David K. McKenzie

Respiratory sensations, cardiovascular control, kinaesthesia and transcranial stimulation during paralysis in humans.

1. To determine whether discomfort associated with breathing (dyspnoea) is related to the chemical drive to breath, three subjects were totally paralysed while fully conscious. Subjective responses to a rising CO2 stimulus were obtained during rebreathing, rebreathing with CO2 added, and breath holding. Dyspnoea was measured with a 10‐point Borg scale. 2. Following nasotracheal intubation and ventilation (oxygen saturation, O2,Sat, 98‐100% and end‐tidal CO2, PET,CO2, 30‐40 mmHg), total neuromuscular blockade was induced by a rapid injection of atracurium (> 2.5 mg kg‐1) and complete paralysis was maintained with an infusion (5 mg (kg h)‐1). Paralysis was confirmed by abolition of the compound muscle action potentials of both the diaphragm and abductor hallucis evoked by supramaximal electrical stimulation of the relevant nerves. Communication via finger movement was preserved for the first 20‐30 min following paralysis by inflation of a sphygmomanometer cuff on one arm. 3. Before and during complete paralysis, dyspnoea increased progressively during hypercapnia produced by rebreathing (with or without CO2 added to the circuit at 250 ml min‐1). The mean PET,CO2 eliciting severe’ dyspnoea was 46 mmHg during rebreathing, 42 mmHg during ‘breath holding’, and 52 mmHg during rebreathing with added CO2. There were no significant differences between the values obtained during paralysis and in the control study immediately before paralysis. The duration of breath holding was not prolonged by paralysis and the PET,CO2 at the ‘break point’ was not altered by paralysis. 4. Thus, dyspnoea is preserved following total neuromuscular blockade. This suggests that chemoreceptor activity, via the central neuronal activity which it evokes, can lead to discomfort in the absence of any contraction of respiratory muscles. 5. During paralysis, attempted contraction of arm, leg and trunk muscles increased heart rate and blood pressure. For attempted handgrip contractions, the increases in heart rate (range, 7‐15 beats min‐1) and mean arterial pressure (range, 20‐32 mmHg) were similar to those recorded with actual contractions in trials immediately before paralysis. In one subject, graded increases in heart rate and blood pressure occurred for attempted contractions of 45 s duration over a range of intensities (0‐100% maximal effort). 6. During complete paralysis, transcranial electromagnetic stimulation of the motor cortex produced illusory twitch‐like movements of the wrist and digits. This also occurred in separate studies during complete ischaemic paralysis and anaesthesia of the forearm and hand.(ABSTRACT TRUNCATED AT 400 WORDS)

Contraction of the human diaphragm during rapid postural adjustments

1 The response of the diaphragm to the postural perturbation produced by rapid flexion of the shoulder to a visual stimulus was evaluated in standing subjects. Gastric, oesophageal and transdiaphragmatic pressures were measured together with intramuscular and oesophageal recordings of electromyographic activity (EMG) in the diaphragm. To assess the mechanics of contraction of the diaphragm, dynamic changes in the length of the diaphragm were measured with ultrasonography. 2 With rapid flexion of the shoulder in response to a visual stimulus, EMG activity in the costal and crural diaphragm occurred about 20 ms prior to the onset of deltoid EMG. This anticipatory contraction occurred irrespective of the phase of respiration in which arm movement began. The onset of diaphragm EMG coincided with that of transverses abdominis. 3 Gastric and transdiaphragmatic pressures increased in association with the rapid arm flexion by 13.8 ± 1.9 (mean ±s.e.m.) and 13.5 ± 1.8 cmH2O, respectively. The increases occurred 49 ± 4 ms after the onset of diaphragm EMG, but preceded the onset of movement of the limb by 63 ± 7 ms. 4 Ultrasonographic measurements revealed that the costal diaphragm shortened and then lengthened progressively during the increase in transdiaphragmatic pressure. 5 This study provides definitive evidence that the human diaphragm is involved in the control of postural stability during sudden voluntary movement of the limbs.

Activation of human muscles at short muscle lengths during maximal static efforts.

1. Human muscle endurance is apparently enhanced during maximal voluntary contractions at short muscle lengths (McKenzie & Gandevia, 1987) but the ability of subjects to activate muscles fully at short lengths has not been established. Therefore this study examined the voluntary capacity to activate muscles fully at control (near resting) lengths and at decreased muscle lengths. Changes in mechanical properties of twitch responses to electrical stimulation of relaxed muscles at short muscle lengths were also documented. The abductor digiti minimi, elbow flexors and tibialis anterior were studied in five subjects. 2. For the three muscle groups, the mean reduction in twitch force between the control and short muscle lengths ranged from 46‐51%. AT the short length there was a 9‐13% reduction in the contraction time and a 21‐27% reduction in the half‐relaxation time. Maximal voluntary force declined by 21‐49% at the short muscle length. A reduction in muscle length produced a shift to the right of the force‐frequency curve as determined by brief trains of electrical stimuli. 3. During maximal efforts single or brief trains of two to four supramaximal stimuli, delivered to the parent nerve or motor point, failed to increase the force at a latency appropriate for onset of a muscle twitch in some but not all attempts. Each subject achieved ‘maximal activation’ of the muscle in a similar proportion of attempts at the control and short muscle lengths. 4. These results suggest that maximal voluntary activation of motoneurone pools is possible at short muscle lengths and that the central nervous system is able to maintain the discharge of motoneurones close to ‘fusion’ frequency despite a decrease in the temporal characteristics of the isometric twitch.

Twitch interpolation of the elbow flexor muscles at high forces

We investigated factors affecting maximal voluntary torque and the assessment of the level of voluntary drive in the elbow flexor muscles. First, the effective compliance of the system was tested by using single, paired, and trains of four stimuli to measure voluntary activation. At high voluntary torques the responses to all these stimuli were identical, suggesting that single stimuli are adequate for estimating voluntary drive. Second, the contribution of torque from synergist elbow flexor muscles was assessed. In attempted maximal voluntary contractions (MVCs), the voluntary activation of brachioradialis (median 91.5%, range 68.9–100%) was lower than for biceps brachii (median 99.1%, range 78.5–100%; P < 0.01). This suggests extra torque may be generated by brachioradialis during elbow flexion, beyond the torque where biceps brachii is maximally activated. Finally, lengthening of the elbow flexors occurred during MVCs, due to slight shoulder movements. This would allow force to increase independently of an increase in voluntary drive.

Activation of human respiratory muscles during different voluntary manoeuvres.

1. This study used three techniques (bilateral phrenic nerve stimulation, motor cortex stimulation and quantitative electromyography) to assess the degree of activation of the diaphragm, intercostal‐accessory muscles and abdominal muscles during postural tasks and respiratory manoeuvres. They included maximal inspiratory and expulsive efforts. 2. Bilateral phrenic nerve stimuli at supramaximal levels produced an average change in transdiaphragmatic pressure (Pdi) of 28 cmH2O during relaxation. During maximal inspiratory or expulsive efforts, all subjects were able to activate the diaphragm fully at functional residual capacity as judged by the failure of stimuli delivered during the voluntary efforts to increase Pdi. Peak voluntary Pdi was about 30% less for inspiratory than expulsive manoeuvres. 3. By contrast, transcranial activation of motor cortical output to the diaphragm and abdominal muscles produced an increment in abdominal pressure of 25 +/‐ 7 cmH2O during maximal voluntary expulsive efforts. Given the lack of response to phrenic nerve stimulation at similar voluntary pressures, this suggests that abdominal muscles, and not the diaphragm, fail to generate their full contractile force during maximal voluntary expulsive manoeuvres. 4. Motor cortical stimulation during weak inspiratory efforts produced a small reduction in oesophageal pressure (i.e. increase in net inspiratory force) of 7‐14 cmH2O. This response could not be extinguished during maximal voluntary inspiratory efforts in two of three subjects. This occurred despite the cortical co‐activation of ‘antagonist’ muscles in the chest wall and abdomen, and passive transmission of pressure from the abdominal to thoracic compartments. 5. Integrated electromyographic activity (EMG) recorded from abdominal muscles (rectus abdominis, external oblique) was greater during trunk flexion than during maximal expulsive efforts. Similarly, integrated EMG of the intercostal‐accessory muscles (sternomastoid, scalenes, parasternal intercostals) was greater during tasks requiring head and/or neck flexion than during the maximal inspiratory efforts. 6. These data show that the diaphragm can be fully activated by the central nervous system during voluntary respiratory tasks but that other agonist ‘respiratory’ muscles need not be activated fully. Given the complex actions of ‘inseries’ respiratory muscles revealed here, it is argued that differences in the transdiaphragmatic pressure during various postural and respiratory tasks do not necessarily imply variation in the level of diaphragmatic neural drive.

Respiratory muscle function and activation in chronic obstructive pulmonary disease

Inspiratory muscles are uniquely adapted for endurance, but their function is compromised in chronic obstructive pulmonary disease (COPD) due to increased loads, reduced mechanical advantage, and increased ventilatory requirements. The hyperinflation of COPD reduces the flow and pressure-generating capacity of the diaphragm. This is compensated by a threefold increase in neural drive, adaptations of the chest wall and diaphragm shape to accommodate the increased volume, and adaptations of muscle fibers to preserve strength and increase endurance. Paradoxical indrawing of the lower costal margin during inspiration in severe COPD (Hoovers sign) correlates with high inspiratory drive and severe airflow obstruction rather than contraction of radially oriented diaphragm fibers. The inspiratory muscles remain highly resistant to fatigue in patients with COPD, and the ultimate development of ventilatory failure is associated with insufficient central drive. Sleep is associated with reduced respiratory drive and impairments of lung and chest wall function, which are exaggerated in COPD patients. Profound hypoxemia and hypercapnia can occur in rapid eye movement sleep and contribute to the development of cor pulmonale. Inspiratory muscles adapt to chronic loading with an increased proportion of slow, fatigue-resistant fiber types, increased oxidative capacity, and reduced fiber cross-sectional area, but the capacity of the diaphragm to increase ventilation in exercise is compromised in COPD. In COPD, neural drive to the diaphragm increases to near maximal levels in exercise, but it does not develop peripheral muscle fatigue. The improvement in exercise capacity and dyspnea following lung volume reduction surgery is associated with a substantial reduction in neural drive to the inspiratory muscles.

Neural drive to human genioglossus in obstructive sleep apnoea

One postulated mechanism for obstructive sleep apnoea (OSA) is insufficient drive to the upper‐airway musculature during sleep, with increased (compensatory) drive during wakefulness. This generates more electromyographic activity in upper airway muscles including genioglossus. To understand drives to upper airway muscles, we recorded single motor unit activity from genioglossus in male groups of control (n= 7, 7 ± 2 events h−1) and severe OSA (n= 9, 54 ± 4 events h−1) subjects. One hundred and seventy‐eight genioglossus units were recorded using monopolar electrodes. Subjects were awake, supine and breathing through a nasal mask. The distribution of the six types of motor unit activity in genioglossus (Inspiratory Phasic, Inspiratory Tonic, Expiratory Phasic, Expiratory Tonic, Tonic and Tonic Other) was identical in both groups. Single unit action potentials in OSA were larger in area (by 34%, P < 0.05) and longer in duration (by 23%, P < 0.05). Inspiratory units were recruited earlier in OSA than control subjects. In control subjects, Inspiratory Tonic units peaked earlier than Inspiratory Phasic units, while in OSA subjects, Inspiratory Tonic and Phasic units peaked simultaneously. Onset frequencies did not differ between groups, but the peak discharge frequency for Inspiratory Phasic units was higher in OSA (22 ± 1 Hz) than control subjects (19 ± 1 Hz, P= 0.003), but conversely, the peak discharge frequency of Inspiratory Tonic units was higher in control subjects (28 ± 1 Hz versus 25 ± 1 Hz, P < 0.05). Increased motor unit action potential area indicates that neurogenic changes have occurred in OSA. In addition, the differences in the timing and firing frequency of the inspiratory classes of genioglossus motor units indicate that the output of the hypoglossal nucleus may have changed.

Panic Attacks and Perception of Inspiratory Resistive Loads in Chronic Obstructive Pulmonary Disease

RATIONALE Panic attacks are common in chronic obstructive pulmonary disease (COPD), and the prevalence of panic disorder is at least 10 times higher than in the general population. In the current study, we examined resistive load perception in patients with COPD with and without panic attacks. OBJECTIVES We tested competing hypotheses, based on conflicting results of earlier studies, that those patients with COPD with panic attacks or panic disorder would show either heightened or blunted perception of dyspnea as the magnitude of inspiratory resistive loads increased. METHODS We compared 20 patients with COPD with panic attacks or panic disorder, 20 patients without panic, and 20 healthy, age-matched subjects using an inspiratory resistive load-testing protocol. MEASUREMENTS AND MAIN RESULTS We administered a diagnostic interview for panic attacks and panic disorder. We measured perceived dyspnea in response to increasing inspiratory resistive loads (modified Borg scale) and several respiratory variables. Dyspnea ratings increased linearly for all groups as the size of resistive loads increased. No significant differences were found between groups on the respiratory variables. Patients with COPD with panic attacks or panic disorder rated their level of dyspnea significantly higher than did other subjects. CONCLUSIONS Patients with COPD with panic attacks showed heightened sensitivity to inspiratory loads. The result reinforces the influence of psychological factors on symptom perception in this disease.

Activation of the human diaphragm during maximal static efforts.

Voluntary activation of the human diaphragm was assessed in four subjects by interpolation of supramaximal stimuli (one to four shocks, interstimulus interval 20 ms) to one phrenic nerve during graded static inspiratory and expulsive efforts at functional residual capacity. There was an inverse relationship between the size of the voluntarily generated pressure and the size of the electrically evoked change in pressure. Each subject activated the diaphragm fully during brief (2‐5 s) maximal inspiratory and expulsive efforts, as judged by the failure of supramaximal stimuli to augment the voluntarily maintained pressure. During prolonged inspiratory efforts or following fatigue of the diaphragm produced by a sustained contraction each subject was able to activate the diaphragm maximally but did not do so on all occasions.

Discharge properties and recruitment of human diaphragmatic motor units during voluntary inspiratory tasks

1 The behaviour of inspiratory motoneurones is poorly understood in humans and even for limb muscles there are few studies of motoneurone behaviour under concentric conditions. The current study assessed the discharge properties of the human phrenic motoneurones during a range of non‐isometric voluntary contractions. 2 We recorded activity from 60 motor units in the costal diaphragm of four subjects using an intramuscular electrode while subjects performed a set of voluntary inspiratory contractions. These included a range of inspiratory efforts above and below the usual tidal range: breaths of different sizes (5‐40 % vital capacity, VC) at a constant inspiratory flow (5 % VC s−1) and breaths of a constant size (20 % VC) at different inspiratory flows (2.5‐20 % VC s−1). 3 For all the voluntary tasks, motor units were recruited throughout inspiration. For the various tasks, half‐way through inspiration, 61‐87 % of the sampled motor units had been recruited. 4 When the inspiratory task was deliberately altered, most single motor units began their discharge at a particular volume even when the rate of contraction had altered. 5 The initial firing frequency (median, 6.5 Hz) was consistent for tasks with a constant flow regardless of the size of the breath. However, for breaths of a constant size the initial firing frequencies increased as the inspiratory flow increased (range across tasks, 4.8‐9.3 Hz). The ‘final’ firing frequency at the end of inspiration increased significantly above the initial frequency for each task (by 0.8‐5.2 Hz) and was higher for those tasks with higher final lung volumes and higher inspiratory flows (range across tasks, 7.8‐11.0 Hz). 6 There was no correlation within a task between the time of recruitment and the initial or final firing frequency for each motor unit. However, for each inspiratory task, initial and final firing frequencies were positively correlated. 7 Because the discharge of three to four units could be recorded simultaneously in a range of tasks, a quantitative ‘shuffle’ index was developed to describe changes in their recruitment order. Recruitment order was invariant in the task with the slowest inspiratory flow, but varied slightly, but significantly, in tasks with higher inspiratory flows. 8 The discharge rates of single motor units were compared for targeted voluntary breaths and non‐targeted involuntary breaths which were matched for size. There were no significant differences in the initial or final firing frequencies, but recruitment order was not always the same in the two types of breath.