Muscles
described in the dog (De Troyer et al., 2005), we call this “neuromechanical matching” of drive to the inspiratory muscles (Butler, 2007; Butler and Gandevia, 2008; Hudson et al., 2011b) and its effect is to produce the most efficient contraction of the inspiratory muscles to produce inspiratory airflow (for review, see De Troyer et al., 2005). In the dog, the pattern of activity is maintained even after muscle afferent feedback is removed by dorsal rhizotomy and section of the phrenic nerve (De Troyer and Legrand, 1995; De Troyer et al., 1996; Legrand et al., 1996), suggesting a preset component to the activation of the muscles (see also Hudson et al., 2007). This relationship between neural output from motoneurons and the mechanical effect of the muscle fibers that they innervate can account for a large part of the nonuniformity of output from the various motoneuron pools. The inspiratory mechanical advantage or inspiratory effectiveness of the intercostal muscles has been measured in dogs (De Troyer et al., 1996b, 1999; Wilson and De Troyer, 1992, 1993) and in humans (Wilson et al., 2001) and it varies around the chest wall depending on a number of factors and is related to the inspiratory pressure that can be generated by selective electrical stimulation of these muscles (De Troyer et al., 2005). In humans, the inspiratory mechanical advantage of the different portions of the intercostal muscles around the chest wall has been measured with the use of a CT images and measurement of the fractional passive length change of the various intercostal muscles during lung inflation. In humans, there are decreasing rostrocaudal gradients of mechanical advantage across spaces for the external and parasternal intercostals and also a decreasing dorsoventral gradient around a space for the external intercostals (Wilson et al., 2001). So, those portions of intercostal muscles with the greatest mechanical advantage for inspiration are located more Time and frequency plots (TAFPLOTs) of motor units recorded from human inspiratory muscles during quiet breathing. (A) TAFPLOTs from five obligatory inspiratory muscles (diaphragm, scalene, 3rd and 5th dorsal external intercostal, and 2nd parasternal intercostal muscles). Each horizontal line represents the discharge of a single motor unit recorded during quiet breathing. The number of lines indicates the number of motor units recorded. The length of each line indicates the timing of discharge relative to the inspiratory time (% inspiratory time). The lines are stacked from bottom to top according to the onset time of discharge of the motor unit. Thin horizontal lines indicate tonic discharge. The line color represents the peak firing frequency for each unit plotted between 5 and 17 Hz. Black dots indicate the time of peak firing frequency relative to inspiration. Onset and end discharge frequencies are indicated by the color of the dots at the beginning and end of the lines, respectively. (B) The same data as in (A) are plotted for the motor units from five obligatory inspiratory muscles on a different frequency scale (10–30 Hz) along with motor units recorded during quiet breathing from genioglossus (a major upper airway dilator muscle, bottom right panel). The data depicted in (A and B) highlight differences in motor unit patterns of activity, timing of recruitment, and motor unit discharge rates across human inspiratory muscles. Adapted from Saboisky et al. (2006, 2007).
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rostrally and dorsally. In dogs, the gradients of mechanical advantage parallel gradients of neural drive to the different portions of muscle (for review, see De Troyer et al., 1996b, 2005; Legrand et al., 1996) and we have now shown this is also the case in humans (De Troyer et al., 2003; Gandevia et al., 2006; Hudson et al., 2011c). The measurement of intramuscular EMG and single motor unit action potentials from human intercostal muscles allows us to quantify the phasic neural drive to various portions of the muscles around the chest. We have measured neural drive in the 3rd, 5th, and 7th spaces of the external intercostal muscles and all five parasternal intercostal muscle spaces in humans to examine the relationship between neural drive and mechanical advantage (De Troyer et al., 2003; Gandevia et al., 2006). The primary measurements made are recruitment time relative to inspiratory time and peak discharge frequency of single motor units during inspiration. Together, these measures provide an index of neural drive based on the mean number of motor unit spikes in a muscle portion during inspiration. For both parasternal intercostal muscles and the dorsal portions of the external intercostal muscles during normal quiet breathing, motor units in the higher more rostral spaces discharge earlier in the breath and reach higher firing frequencies than those in the lower spaces such that there is a decreasing rostrocaudal gradient of neural drive (De Troyer et al., 2003; Gandevia et al., 2006). For the external intercostal muscles, there was also progressive recruitment of the ventral portions of the muscles (measured in the 3rd space; De Troyer et al., 2003). Thus, here there is also a dorsoventral gradient of neural drive. These gradients in neural drive are similar to the gradients of mechanical advantage around the chest wall in humans (De Troyer et al., 1998; Wilson et al., 2001). When the known measures of mechanical advantage of each intercostal muscle in humans for each space are plotted against the mean number of motor unit spike during inspiration, which takes into account firing rate and time of firing, there is a strong linear relationship between mechanical advantage and neural drive for both the parasternal intercostal muscles (Fig. 2A) and external intercostal muscles (Fig. 2B) that holds for both across the dorsal portions and within a single intercostal space through to ventral portions where the mechanical advantage and corresponding neural drive is significantly lower than the dorsal portions. The difference in neural drive around the 3rd external intercostal muscle from dorsal to ventral is illustrative of a need for premotoneuronal control of the motoneuron output. Here, the muscle fibers across this space are all innervated by motoneurons in the T3 motor nucleus. The muscle fibers in the dorsal portion have a high mechanical advantage for inspiration, whereas the muscle fibers in the ventral portion have a low mechanical advantage. Rather than the whole motoneuron pool being recruited simply in order of cell size, the descending drive is distributed preferentially to motoneurons that innervate dorsal regions with high mechanical advantage for inspiration and then as inspiratory drive increases further, the ventral portions are recruited. This is unlikely to be due to motoneuron threshold or cell size (Zhan et al., 2000). We have proposed that the recruitment of the muscles is governed by a principle of neuromechanical matching, which is superimposed on normal motoneuron recruitment by Henneman’s size principle. Drive is directed to motoneurons
3 Neuromechanical Matching of Drive to the Inspiratory Muscles
FIGURE 2 Relationship between mechanical advantage and inspiratory drive in human intercostal muscles during quiet breathing. The linear relationships for parasternal intercostal muscles and external intercostal muscles, between the inspiratory mechanical advantage (calculated in human subjects from the passive length changes in intercostal muscle fibers during lung inflation) and the inspiratory neural drive (measured in a separate study and indicated by the mean number of motor unit spikes per breath). Higher negative values for inspiratory mechanical advantage indicate larger relative shortening of muscle length during passive inflation and correspond to higher airway opening pressures. For parasternal intercostal muscles, mechanical advantage was measured only for muscles in the 2nd to 5th interspaces and is estimated for the 1st interspace from the motor unit data. For external intercostal muscles, measures were made of inspiratory mechanical advantage and neural drive in the dorsal portions of the 3rd, 5th, and 7th interspaces and the ventral portion of the 3rd interspace. Adapted from Gandevia et al. (2006), De Troyer et al. (2003), and Butler and Gandevia (2008).
depending on the mechanical effectiveness of the muscle they innervate for the task, and this applies to motoneurons that innervate muscle fibers not only around an intercostal space but also across spaces (Butler, 2007; Butler and Gandevia, 2008; Hudson et al., 2011c). Furthermore, during voluntary breaths matched to quiet breaths, the gradient of neural drive across the interspaces are maintained and the active motor units are largely the same ones in each task (Hudson et al., 2011c). Thus, we suggest that the level of organization for their neuromechanically matched outputs may be somewhere at the spinal cord: a common component in the involuntary and voluntary pathways to the motoneurons. Further evidence for spinal organization of the output across inspiratory muscles comes from recent experiments in the dog (DiMarco and Kowalski, 2011, 2012).
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In these experiments, the same patterns of muscle activation seen in spontaneous breathing, that are matched to the gradients of mechanical advantage, are maintained in breathing evoked by high-frequency stimulation of the ventral surface of the spinal cord at T2 in dogs with a C2 spinal section. Not only is the pattern of EMG similar but also the firing rates of motor units are the same in spontaneous and stimulated breathing when the rib cage excursion is matched (DiMarco and Kowalski, 2011). Additionally, in support of a spinal network of respiratory muscle activation, the same type of stimulation at T2 can activate phrenic motor output through spinal connections (DiMarco and Kowalski, 2012). As inspiratory intercostal motoneurons are recruited by a principle of neuromechanical matching where neural output is related to the mechanical advantage of the portion of muscle in (i) quiet breathing, (ii) voluntary breathing, and (iii) stimulated breathing, the evidence is accumulating to suggest that organization of the output may be at the level of the spinal cord. It may be organized through a premotoneuronal network of interneurones or possibly through varying intrinsic properties of motoneurons. However, the exact mechanism is unknown.
4 INTERACTION OF VOLUNTARY AND INVOLUNTARY DRIVES TO HUMAN INSPIRATORY MOTONEURONS It is possible to make nonrespiratory voluntary contractions of the inspiratory muscles, for example, during trunk or neck flexion or rotation (Gandevia et al., 1990; Rimmer et al., 1995; Whitelaw et al., 1992). These voluntary movements are likely controlled by corticospinal projections. In a series of experiments, we have used the task of voluntary trunk rotation combined with quiet breathing to examine how the voluntary and involuntary pathways to the motoneurons might interact (Hudson et al., 2010, 2011a). During voluntary isometric rotation efforts of the trunk against in each direction, we measured the EMG activity of parasternal intercostal muscles (2nd space) and the diaphragm. The trunk rotation was divided into the initial part of the rotation, performed at rest at functional residual capacity, and the maintained rotation where the subjects breathed normally while maintaining the isometric rotational effort. The behavior of the two muscles during initial and maintained trunk rotation was quite different (Hudson et al., 2010, 2011a). For the parasternal intercostal muscles, there are differential bilateral effects of voluntary trunk rotation. During the initial part of ipsilateral (isometric) trunk rotation, about half (45%) of the parasternal intercostal motor units recorded during quiet breathing in the neutral position were active. Then, in the maintained ipsilateral rotation, parasternal intercostal phasic inspiratory activity increased twofold and there was earlier recruitment of the muscles relative to the onset of inspiratory flow. During contralateral trunk rotation efforts, no activity occurred in the initial part of rotation. During maintained contralateral trunk rotation parasternal intercostal phasic inspiratory activity was reduced by 30% and recruitment time was delayed
5 Evolutionary Considerations
relative to the onset of inspiratory flow (Hudson et al., 2010). The increases and decreases in parasternal intercostal activity during maintained trunk rotation efforts were due to both increasing and decreasing firing rates as well as the recruitment and derecruitment of motor units (Hudson et al., 2010). For the diaphragm, during the initial part of ipsilateral trunk rotation, inconsistent small amounts of activity occurred in only a small proportion (10%) of all the diaphragm motor units recorded in quiet breathing in the neutral position, some of which were also active in contralateral rotation efforts. However, voluntary trunk rotation in either direction had no effect on the diaphragm phasic inspiratory activity, the timing of the activity during breathing, or the firing rates of the diaphragm motor units (Hudson et al., 2011a). The differences in behavior of the inspiratory neural drive to the two inspiratory muscles during this voluntary task (Fig. 3) highlight two points. Firstly, that the roles of the two inspiratory muscles in trunk rotation are different presumably because the mechanical effect of parasternal intercostal muscle fibers for trunk rotation is greater than for the costal diaphragm muscle fibers. Secondly, that the interactions of voluntary and involuntary drives differ across the motoneuron pools and importantly for parasternal intercostal muscles across sides. The way that the voluntary drive interacts with the involuntary inspiratory drive for these two muscles suggests that the cortical and pontomedullary drives are integrated at the spinal level rather than at the medulla for a number of reasons: (i) we know that many of the bulbospinal projections to inspiratory muscles are bilateral (e.g., Feldman et al., 1985; Lipski et al., 1994; Merrill and Lipski, 1987; RikardBell et al., 1984; Tian and Duffin, 1996) and yet, for parasternal intercostal muscles during voluntary trunk rotation, inspiratory output changes in a direction specific manner; (ii) because the effects of voluntary rotation are specific to one set of inspiratory muscles (parasternal intercostals) and not a global effect across inspiratory muscles as may be expected (De Troyer, 1991; Feldman et al., 1985; Hilaire and Monteau, 1976; Lipski et al., 1994); and (iii) because as mentioned at the beginning of this review there is little, if any, anatomical or physiological evidence to show any excitatory connections between the cortex and the medulla. Therefore, one explanation for our findings in this task is that the integration of involuntary and voluntary pathways to inspiratory muscles is at the spinal cord.
5 EVOLUTIONARY CONSIDERATIONS In mammals, axial muscles are innervated by multiple descending pathways and these have been imposed at different points in vertebrate evolution to achieve critical respiratory and other functions. Prior to lung respiration, axial muscles were used for swimming and postural movements (Fetcho, 1992), while ventilation was achieved by gill respiration (Hickman et al., 1982) or a buccal pump (Brainerd et al., 1993). Therefore, innervation of axial muscles by reticulospinal pathways was present before descending bulbospinal respiratory pathways from
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FIGURE 3 Motor unit discharge rates during quiet breathing with and without isometric trunk rotation. Motor unit discharge rates during quiet breathing without trunk rotation (y axes, neutral breaths) and quiet breathing during isometric trunk rotation (x axes, with ipsilateral rotation indicated to the right and contralateral rotation indicated to the left) for (A), parasternal intercostal muscles and (B), diaphragm. The peak discharge of motor units active in both conditions are represented by the open circles (mean shown by filled circles) and the peak discharge of motor units active in only one condition (either recruited or derecruited) are shown by open squares (mean shown by filled squares).
the medulla. With the development of lungs, the axial muscles were used first for expiration, as in amphibians (Brainerd et al., 1993), and then were also used for inspiration in birds, reptiles, and mammals (e.g., Carrier, 1989). Given that ventilatory efficiency is likely to have always been crucial for survival, we propose that higher vertebrates retained the spinal networks through which coordinated
References
breathing was first achieved. Furthermore, later descending systems which needed “access” to drive the inspiratory muscles (such as for voluntary movement in primates), have done so through the same spinal networks. Such an arrangement is not only parsimonious in terms of neural circuitry but would probably enhance the adaptive capacity of the truncal musculature.
Acknowledgments We wish to acknowledge the important contributions to this work of our colleagues Prof. Andre De Troyer, Assoc. Prof. David McKenzie, Dr. Robert Gorman, and Dr. Julian Saboisky.
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