Drive to the human respiratory muscles

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Respiratory Physiology & Neurobiology 159 (2007) 115–126

Frontier review

Drive to the human respiratory muscles Jane E. Butler ∗ Prince of Wales Medical Research Institute, University of New South Wales, Sydney, NSW 2031, Australia Accepted 7 June 2007

Abstract The motor control of the respiratory muscles differs in some ways from that of the limb muscles. Effectively, the respiratory muscles are controlled by at least two descending pathways: from the medulla during normal quiet breathing and from the motor cortex during behavioural or voluntary breathing. Neurophysiological studies of single motor unit activity in human subjects during normal and voluntary breathing indicate that the neural drive is not uniform to all muscles. The distribution of neural drive depends on a principle of neuromechanical matching. Those motoneurones that innervate intercostal muscles with greater mechanical advantage are active earlier in the breath and to a greater extent. Inspiratory drive is also distributed differently across different inspiratory muscles, possibly also according to their mechanical effectiveness in developing airway negative pressure. Genioglossus, a muscle of the upper airway, receives various types of neural drive (inspiratory, expiratory and tonic) distributed differentially across the hypoglossal motoneurone pool. The integration of the different inputs results in the overall activity in the muscle to keep the upper airway patent throughout respiration. Integration of respiratory and non-respiratory postural drive can be demonstrated in respiratory muscles, and respiratory drive can even be observed in limb muscles under certain circumstances. Recordings of motor unit activity from the human diaphragm during voluntary respiratory tasks have shown that depending on the task there can be large changes in recruitment threshold and recruitment order of motor units. This suggests that descending drive across the phrenic motoneurone pool is not necessarily consistent. Understanding the integration and distribution of drive to respiratory muscles in automatic breathing and voluntary tasks may have implications for limb motor control. © 2007 Elsevier B.V. All rights reserved. Keywords: Control of breathing in humans; Single motor units; Neuromechanical matching; Neural drive; Upper airway; Motoneurones

1. Introduction Although we may think of breathing as a mostly automatic function, we regularly make complex and precise voluntary changes in breathing, for example, to speak, eat and hold our breaths under water. The human inspiratory and expiratory muscles are skeletal muscles, but their neural control is quite different from that of most other skeletal muscles such as limb muscles. Some unique aspects of the neural control of human inspiratory muscles will be the focus of this review. How do the inspiratory muscle motor units behave? Is their neural control like other skeletal muscles? Does the size principle of recruitment apply to human inspiratory motoneurones? From a motor control point of view, the neural circuitry for the respiratory muscles is unique because the motoneurones must

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be activated rhythmically and repeatedly to maintain ventilation. Their control is via two major descending pathways: the control can be automatic via bulbospinal pathways from the medulla to the motoneurones (e.g. during normal breathing) or voluntary via at least some direct corticospinal pathways (e.g. during a sniff). Additionally, the descending drive must be coordinated appropriately to activate all the inspiratory pump muscles that act on the chest wall, in concert with the upper airway muscles so as to breathe through a patent airway (Fig. 1). This coordination must occur all the time: when we are awake, sleeping, speaking, eating or exercising. The ability to study motor unit activity in human inspiratory muscles makes it possible for us to examine the behaviour of single inspiratory motoneurones during involuntary breathing or in voluntary tasks without the effects of sedation or anaesthesia. This is not easily done in animal studies. Our laboratory has attempted to address the way that human inspiratory muscle motor control is organised and some results will be described in this review.

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Fig. 1. Schematic representation of the control of the muscles of respiration. Direct corticospinal and bulbospinal pathways to respiratory motoneurones and a putative connection between the motor cortex and the pontomedullary respiratory centres are shown. The output from the motoneurones to respiratory muscles includes ‘pump’ muscles that act on the chest wall and ‘valve’ muscles of the upper airway. Feedback from lung, airway, and muscle afferents reaches the three levels cortex, medulla, and motoneurones through reflex pathways.

2. Descending neural drive to respiratory muscles Clinical experience suggests that the automatic pathways and voluntary pathways controlling breathing are distinct and can operate independently. Patients with Ondine’s curse (first described by Severinghaus and Mitchell, 1962; see also Severinghaus, 1998) and some patients with congenital hypoventilation syndrome, who have lesions in the brain stem and/or the descending pathways do not have normal automatic control of breathing when they are asleep and need to be ventilated (for review, see Shea, 1996). On the other hand, patients with the rare “locked-in syndrome” due to bilateral ventral pontine infarctions, have normal automatic control of breathing but cannot take breaths at will or make voluntary movements apart from eye movements (described by Plum and Posner, 1972). Interestingly, locked-in syndrome patients make appropriate emotionally triggered respiratory movements such as laughing or sighing. Thus, there may also be connections to the respiratory motoneurones from the limbic cortex (see also Straus et al., 1997). The way that we coordinate the timing and amount of neural drive to the respiratory muscles is complex. In some cases there may be a need to combine descending automatic, voluntary and/or postural drive to the respiratory muscles. Then, there must be integration of the different descending neural inputs but precisely where this occurs is not known. Integration could occur at the motoneurones or interneurones at a spinal level or at a higher pre-motoneuronal level, e.g. in the medulla. 2.1. Automatic control of breathing Briefly, during quiet breathing, i.e. breathing automatically under resting conditions, it has been generally accepted that the

rhythm or pattern of breathing is generated in the rostral ventrolateral medulla. Recent evidence from the rat suggests that the respiratory patterns may be driven by two oscillators: one inspiratory, located in the pre-B¨otzinger complex is the dominant rhythm generator, and the other active during expiration, located just rostral in the area of the retrotrapezoid nucleus or parafacial respiratory group of neurones (for review, see Feldman and Del Negro, 2006). Normally, these oscillators are coupled in action and form a continuous structure known as the ventral respiratory column. The group-pacemaker hypothesis proposes that the breathing pattern is generated by the “emergent” behaviour of inspiratory and expiratory systems (Feldman and Del Negro, 2006). During quiet breathing in humans, inspiration is active while expiration is largely passive (De Troyer et al., 1987). Expiratory neural activity in the medulla is activated strongly only when ventilatory drive in increased, e.g. under hypercapnic conditions (Smith et al., 1989; Fregosi et al., 1992). Inspiratory drive originates from inspiratory neurons located mainly in dorsal and ventral respiratory groups of neurones located in the dorsomedial and rostral venterolateral medulla, respectively (Berger et al., 1977a,b,c; Feldman, 1986; von Euler, 1986; Richter and Spyer, 2001). The timing of the inspiratory bursts of activity in the medulla can be altered by reflex input coming from the lungs (which tends to reduce ventilatory drive (Coleridge and Coleridge, 1986)) and from central and peripheral chemoreceptors sensitive to increases in arterial PCO2 (which tend to increase ventilatory drive (Saupe et al., 1992)). The output of the medullary cells reaches the target motoneurones to produce depolarising currents known as central respiratory drive potentials (CRDPs). The CRDPs are induced in inspiratory intercostal and phrenic spinal motoneurones mainly through contralateral bulbospinal projections in the cat (von Euler, 1973; von Euler et al., 1973a,b; Kirkwood and Sears, 1978; Monteau and Hilaire, 1991) although in the rat there are bilateral projections from the same inspiratory neurone (Tian and Duffin, 1996). Some of these projections have been shown to be monosynaptic in animals (Merrill, 1971; Cohen et al., 1974; Kirkwood and Sears, 1978; Davies et al., 1985a; Rikard-Bell et al., 1985; Duffin and Lipski, 1987; Monteau and Hilaire, 1991). While some studies suggest the monosynaptic connections are fast conducting and strong (Duffin and Lipski, 1987; Tian and Duffin, 1996), others suggest much weaker connections (Davies et al., 1985b; Merrill and Lipski, 1987). This may depend on the motoneurone pool studied, the animal model, or other methodological differences such as the level of anaesthesia. Thus, the prevailing view is that the distribution of neural drive from the inspiratory neurones in the medulla to each of the inspiratory motoneurone pools is timed similarly and thus reaches the motoneurone pools at roughly the same time through partly monosynaptic pathways (von Euler et al., 1973a,b; Feldman, 1986; Rekling et al., 2000). Some inspiratory neurones even project monosynaptically to intercostal motoneurones at a number of different thoracic levels (Davies et al., 1985a). Subsequent activation of motoneurones is thought then to depend on their size and intrinsic properties (Budingen and Yasargil, 1972; Hilaire et al., 1972; Nail et al., 1972; Iscoe et al.,

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1976; Berger, 1979) but can be sculpted depending on reflex or perhaps even tonic inhibitory drives (De Troyer et al., 2005). There is also, in the cat, a vast system of spinal interneurones through which integration of respiratory drive may occur (Aminoff and Sears, 1971). The proportion of pontomedullary projections from inspiratory neurones that project to spinal motoneurones via interneurones in the cat appears to be larger than for expiratory neurones (Davies et al., 1985a; Saywell et al., 2007). This system of interneurones may also account for some of the sculpting of drive reaching inspiratory motoneurones. 2.2. Voluntary control of breathing A balance of spontaneous patterns of activity from the central respiratory pattern generator and reflex inputs maintains ventilation and automatically compensates for changes in homeostasis. Even so, it is often necessary to interrupt the automatic control of respiration to produce a range of necessary voluntary functions (e.g. speech, singing, a breath hold, whistling, swallowing food, sipping through a straw, expulsive manoeuvres such as defaecation, or even a voluntary cough). Direct anatomical connections between pyramidal cells in the motor cortex and thoracic motoneurones have been shown in cats (Rikard-Bell et al., 1985). In humans, there is some neurophysiological evidence for direct cortico-spinal pathways to inspiratory muscles. With the use of transcranial electrical stimulation of the motor cortex and spinal stimulation, it was shown that the central conduction time (between the motor cortex and the motoneurons) for the diaphragm was at least as fast as for the deltoid muscle the motoneurone pool of which overlaps the diaphragm at C4 and C5 (Gandevia and Rothwell, 1987) and was also comparable to that shown previously for other distal limb muscles of the human hand (Cowan et al., 1984; Rossini et al., 1985; Snooks and Swash, 1985). Thus, it is possible that these pathways bypass the pontomedullary respiratory centres (see also Rikard-Bell et al., 1985; Corfield et al., 1998; Sharshar et al., 2004, 2005). If this is the case, integration of voluntary and involuntary drive would need to be at the level of the spinal motoneurones or interneurones. The cortical region representing the diaphragm was first described in 1936 (Foerster, 1936) using electrical stimulation of the exposed brain (see Shea, 1996) and is located close to the vertex in the primary motor cortex (Maskill et al., 1991; Davey et al., 1996). However, while imaging studies (Colebatch et al., 1991; Ramsay et al., 1993; Guz, 1997; Corfield et al., 1999; Evans et al., 1999; McKay et al., 2003), EEG studies (Macefield and Gandevia, 1991; Raux et al., 2007) have shown that the motor cortex needs only to be activated during voluntary breathing tasks, the fMRI studies have revealed that there also may be some involvement of the medulla during voluntary breathing (McKay et al., 2003). Afferent input to the medulla related to respiration may explain some of this rhythmic activity, but perhaps not all projections from the motor cortex bypass the medulla. We know, for example, that in the cat, stimulation of the motor cortex (Bassal and Bianchi, 1981a,b, 1982) or behavioural tasks (Orem and Netick, 1986; Orem, 1989; Orem and Trotter, 1992) can influence the inspiratory and expiratory cells in the pontomedullary respiratory centres. Volitional inhi-

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bition (perhaps from the motor cortex) of the central respiratory drive from the medulla must also occur in humans, for example during a breath hold, but this has not been formally demonstrated. Whether a proportion of descending excitatory outputs from the motor cortex is integrated at, or synapses at, the level of the medulla is not known, despite indirect efforts to determine this (Corfield et al., 1998; Lefaucheur and Lofaso, 2002; Sharshar et al., 2003). A recent study has shown cortical activity to be present in the form of Bereitschaft (readiness) potentials at just over one second prior to both voluntary sniffs as well as inspiratory resistive loaded breathing, suggesting a cognitive role in overcoming inspiratory loads even at very low loads (Raux et al., 2007). 2.3. Inspiratory spinal motoneurones The final integration of descending respiratory drive occurs at the motoneurone. The precise timing and the amount of excitatory drive that reaches the motoneurones from medullary, cortical and other regions may be determined by the convergence of these inputs with reflex and other excitatory and inhibitory inputs acting via networks of interneurones. The motoneurone is often referred to as the final common output of the central nervous system to the muscle (e.g. Liddell and Sherrington, 1925). By studying the motor unit firing properties of the respiratory muscles, we have been able to develop an understanding of how neural drive is distributed across and within the respiratory motoneurone pools in humans. The timing of firing and the firing rates of the motor units indicate the neural drive to the motoneurone pool. The results have proven to be more complicated for the respiratory muscles than for limb muscles possibly because of the specialised function of respiratory muscles and its dual control system. 3. Distribution of drive to respiratory motoneurones in humans Detailed studies of the timing and firing characteristics of single human inspiratory motor units in both inspiratory ‘pump’ muscles and upper airway muscles, have given some insight into their neural control. From our data, it seems that not all respiratory motoneurones receive the same distribution of drive from higher centres. Automatic drive appears to be differentially distributed both within a pool and across pools (De Troyer et al., 2003; Gandevia et al., 2006; Saboisky et al., 2006, 2007) and the combination of voluntary and automatic descending input to the respiratory motoneurones appears to be distributed differently across motoneurones within a pool (Butler et al., 1999). Henneman’s size principle states that motoneurones are recruited according to their size which determines, in part, their intrinsic properties, membrane resistance and hence, their “excitability” (for reviews, see Henneman and Mendell, 1981; Binder et al., 1996). This means that small motoneurones are recruited before large ones. With few exceptions, this holds for most limb motoneurone pools (Cope and Pinter, 1995). However, the size principle works under the assumption that descending synaptic inputs are distributed evenly to all motoneu-

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rones. Therefore, in some circumstances, the recruitment order of motoneurones within a pool can be altered depending on task (ter Haar Romeny et al., 1982; Nardone et al., 1989; Puckree et al., 1998), reflex input (e.g. Kernell and Hultborn, 1990), or local depolarising currents (Gorassini et al., 1998, 2002; Heckmann et al., 2005). 3.1. Gradients of neural drive to intercostal muscles The recruitment of the intercostal muscles has been studied in much detail in the dog by De Troyer and colleagues (for reviews see De Troyer, 2002; De Troyer et al., 2005) and also in some detail in humans (De Troyer et al., 2003; Gandevia et al., 2006). This topic is reviewed in more detail elsewhere (De Troyer et al., 2005). The intriguing part of the control of the intercostal muscles is that in both humans and dogs the neural drive is not uniform, but directed preferentially to those muscles or portions of muscles with the greatest mechanical advantage for the task to be performed. The mechanical advantage (expressed as the specific airway opening pressure of a portion of muscle) has been calculated for most inspiratory muscles in the dog (De Troyer et al., 1996b, 1998; Legrand et al., 1996b) and in the human (De Troyer et al., 1998; Legrand et al., 2003) and is related to the fractional change in muscle length as the chest wall expands from FRC to TLC (Wilson and De Troyer, 1992, 1993). Therefore, for the intercostal muscles there is a principle of motoneurone recruitment related to “neuromechanical matching” of central respiratory drive (Butler et al., in press). This may be for metabolic efficiency reasons (De Troyer et al., 2005). For the case of the inspiratory dorsal external intercostal muscles in humans and dogs, the activation occurs earlier in the breath and to a larger extent in spaces where mechanical advantage is largest (Legrand and De Troyer, 1999; Wilson et al., 2001; De Troyer et al., 2003). In humans, in the rostral spaces the motor units fire at higher frequencies (11.9 Hz) than for more caudal spaces (6.7 Hz), while within a space, activation is greatest dorsally and less ventrally (6.0 Hz). For the parasternal intercostal muscles there are similar rostrocaudal gradients of neural drive for both humans and dogs (De Troyer and Legrand, 1995; De Troyer et al., 1996b; Legrand et al., 1996a; De Troyer and Wilson, 2000; Gandevia et al., 2006). The average firing rate for parasternal intercostal motor units recorded from the first space was 13.4 Hz compared with 8.0 Hz in the 5th space. Along the intercostal space, however, the neural drive is greatest medially and reduced more laterally for the dog (Legrand et al., 1996b) while there is no difference for the human (Gandevia et al., 2006). This may reflect the difference in rib curvature and therefore muscle fibre orientation between the human and the dog (De Troyer et al., 2005). The gradients of activity are preserved in dogs even when all respiratory muscle, joint and skin afferent feedback is removed by phrenic nerve section and complete thoracic dorsal rhizotomy (De Troyer and Legrand, 1995; De Troyer et al., 1996a; Legrand et al., 1996a). Thus, the patterns of activation appear to be ‘hard-wired’. Although equivalent experiments cannot be done, it is most likely the case also for humans. The implications of these data are that the descending drive to breathe is not only differentially distributed to each intercostal

motoneurone pool, but even within a motoneurone pool innervating a muscle within an intercostal space there is differential activation of specific motoneurones according to their mechanical effectiveness for a specific task. It is not clear whether these apparently pre-set patterns of neuromechanical matching of drive are organised at a spinal level via different sized motoneurones, through a network of inhibitory interneurones, or at a higher level. The concept of activation strategies for maximum efficiency is not restricted to respiratory muscles. For example, locomotion depends on coordinated timing of activation of different muscles determined by the most efficient means of creating a specific pattern of movement (e.g. Anderson and Pandy, 2003; Pandy, 2003). However, so far the intercostal motoneurones are unique in having differential distribution of drive to specific motoneurones that depends on their mechanical effectiveness for a particular task. It is possible, that this type of neuromechanical principle of recruitment may also be superimposed on the Henneman’s size principle of motoneurone recruitment for limb motoneurone pools in more complex tasks where joint angle and fibre orientation are changing. This is yet to be tested. 3.2. Activation among different inspiratory pump muscles There also seems to be a gradient of recruitment across some other inspiratory muscles. Recent studies of five different human inspiratory muscles during normal breathing have also shown variations in the timing and amount of drive to the different muscles (Fig. 2A–E (Saboisky et al., 2007)). The diaphragm is recruited first, while the 5th space dorsal external intercostal is recruited significantly later and to a lesser extent. The diaphragm motor units were recruited throughout inspiration but activated on average after 26% inspiratory time and reached firing rates of 12.6 Hz, whereas the 5th space dorsal external intercostal motor units, although also recruited throughout inspiration, were recruited on average after 43% inspiratory time and fired at 10.1 Hz. The third space dorsal external intercostal muscle, scalenes muscle and parasternal intercostal muscles were recruited in between, with distinct activation times. The pattern of recruitment for this selection of inspiratory muscles suggests a non-uniform activation of the motoneurone pools that may have a function related to efficiency of ventilation. Fig. 2 (panels A–E) shows the recruitment and derecruitment times, relative to inspiratory time, of the various motor units measured during normal breathing. The motor units are ordered according to their onset times. For each muscle, the differences in timing of recruitment during inspiration can be seen by the distinct differences in the slope of the profile of the onset times for all units in each muscle. There are also differences in the proportion of tonically firing motor units in the different muscles. While the diaphragm had none, the largest numbers of tonically firing units were active in the 5th space dorsal external intercostal muscles. Even though these units are active tonically, the inspiratory related increase in firing occurs throughout and late into the breath. This suggests that the late activation of motor units does not depend on recruit-

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ment threshold alone and that there must be organisation of the distribution of drive at a pre-motoneuronal level (Saboisky et al., 2007). This pattern of activation of different muscles may be organised for optimal efficiency, but would also need to be adaptable in the case of changes in the mechanical advantage of a muscle that may occur with changes in posture or lung function associated with respiratory disease.

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3.3. Increases in the neural drive to breathe Chronic obstructive pulmonary disease is one example of a respiratory disease in which the mechanics of the chest are significantly altered. In addition to an increased airway resistance and elastic loads, patients are hyperinflated and the inspiratory muscles are forced to operate at shorter than optimal lengths.

Fig. 2. Timing of the discharge of motor units in six human inspiratory muscles. Panels A–F show the firing time for each single motor unit recorded from five different chest wall inspiratory muscles (upper panels A–E) and one upper airway muscle (genioglossus, panel F) during quiet breathing, relative to the time of inspiration or expiration (expiratory time is shaded grey). For each unit, the thick horizontal line represents the time that the firing frequency increases in the inspiratory or expiratory phase of respiration. The thin horizontal line indicates tonic firing of the motor unit at other times. The units are ordered relative to their onset time. Phasically firing units during inspiration (IP) or expiration (EP) are shown on top, tonically firing units that increased their discharge during either inspiration (IT) or expiration (ET) are shown beneath. Tonically firing units that did not increase their firing in time with respiration (TT) are also shown. The proportion of tonically active units (IT, ET and TT) is higher for genioglossus (panel F) than the chest wall muscles. TT, EP and ET units have not been observed in the inspiratory muscles that act on the chest wall (panels A–E). The different slope of the onset times for the population of motor units for each muscle (e.g. panel A compared to panels E and F) represents different inspiratory drive to each muscle that may be controlled at the motoneurones or at a higher level. Adapted from Saboisky et al. (2006, 2007) used with permission.

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As a result, the neural drive to breathe in COPD patients is elevated. Although the diaphragm is shorter in COPD, the excursion of the diaphragm during tidal breathing is the same in patients with COPD as in age matched control subjects (McKenzie et al., 2000; Singh et al., 2001; Gorman et al., 2002). At this compromised muscle length, the neural drive to the diaphragm is considerably higher for COPD subjects compared to the matched control subjects. Studies of the firing frequencies during normal breathing of single motor units from the diaphragm in COPD and control subjects suggest that this is the case. Firing rates were almost double in COPD patients than controls (17.9 Hz versus 10.5 Hz, respectively; (De Troyer et al., 1997)). These data are consistent with a recent study that showed a 3-fold increase in diaphragm activity in COPD patients (34% of maximum) compared to control subjects (11% maximum) during normal breathing (Jolley et al., 2006). An increase in neural drive translates into recruitment of new motor units and increased firing frequency of active motor units. The extent to which each occurs depends on the specific properties of each of the motoneurone pools (De Luca et al., 1982a,b; Binder et al., 1996). There are also increases in the neural drive to the scalenes and parasternal intercostal muscles in COPD patients but the differences in motor unit firing frequency are not as large as for the diaphragm (11.4 Hz versus 8.5 Hz for scalenes and 13.4 Hz versus 10.1 Hz for parasternal intercostals, for COPD and control subjects, respectively (Gandevia et al., 1996)). After lung volume reduction surgery, the length of the diaphragm increases and the motor unit firing rates of the diaphragm and scalenes are significantly reduced towards normal values (Lando et al., 1999; Gorman et al., 2005). The disproportionately higher firing rates of motor units in the diaphragm compared to the other inspiratory muscles in COPD is worth mentioning. Especially given that we know that in COPD the diaphragm is at a shorter length at FRC and therefore, potentially, at a lower mechanical advantage (McKenzie et al., 2000). It may be that the neural drive is differentially increased to the diaphragm which is, after all, the major generator of inspiratory flow (Aliverti et al., 1997). On the other hand it may be that the same increases in neural drive are distributed equally to the different motoneurone pools but are translated into firing frequencies differently depending on the specific intrinsic properties of the motoneurones (Binder et al., 1996). When healthy volunteers are rebreathing through an external deadspace, long enough to increase ventilation by 2–3 times, the firing rates of the diaphragm motor units also increase disproportionately compared to the firing rates of motor units in scalenes and parasternal intercostals. Despite this, the ratio of rib cage to abdominal expansion during inspiration was similar (Gandevia et al., 1999b). Therefore, in this case, if neural drive is reflected by the functional output of the muscles, then it appears to be increased similarly to all motoneurone pools and not necessarily preferentially to the diaphragm. A tendency for increased motor unit recruitment in scalenes and parasternal intercostal muscles rather than increased firing frequency could explain these findings. At these increased levels of ventilation, driven by CO2 rebreathing, the firing rates of motor

units for diaphragm, scalenes and parasternal intercostal muscles (17.7, 9.5 and 11.9 Hz, respectively) were comparable to those recorded during normal breathing in COPD patients; (Gandevia et al., 1999b). It is not known whether there are changes in the timing of the descending drive to inspiratory muscles in COPD that may be associated with the changes in inspiratory muscle length or mechanical advantage. 3.4. The neural control of genioglossus The genioglossus is one of the major upper airway dilator muscles. Because of its importance in health and diseases such as obstructive sleep apnoea (OSA), the neural control of genioglossus has been the subject of many studies. The muscle is active throughout respiration with increased activity during inspiration and a tonic or background level of activity during expiration (Mezzanotte et al., 1992; Tangel et al., 1992). There is strong reflex activation of genioglossus in response to negative pressure in the upper airway (Horner et al., 1993, 1994; Wheatley et al., 1993; Malhotra et al., 2000, 2002, 2004; Berry et al., 2003) but the genioglossus also receives central respiratory descending drive (Akahoshi et al., 2001; Pillar et al., 2001; Fogel et al., 2003; Saboisky et al., 2006). The descending drive is responsible for pre-activation of the genioglossus 50–150 ms prior to inspiratory flow and is abolished during hypocapnic negative pressure ventilation when central drive to breathe is removed. Thus, the difference in the timing of the activation between the genioglossus and the other respiratory pump muscles during quiet breathing is ∼100 ms (see also Strohl et al., 1980). While the purpose of this may seem obvious, to stiffen the upper airway prior to the production of negative pressure by the pump muscles, it is less obvious how the timing of the activation of the muscle is controlled. While respiratory related monosynaptic excitatory and inhibitory connections project from the pontomedullary respiratory centres to phrenic and intercostal motoneurones (Davies et al., 1985b; Saywell et al., 2007) and even to laryngeal motoneurones (Ono et al., 2006) this is not the case for hypoglossal motoneurones. Anatomical and functional studies in animals suggest that there are inspiratory monosynaptic connections to hypoglossal motoneurones from pre-motoneurones in the lateral tegmental field (Peever et al., 2002). Separate origins of respiratory drive would be beneficial to allow some independent activation of upper airway and pump muscles but it is not known how the advance in inspiratory activation of the genioglossus compared to pump muscles is controlled. The activity of the genioglossus measured by intramuscular electrodes measuring multi-unit EMG indicates that the muscle is activated throughout respiration. The inspiratory pump muscles are not active during expiration with the exception of a relatively small proportion of tonically active motor units (see above and Fig. 2A–E). The apparent differences in the neural control of the genioglossus and the pump muscles (e.g. the diaphragm) led us to study the behaviour of single motor units in this muscle, in order to understand the composition of the overall pattern of its activity. In terms of their firing patterns, the motor units of the genioglossus muscle exhibit some remark-

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able characteristics. The activity of single motor units in the genioglossus during quiet breathing is by no means uniform (Fig. 2F) and their firing rates are substantially higher than those of motor units in the pump muscles. Firing rates reach up to ∼25 Hz on average for tonically active units (Saboisky et al., 2006). Fig. 2 (panel F) depicts the firing profiles of the population of genioglossus motor units sampled from healthy human subjects during quiet breathing (adapted from Saboisky et al., 2006). The largest proportion of units (39%) is active predominantly during inspiration only, while another set (12%) increase their firing rate during inspiration but are also active throughout respiration. In contrast to the chest wall respiratory muscles, there are also a large number of motor units (29%) that fire tonically throughout respiration without any respiratory related modulation of activity. Furthermore, a smaller proportion (16%) increases their discharge during expiration. Expiratory units were recorded simultaneously with units that were active largely during inspiration inspiratory units, so although they were active during opposite phases of the respiratory cycle they are likely to have a complimentary function. While the results may seem unusual in comparison to the behaviour of most limb motoneurones within a pool, for hypoglossal motoneurones, the results were not entirely unexpected. Similar patterns of activity are seen in intact animal preparations (Hwang et al., 1983), in contrast to hypoglossal motoneurone slice preparations (e.g. Ladewig and Keller, 2000), and some of the different classes of motor units had also been previously described in a smaller study of human genioglossus motor units (Tsuiki et al., 2000). Clearly, there are differences in the distribution of inspiratory and expiratory drive across the hypoglossal motoneurone pool. Many of the tonically active units received no respiratory drive and may be activated by a separate tonic perhaps postural drive or even by local depolarising currents (Feldman et al., 2005; Heckmann et al., 2005). Fig. 3 postulates a combination of descending drives that might be distributed differently across the motoneurones of the hypoglossal motor nucleus. However,

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it is not clear yet where the patterns of drive are integrated and whether the different classes of motor units relate to threshold or function. 3.5. Postural activity in inspiratory muscles Many of the respiratory pump muscles and particularly the inspiratory valve muscles show activity during both inspiration and expiration. Some motor units fire tonically with no respiratory modulation while others increase their firing in inspiration or even expiration as described for the genioglossus. This tonic or non-inspiratory activity may result from a number of mechanisms including local depolarising currents in the dendrites of the motoneurones, reduced active inhibition during expiration, or even direct tonic descending drive from higher centres. The function of such tonic activity has been postulated to be postural and may act to stiffen the rib cage or the airway (Butler et al., 2001; Gandevia et al., 2006; Saboisky et al., 2006). Although the major function of the inspiratory pump muscles is the rhythmic contraction to produce ventilation, they are also activated during other important, mainly postural, tasks such as the maintenance of trunk and head position as well as trunk and head rotation. Although tonically firing motor units are rarely recorded from the diaphragm (Butler et al., 2001; Saboisky et al., 2006). A postural role for the diaphragm has been demonstrated. First, the diaphragm is activated in advance of limb muscles during a voluntary destabilising postural disturbance (Hodges and Gandevia, 2000a, 2000b; Gandevia et al., 2002). The contraction of the diaphragm in conjunction with abdominal and pelvic floor muscles is thought to increase abdominal pressure and stabilise the lower spine (Hodges, 1999; Sapsford et al., 2001; Shirley et al., 2003; Hodges et al., 2005). When respiratory demands are increased, for example during hypercapnia, the postural activity of the diaphragm is diminished while the respiratory modulation is increased (Hodges et al., 2001). These data suggest a convergence of postural and descending bulbospinal drive perhaps at

Fig. 3. Schematic of the proposed control of human genioglossus motor units. This proposed control system suggests that a combination of inspiratory, tonic, and expiratory drives can act differentially on the hypoglossal motoneurone pool and combine to result in the five distinct patterns of motor unit firing observed in human genioglossus motor units. Examples of instantaneous firing frequency plots for each type of motor unit are shown in the bottom five panels. Inspiratory time is indicated in each by a diagrammatic representation of inspiratory tidal volume (ramps). While the origin of inspiratory and expiratory drive is considered to be supraspinal, the origin of the tonic drive is not known.

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the spinal level rather than a specific population of motoneurones designated to perform postural tasks. 3.6. Respiratory activity in limb muscles Anecdotally, patients in the vegetative state with an intact brainstem will show rhythmic contraction of the limbs when there is high chemical drive to breathe. There are a few reports of central respiratory drive potentials reaching limb motoneurones. CRDPs have been recorded from the hindlimb motoneurones in the cat during hyperoxic hypercapnia (Kirkwood et al., 2005; Ford and Kirkwood, 2006) and are associated with plateau potentials triggered by the depolarizing phase of the CRDP itself (Kirkwood et al., 2005). In humans, the H reflex in the limb can alter its size during coughing, forced expiration (Gandevia et al., 1998), laughing (Gandevia et al., 1999a; Overeem et al., 1999; or mirth on its own Overeem et al., 2004) and other respiratory tasks (Overeem et al., 2004), suggesting that respiratory events can change the excitability of the soleus motoneurone pool even in the awake human. The function of this may be to coordinate or entrain breathing and cyclic limb movements such as walking or running but at this point this is purely speculation. 3.7. Voluntary drive to inspiratory motoneurones How are motoneurones recruited during voluntary breaths in humans? Does Henneman’s size principle apply here? For the human diaphragm, in some cases, large alterations in recruitment order of motor units occur depending on the voluntary task (Butler et al., 1999). In order to study the recruitment properties of human diaphragm motor units, we made multiple recordings of three or more single motor units simultaneously. Thus, the recruitment order of the same set of simultaneously recorded units was determined across different voluntary inspiratory tasks. The voluntary tasks were simply targeted breaths in to different lung volumes at different rates. Generally, diaphragm motor units were recruited with a relatively stable threshold related to lung volume. Firing rates ranged across the tasks from 7.8 to 11.0 Hz and, as for limb muscles, were highest for those tasks requiring higher neural drive. A method, known as the shuffle index, was developed to quantify any changes in recruitment order of the simultaneously recorded motor units from the human diaphragm (see Butler et al., 1999). Unexpectedly, this method showed that there were larger changes in recruitment order between different voluntary tasks than when the same task was repeated multiple times. This was interpreted to suggest that there are task related differences in the neural strategies used for the different voluntary inspiratory tasks. The majority of motor units had a relatively stable recruitment threshold between the different tasks. However, sometimes there were some large changes in recruitment threshold depending on the task performed. In about a quarter of recording sites, there were large systematic changes with task in the recruitment threshold of one unit compared to the others recorded at the same time. Sometimes a motor unit that was recruited early in a voluntary inspiratory breath to a small volume could be recruited up to two seconds later in a voluntary inspiratory breath to a large volume

Fig. 4. Alteration in recruitment threshold and order for diaphragmatic motor units. Two diaphragmatic motor units (Units 1 and 2) recorded simultaneously with a monopolar electrode in the costal region. The superimposed motor unit action potentials for each unit are shown in the right panels for A and B. Clearly, the same units are active in A and B. (A) The subject performs a small voluntary inspiration to 5% vital capacity (VC) above functional residual capacity (FRC) at a rate of 5% VC/s. Lung volume trace is shown (solid black line, left panel). The dotted line represents the profile of lung volume in task B. (B) The subject performs a large voluntary inspiration at the same rate (5% VC/s) to 40% VC above FRC. Lung volume trace is shown (solid black line, left panel). The dotted line represents the profile of lung volume in task A. The recruitment threshold of Units 1 and 2 are shown in each task (black arrows). While Unit 2 is recruited at approximately the same volume threshold in each task, the recruitment threshold of Unit 1 is significantly delayed in B. This suggests a different synaptic drive has recruited Unit 1 in the two tasks. Adapted from Butler et al. (1999), used with permission.

(Fig. 4). This was despite the same target flow and presumably descending inspiratory drive. This caused obvious changes in both recruitment threshold and recruitment order of motor units that could not be attributed to differences in afferent feedback or the final motor performance. Fig. 4 shows an example of this for two simultaneously recorded units. In addition, involuntary breaths matched for size to voluntary breaths also show alterations in recruitment order in the same range as was observed across voluntary tasks. The motor units apparently violate the Henneman’s size principle of orderly recruitment. These data are difficult to explain other than to suggest that there must be differences in the distribution of voluntary and automatic descending inputs across the phrenic motoneurone pool which can alter the apparent recruitment threshold of motoneurones, possibly when strategies used to perform a task differ (see Fig. 1). 4. Summary From a motor control point of view, descending drive to inspiratory muscles forms an intricate and coordinated system for efficient and coordinated ventilation. In general, the neural control of inspiratory muscles is very similar to the neural control of limb muscles but there are also many caveats. It may be that there are hardwired differences between limb and inspiratory

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