% of the stimulated elbow flexors compared with % of the. efforts, %) than for the limb muscle ( %, P < 0-01).

Transcription

1 Journal of Physiology (1992), 454, pp With 7 figures Printed in Great Britain CENTRAL AND PERIPHERAL FATIGUE OF HUMAN DIAPHRAGM AND LIMB MUSCLES ASSESSED BY TWITCH INTERPOLATION BY D. K. McKENZIE, B. BIGLAND-RITCHIE*, R. B. GORMAN AND S. C. GANDEVIA From the Departments of Respiratory Medicine and Clinical Neurophysiology, The Prince Henry and Prince of Wales Hospitals and Prince of Wales Medical Research Institute, Faculty of Medicine, University of New South Wales, Sydney, Australia (Received 10 September 1991) SUMMARY 1. This study used a sensitive modification of the twitch interpolation technique to compare the extent of voluntary neural drive to the diaphragm and the elbow flexors during fatigue. For the diaphragm both inspiratory and expulsive efforts were tested, and fatigue was induced by expulsive efforts which were either maximal voluntary contractions (MVCs, 10s duration, 50 % duty cycle) or submaximal contractions (50% MVC, 3 s duration, 60 % duty cycle). 2. Over the series of thirty MVCs peak elbow torque declined to '0 % (mean+ S.E.M.) of the initial value while maximal inspiratory pressure declined to 78X % (P < 0-05). For the diaphragm the relative decline in voluntary peak inspiratory (and expulsive) force was similar to the decline in twitch responses to single and twin (10 ms interval) stimuli. However, for the elbow flexors the decline in twitch force was disproportionately greater than the decline in maximal voluntary force. The decline in twitch force for the diaphragm could not be attributed to failure at the neuromuscular junction. 3. At the start of the exercise, twitch potentiation (following three brief MVCs) was significantly less for the diaphragm than for the elbow flexors (20 % versus 61 %, P <0-01). 4. In the unfatigued state maximal voluntary efforts by subjects activated % of the stimulated elbow flexors compared with % of the diaphragm (P < 0 05). During the exercise period there was a progressive failure in the ability to activate the limb muscle ('central fatigue'; voluntary drive declined from to %, P < 0-01) whereas the decline in voluntary activation during inspiratory contractions was not significant (from to %). 5. Voluntary activation during attempted maximal efforts was less complete for both muscles when stimuli were delivered without warning. The index of voluntary activation for unwarned stimuli was lower for the diaphragm (performing expulsive efforts, %) than for the limb muscle ( %, P < 0-01). 6. During repeated submaximal expulsive efforts we confirmed that subjects * Usual address: John B. Pierce Laboratory, 290 Congress Avenue, New Haven, CT 06519, USA. MS 9721

2 644 D. K. McKENZIE AND OTHERS develop a marked inability to contract the diaphragm voluntarily, but when the diaphragm performed inspiratory manoeuvres at the same level of contractile fatigue, the index of voluntary drive was greater than 94%. 7. In conclusion, when tested with inspiratory efforts the diaphragm developed less central fatigue than the limb muscle over the same exercise period. However, substantial central fatigue of the diaphragm does develop during prolonged series of expulsive contractions which markedly elevates abdominal pressure. INTRODUCTION Diaphragmatic fatigue may contribute to the development of ventilatory failure, particularly in patients with severe pulmonary disease and it can be produced experimentally with respiratory loads (e.g. Bellemare & Grassino, 1982). Previous studies have shown that the diaphragm is more resistant to the development of fatigue than the elbow flexors during series of maximal static voluntary contractions (MVCs; Gandevia, McKenzie & Neering, 1983; McKenzie & Gandevia, 1991) and more resistant to fatigue than the quadriceps but not soleus during submaximal efforts (Bigland-Ritchie, Furbush & Woods, 1986; Bellemare & Bigland-Ritchie, 1987; V0llestad, Sejersted, Bahr, Woods & Bigland-Ritchie, 1988). Fatigue is defined here as any reduction of the maximal force output of the muscle regardless of whether it is caused by peripheral contractile fatigue or by a progressive failure of voluntary neural drive ('central fatigue'). This difference between the diaphragm and limb muscles could not be accounted for by a difference in the extent of voluntary activation of the unfatigued muscles. Using the technique of twitch interpolation (a twitch superimposed on a voluntary contraction), it has been documented that cooperative subjects are capable of almost complete voluntary activation of most limb muscles including the elbow flexors (Merton, 1954; Belanger & McComas, 1981; Bellemare, Woods, Johansson & Bigland-Ritchie, 1983; Gandevia & McKenzie, 1988a). Several techniques have been used to document that healthy subjects are also capable of almost complete voluntary activation of the unfatigued diaphragm during both static inspiratory and expulsive manoeuvres (Bellemare & Bigland- Ritchie, 1984; Gandevia & McKenzie, 1985; Gandevia, McKenzie & Plassman, 1990). Diaphragmatic endurance is impaired during manoeuvres which elevate abdominal pressure (P.b), with the final sustainable force (relative to initial force) after a series of maximal expulsive efforts below that for inspiratory efforts (without elevation of Pab) but above that for elbow flexors (Gandevia & McKenzie, 1988 b). The variation in diaphragmatic endurance was attributed to an impairment of diaphragmatic perfusion by the large positive Pab developed during expulsive manoeuvres (see also Buchler, Magder, Katsardis, Jammes & Roussos, 1985; Decramer, Jiang & Reid, 1990). From a limited number of observations Gandevia & McKenzie (1988b) claimed that little central fatigue occurred during these series of attempted maximal expulsive efforts performed with a 50 % duty cycle for 6 min. By contrast, Bigland- Ritchie and colleagues (Bellemare & Bigland-Ritchie, 1987) reported that intermittent submaximal voluntary expulsive contraction of the diaphragm continued for min (50 % MVC; 60% duty cycle) reduced maximal force by approximately 50 % with about half of this decline due to a loss of central activation. The

3 CEN.TTRAL FATIGUE IN HUMAN DIAPHRAGM discrepancy between the studies may reflect differences in the duration of the exercise and the way the expulsive manoeuvre was performed. The present study sought to determine whether central fatigue would develop over a similar time course for the diaphragm and elbow flexors when tested under comparable conditions. Secondly, we examined whether central fatigue of the diaphragm was task dependent, being more marked for expulsive than inspiratory efforts. Preliminary results have been published as an abstract (McKenzie, Bigland- Ritchie, Gorman & Gandevia, 1990). 645 METHODS Experiments were performed on four healthy male subjects (age years). All subjects were familiar with performing maximal voluntary efforts of respiratory and limb muscles but only two were aware of the hypotheses being tested. All procedures were approved by the institutional ethics committee and informed consent was obtained. Studies of diaphragmatic and limb muscle endurance were performed on separate days. Limb muscle studies Maximal contractions of the elbow flexors were performed with the subject seated at a table and the fully supinated right forearm fixed to a vertical isometric myograph with the elbow flexed at 90 deg (see Gandevia & McKenzie, 1988a for details). Electrodes (8 mm x 8 mm, foil wrapped in gauze. soaked in saline and covered with electrode paste) were taped over the motor point of biceps brachii and the distal biceps tendon. This electrode arrangement is stable for more than 2 h (McKenzie & Gandevia. 1991). The voltage required for a single electrical stimulus (100,us duration) to elicit a threshold and a maximal response from the relaxed, rested muscle was determined and increased 15-20% above maximal for the remainder of the experiment (voltage range: V). Torque was monitored continuously and displayed to the subject on an array of light emitting diodes. During maximal efforts the subject was continually and loudly exhorted to keep as many lights illuminated as possible. However, the input gain to the device was changed between contractions to remove feedback about how much the absolute force had declined. For both the limb and respiratory muscles subjects performed four sequences of 'test' contractions alternating with three 'fatigue' sequences (Fig. 1). This protocol was performed on two separate days for the limb muscle and once for the respiratory muscles. A ssessment of voluntary activation The 'test' sequence consisted of three brief (3-5 s) MVCs with interpolation of twin stimuli at maximal voluntary force levels to assess the degree of voluntary activation. As shown in Fig. 2, the small time-locked fluctuations of force evoked by the stimuli were captured and amplified 10 times for analysis (see Hales & Gandevia. 1988; Gandevia et al. 1990). Resting twitches of the relaxed muscle were obtained immediately after the maximal efforts which 'potentiated' the responses. Single and twin stimuli (10 ms interval) were delivered (Fig. 1). The degree to which voluntary effort failed to activate the (stimulated) muscle was quantified as the ratio of the twitch response (to twin stimuli) during maximal effort to the potentiated twitch response (to twin stimuli) obtained from the relaxed muscle immediately after (Fig. 2). This was expressed as a percentage, subtracted from 100%, and referred to as the 'voluntary activation index'. The three values obtained in each test sequence were retained for analysis of group data. Each 'fatigue' sequence consisted of ten MVCs of 10 s duration separated by rest intervals of 10 s (50 % dutv cycle). Voluntary activation was assessed using twitch interpolation with twin stimuli (see above) but delivered without warning during one of the first four ('early') and one of the last four ('late') contractions. After the 5th contraction in each sequence the potentiated resting twitch response to twin stimuli was measured (Fig. 1). The values for voluntary activation from the early and late measurement in each sequence were averaged for analysis of group data. The time between the sequences to allow completion of the 'test' measurements was about 50 s.

4 646 D. K. McKENZIE AND OTHERS r,i I Fatigue 1 10 s Fatigue 2... Fig. 1. Experimental protocol for both respiratory and limb studies consisted of four 'test' sequences alternating with three 'fatigue' sequences. Each 'test' sequence consisted of three brief maximal voluntary contractions (MVCs) with interpolation of supramaximal electrical stimulation (twin stimuli, at double arrows). Immediately after these contractions the potentiated twitch response of the muscle to single and twin (10 ms interval) stimuli were obtained (at arrows). Each fatigue sequence consisted of ten MVCs (1O s duration, 50% duty cycle) with interpolated stimuli delivered during an early contraction, and a late one. The relaxed response to twin stimuli was obtained after the 5th contraction in each fatigue sequence to enable calculation of the index of voluntary activation. For the respiratory experiment 'test' MVCs were Mueller manoeuvres and 'fatigue' MVCs were expulsive manoeuvres (glottis open). Diaphragm Limb 110 cmh20 I6 Nm 4# \\ lo\100ms Ms Fig. 2. Measurement of interpolated twitches during two attempted MVCs of diaphragm (left traces) and elbow flexors (right traces) was made at high gain (usually x 10 but shown here x 5) and the amplitude compared with the response of relaxed muscle. All responses are to twin supramaximal stimuli (at arrows; interstimulus interval 10 ms). For each muscle one of the attempted MVCs shows a small response to stimulation while in the other there was no discernible evoked increase in force or pressure (i.e. the effort was maximal). Respiratory muscle protocol An identical protocol was used to test the diaphragm except that maximal inspiratory efforts (Mueller manoeuvres) were used for the brief 'test' contractions while maximal expulsive efforts with glottis open were used during the 'fatigue' sequences because they produce greater contractile failure than pure inspiratory efforts (Gandevia & McKenzie, 1988b).

5 CENTRAL FATIGUE IN HUMAN DIAPHRAGM 647 The phrenic nerves were stimulated bilaterally with single and twin pulses (200 Its duration) via stainless-steel hook-wire electrodes (75 4um diameter, bared of insulation for 1-2 mm) introduced via 25 gauge hypodermic needles (20 mm length) at the level of the cricoid cartilage posterior to sternocleidomastoid (Hubmayr, Litchy, Gay & Nelson, 1989). The anodes were similar wires A EMG Left Pd, Right 320 cmh20 10 ms 50 ms B 150- G1) a ) 1C No I Test Test Test Test Fig. 3. A, EMG (left traces) and twitch responses of relaxed diaphragm (Pdi, right traces) to single stimuli (above) and twin stimuli (below) obtained during the four 'test' sequences in a typical study (see Fig. 1). EMG responses of left and right costal diaphragm were obtained with surface electrodes. Note the decline in twitch amplitude following each fatigue sequence. The smallest EMG responses were obtained during the first test prior to development of fatigue. Vertical calibration for EMG 1 mv. B, amplitude of compound muscle action potentials recorded from the hemidiaphragm during relaxation after each test sequence to a single stimulus. Pooled data from four experiments, normalized to value from first test (mean + S.E.M.). Data shown for the amplitude of the negative phase of the compound action potential (l) and the peak-to-peak amplitude (0). I inserted subcutaneously at the same level, but anterior to sternocleidomastoid. Maximal responses were generally obtained at stimulus intensities of V, then increased 20-50% for the experiment.

6 648 D. K. McKENZIE AND OTHERS Electromyographic activity (EMIG) of the diaphragm was recorded bilaterally from surface electrodes placed over the 6th or 7th costal interspaces in the midelavicular line with the indifferent electrodes 5 cm inferior (Figs 3 and 4). Diaphragmatic EAIG was also recorded from electrodes placed on a multi-lumen gastro-oesophageal catheter which also recorded oesophageal, gastric and Test Left Right 2 4 J 10 ms Fig. 4. EMG responses of left and right hemidiaphragms to twin stimuli delivered (at arrows) during two of the MVINCs from each of four test sequences in a representative subject. Conditions for stimulation and recording remained stable. Vertical calibration 1 mv. transdiaphragmatic pressures (P.,,, Pga or P,, and PI) via respiratory balloons inflated to 10 and 2 0 ml respectively (McKenzie & Gandevia. 1985). Mouth pressure (Pm) was recorded proximal to via an x-y display. a manually operated shutter. Subjects received visual feedback of Pga and P.,, They were instructed to maintain Pga close to baseline during maximal inspiratory efforts and to monitor P.,5 during expulsive efforts to avoid glottic closure. All manoeuvres began after inspiration to total lung capacity and expiration to the usual endexpiratory level. In some studies linearized magnetometers were used to provide an index of diaphragmatic length. The signal was displayed to the subject on a separate oscilloscope at high gain around the usual end-expiratory position. Submaximal expulsite efforts A modification of the protocol used by Bellemare & Bigland-Ritchie (1987) was tested in two subjects to determine whether peripheral fatigue induced by submaximal expulsive efforts would result in the same voluntary activation of the diaphragm for maximal inspiratory and expulsive efforts. Using visual feedback of PoeS and Pga subjects repeatedly generated PJi values of 50% maximum during static expulsive efforts (glottis open: Pga approximated PdI). each held for 3 s with 2 s rest (60% duty cycle). The timing and target Pga for one complete cycle were marked on an oscilloscope. This pattern was continued for about 10 min beyond the endurance time (i.e. when the target Pga could no longer be sustained throughout several successive contractions). At intervals of 1-2 min, single supramaximal stimuli were delivered to both phrenic nerves during and between the expulsive efforts. In the 10 min beyond the endurance time a series of about ten brief maximal inspiratory efforts with interpolation of bilateral phrenic stimuli were interspersed among the standard expulsive efforts of the protocol. Data analysis and statistics Force and pressure signals were monitored on a digital oscilloscope equipped with cursors and separately analysed on-line with software for measuring twitch profiles (Hales. Gorman. Gandevia & McKenzie, 1991). A computer sampled torque (or three pressure signals) at 50 Hz, together with

7 CENTRAL FATIGUE IN HUMAN DIAPHRAGM amplified (x 10; stimulus-triggered) force (or PI) signals offset to zero at 1000 Hz (Hales & Gandevia, 1988). The computer displayed the peak and average sustained force (or pressure) achieved during each contraction, and the force at the time any stimulus was delivered. The amplitude of the evoked twitch, the time-to-peak and half-relaxation time were also measured. All twitch profiles (whether resting or superimposed on voluntary effort) were subsequently recalled for visual inspection to check computer-derived measurements. Data were also recorded on FM tape (DC-1 25 khz) for off-line review and EMG analysis. Unless stated otherwise, the mean value and the standard deviation of the mean are reported. Student's t tests and analyses of variance were used to compare results between the muscle groups and between diaphragmatic manoeuvres. 649 RESULTS Control values (unfatigued) Maximal voluntary torque of the elbow flexors (mean + S.D.) was Nm (range 50 to 89). Maximal static inspiratory efforts resulted in a mouth pressure (Pm) of cmh2o (range -120 to -151) and a maximal Pdi of cmh2o (range 119 to 212). During maximal expulsive efforts (with the glottis open), gastric pressure (Pga' which in this manoeuvre approximates Pdi) was cmh2o (range 195 to 242). The twitches elicited from relaxed, rested muscle in response to single and twin stimuli are listed in Table 1 together with the responses potentiated by the first sequence of 'test' contractions. Potentiation was greater in all subjects for the elbow flexors ( %) than the diaphragm ( %; P < 0-0 1). The sensitivity of the twitch interpolation technique depends in part on the ratio of the amplitudes of the control (relaxed, potentiated) response and the MVC. This was 26 % for the elbow flexors and 22 % for the diaphragm (in expulsive efforts). Peripheral fatigue during attempted maximal efforts The decline in force-generating capacity of the diaphragm is illustrated for a representative subject in Fig. 3A which shows the force and EMG responses to single and twin stimuli applied during each of the four test sequences. These records, and those of Fig. 4 also illustrate the stability of the phrenic nerve stimulation and EMG recording. Throughout each study there was no decline in amplitude of compound muscle action potentials recorded at rest or during attempted maximal efforts. Indeed, the amplitude of compound potentials obtained at rest increased by % in each subject during the experiment (Fig. 3B), as reported for limb muscles by Hicks, Fenton, Garner & McComas (1989). This indicates that failure of transmission at the neuromuscular junction does not underlie the progressive reduction in twitch force observed in these studies. During the series of thirty maximal voluntary contractions peak elbow torque declined to '0 % (mean + S.E.M.) of the initial value, while the maximal inspiratory pressure declined to % (P < 0'05). The relative decline over the sequence of contractions in the average force sustained during each contraction was slightly greater than that for peak force, especially for the diaphragm performing expulsive efforts (Fig. 5). Figure 6 compares the changes with time for respiratory data (A) and data from the elbow flexors (B). For the elbow flexors there was relatively greater decline in twitch amplitude than in maximal voluntary force especially for single stimuli (see also Edwards, Hill, Jones & Merton, 1977), whereas

8 650 D. K. McKENZIE AND OTHERS 100 Peak 100-0* Average E E x O 0 UL Contraction number Contraction number Fig. 5. Pooled data for four subjects showing decline in relative peak force (left panel) and average force sustained for 10 s (right panel) during three fatigue sequences of ten MVCs (mean + S.E.M.). Data shown for elbow flexors (limb, *, eight experiments) and diaphragm (0 four experiments). Note the slight recovery at the second and third 'fatigue' sequence due to the intervening test sequence (see Fig. 1). Relative force was better sustained by the diaphragm. TABLE 1. Amplitude (Nm or cmh2o) Time to peak (ms) Half-relaxation time (Ms) Control data for twitch responses in the elbow flexors and diaphragm Elbow flexors Diaphragm Single stimulus Resting Potentiated (3 6) (4.1) (4 0) (6 2) (13-6) (9 9) Twin stimulus Potentiated 17-5 (8-3) 723 (9-7) 73.3 (15 2) Single stimulus Potentiated Resting (4-5) (7-3) 118 (14.2) 102 (15-8) 111 (92) 78-0 (9-2) Twin stimulus Potentiated 45-0 (10-7) 114 (22) 70-7 (84) All values are means, with numbers in parentheses representing one standard deviation. Amplitude in Nm for elbow flexors and in cmh20 for diaphragm (Pd,). Twitch responses of relaxed muscle either 'rested' or potentiated by the three brief maximal contractions of the first test sequence. Responses evoked by single stimuli or twin stimuli (10 ms interstimulus interval) are shown. Time to peak is taken from the onset of force production. all measures of diaphragm peak force declined at a similar rate. Throughout the exercise there was a smaller decline in all measures of force for the diaphragm than the elbow flexors. Central fatigue The extent to which the decline in voluntary force reflected failure of voluntary neural drive was assessed by twitch interpolation (twin stimuli, 10 ms apart) during each maximal effort of the test sequences and also early and late during each fatigue

9 CENTRAL FATIGUE IN HUMAN DIAPHRAGM sequence. In control measurements before exercise, the mean 'voluntary activation index' (i.e. based on the ratio of the twitch force evoked during 'maximal' voluntary efforts to the control potentiated twitch; see Methods) was less for the diaphragm (95 0 %) than the elbow flexors (98A4 %, P < 005). For the elbow flexors the index of 651 A T B a j g- ' x E - 40 Insp. MVC 400 * Expul. MVC omvc a X 20 *DS 20 *DS SS Diaphragm a SS Limb 0 I I I I I I I 0 J I Test 1 F1 Test 2 F2 Test 3 F3 Test 4 Test 1 F1 Test 2 F Test 3 F3 Test 4 Fig. 6. A, indices of contractile failure of the diaphragm during the four 'test' and three 'fatigue' (F) sequences. The relative decline in force was similar for inspiratory MVC (insp. MVC; test only, 0), expulsive MVC (expul. MVC; fatigue only, *), and the resting response to twin stimuli (DS, *) and single stimulus (SS, EJ). All data have been normalized to the highest values in each study and then pooled. B, indices of contractile failure of the elbow flexors (limb) during the four test and three fatigue sequences. The relative decline in force was greatest for the single stimulus (SS, LJ), intermediate for the twin stimuli (DS, *) and least for MVCs. Both voluntary forces and those evoked by stimulation declined more for the elbow flexors than the diaphragm. voluntary activation decreased progressively during the test sequences from 98' % (mean + S.E.M.) prior to the first fatigue sequence to % after the third fatigue sequence (P < 0.01, Fig. 7). However, for the inspiratory test manoeuvres this index did not decrease significantly (from to %, Fig. 7). There was a significant decline in the voluntary activation over the four test sequences in three of the four subjects for the limb muscle (6 of 8 experiments, P < 0.05, assessed by linear correlation). In no subject did a significant decrease occur for the diaphragm. There was no trend for the ability to activate either muscle to improve during any set of three test contractions although there was some recovery of voluntary force from one fatigue sequence to the next (Fig. 5). Voluntary drive was less for both muscles (compared with test contractions) when the stimuli were delivered without warning early and late within each sequence of fatiguing contractions (Fig. 7). In these sequences voluntary activation was significantly less for the diaphragm (performing expulsive efforts) than the limb muscle. For all unwarned stimuli the index of voluntary drive was % for elbow flexors and % for the diaphragm (P < 0-01). The index decreased progressively over the three fatigue sequences but this was statistically significant only for the elbow flexors (3-factor ANOVA).

10 652 D. K. McKENZIE AND OTHERS Figure 7 also shows mean results for the subject who demonstrated the best overall ability to activate both muscles. This subject was able to activate the fatigued elbow flexors fully in all test sequences and in the final fatigue sequence. Full activation of the fatigued diaphragm was possible only during inspiratory (test) contractions. 100 o a * 0 t90 E Diaphragm 70 (inspiration) FaTest1 Test 2 Test 3 Test U80,- 75-0~~~~~~ Diaphragm 70 - (expulsion) Fatigue 1 Fatigue 2 Fatigue 3 Fig. 7. Index of voluntary activation (group data, see Methods) for the diaphragm and the limb muscle during the four test sequences (above) and the three fatigue sequences (below). Data for the 'best' subject indicated for limb muscle (S) and diaphragm (0). Means for all trials in each test and fatigue sequence shown. Diaphragm tested with maximal inspiratory manoeuvres during test MVCs and expulsive manoeuvres during fatigue MVCs. Note the gradual reduction in voluntary drive with time and the reduced activation during the fatigue sequence, especially for diaphragm (expulsive manoeuvre). Among the group of subjects, the highest individual activation index for the diaphragm performing expulsive efforts in the final fatigue sequence was 97 %, with all other values below 90 %. Diaphragm fatigue induced by submaximal expulsive efforts In three experiments, two subjects repeatedly produced Pdi values of 50 % maximum with static expulsive efforts (glottis open) of 3 s duration with 2 s rest intervals. At the limit for endurance, reached after min, all efforts were 'maximal' in that neither subject could sustain the target pressure throughout successive contractions. The protocol was then continued for a further 10 min with repeated 'maximal' expulsive efforts. In all three experiments superimposed twitches were still clearly visible in all expulsive contractions made at the limit of endurance. At that time their amplitudes were 35-50% of a relaxed twitch. That significant contractile failure occurred prior to the endurance time was indicated by the decline

11 CENTRAL FATIGUE IN HUMAN DIAPHRAGM in the potentiated relaxed twitch amplitude to about 67 % of the initial value (range for a number of twitches in two subjects: %). These results are quantitatively similar to those obtained by Bellemare & Bigland-Ritchie (1987) using a similar protocol. The activation index for the expulsive efforts decreased substantially (from 92 % in the control period to 61 %; mean of all measurements in both subjects). During the ensuing 10 min the amplitude of twitches elicited from relaxed muscle increased somewhat, in spite of continuing 'maximal' effort, presumably reflecting some recovery of the peripheral contractile mechanism (see also Bellemare & Bigland-Ritchie, 1987). Voluntary activation was also tested during a number of brief maximal inspiratory and expulsive efforts (i.e. 'test' contractions as above) performed in the control period and after the endurance time was reached. By contrast with the results for expulsive efforts, there was a much smaller decline in activation for inspiratory efforts (from 975 to 940%). 653 DISCUSSION The present study indicates several differences in peripheral fatigue mechanisms between the diaphragm and the elbow flexors tested under identical conditions. First, twitch forces of the diaphragm declined less than those of the elbow flexors. None of the peripheral diaphragmatic fatigue could be attributed to a progressive impairment of neuromuscular transmission because there was pseudofacilitation rather than a decline in the amplitude of compound muscle action potentials (Hicks et al. 1989; cf. Aldrich, 1987). Second, the decline in the twitch amplitude of the elbow flexors was relatively greater than that for maximal voluntary force (i.e. 'lowfrequency fatigue', see Edwards et al. 1977) but this phenomenon was very small for the diaphragm. Finally, the diaphragm showed less twitch potentiation following a series of maximal voluntary efforts (Table 1). These differences probably reflect specialization of diaphragm muscle fibres. Other major findings relate to voluntary neural drive which declines significantly for the diaphragm during expulsive efforts (Bellemare & Bigland-Ritchie, 1987; confirmed here) but not for inspiratory efforts. Some possible reasons for this will be considered below together with a critique of the methods used to assess voluntary activation for the two muscle groups. Although the technique of twitch interpolation has been used since 1954 (Merton, 1954) its sensitivity has been questioned, particularly for the diaphragm due to compliance of the chest wall (e.g. Hershenson, Kikuchi & Loring, 1988; see also Bellemare & Bigland-Ritchie, 1987). To make this study feasible we addressed potential problems with the method including: (i) maintenance of a maximal stimulus; (ii) detection of small evoked twitches superimposed on the high background force; and (iii) changes in the mechanical properties of muscle with fatigue. First, because maintenance of maximal phrenic nerve stimulation is difficult during strong inspiratory efforts when the accessory muscles in the neck contract, hook-wire electrodes were used in the present study. The amplitude of compound muscle action potentials (Figs 3 and 4) and the stimulus thresholds for minimal and maximal compound potentials did not change by more than 10 % over the course of any experiment. Second, detection of small twitches superimposed on the

12 654 D. K. McKENZIE AND OTHERS physiological 'noise' of the force trace was enhanced using a sample-and-hold amplifier (Hales & Gandevia, 1988) and computer-aided measurement of the timelocked increments in force or pressure (Hales et al. 1991). Increments in force of less than 1 % of the control twitch response could be detected reliably. A recent study indicates that compliance of the chest wall cannot explain the extinction of superimposed diaphragmatic twitches during maximal respiratory manoeuvres (Gandevia, Gorman, McKenzie & Southon, 1991). Third, because the twitch response to a single stimulus declines disproportionately after fatigue compared with the tetanic response or maximal voluntary force (e.g. Edwards et al. 1977; Bigland- Ritchie et al. 1986), twin stimuli (10 ms interval) were used. The diaphragm did not show this 'low-frequency' fatigue. Failure of activation and central fatigue The present study has documented for the first time that the unfatigued diaphragm is significantly more difficult to activate fully than the elbow flexors. This may represent a difference in voluntary control between limb muscles and the partly involuntary respiratory muscles or it may simply reflect the fact that maximal efforts of the diaphragm are rarely required in everyday activities. Recent studies of limb muscles, involving prolonged sequences of intermittent maximal or submaximal static contractions, have documented some central fatigue even in well-motivated subjects (e.g. Bigland-Ritchie et al. 1986; Thomas, Woods & Bigland-Ritchie, 1989; Lloyd, Gandevia & Hales, 1991; McKenzie & Gandevia, 1991). In one study, the extent of central fatigue did not appear to be related to duty cycle (McKenzie & Gandevia, 1991). The present study confirms for the elbow flexors that central fatigue develops in most subjects during exercise lasting min even when subjects knew that interpolated shocks would be delivered during the brief test MVCs. In addition, we formally documented that central fatigue is more prominent when stimuli are delivered without warning, in spite of the provision of auditory and visual feedback. When the diaphragm performed a primarily inspiratory task an insignificant decline in voluntary activation occurred with fatigue. By contrast, when performing expulsive contractions, the degree of central fatigue (measured with unwarned stimuli) was almost twice that observed for the elbow flexors at any time during the maximal exercise. Central fatigue also developed during submaximal expulsive contractions and was quantitatively similar to that reported by Bellemare & Bigland-Ritchie (1987). The ability to activate the diaphragm voluntarily during fatiguing contractions is thus task dependent, with voluntary drive more easily maintained during inspiratory than expulsive efforts. The present comparison of central fatigue for the diaphragm and limb muscles is limited because the diaphragm is resistant to development of contractile fatigue and the duration of exercise was not extended for the diaphragm to allow a comparable decline in force. Thus our conclusions about differences in central fatigue between the diaphragm and elbow flexors refer to comparisons made at the same times within the exercise period and not at the same level of peripheral contractile failure. More strenuous respiratory tasks would be required to assess this fully. However, it is notable that in the prolonged studies using submaximal contractions, the indices of

13 CENTRAL FATIGUE IN HUMAN DIAPHRAGM voluntary drive for maximal inspiratory efforts decreased by only 3-5 %, while twitch forces had declined by 33 %. The greater central fatigue for expulsive efforts may result from the large positive intra-abdominal pressure which impedes venous return. Inhibitory feedback to motoneurones could be mediated by nociceptive visceral or somatic afferents or even baroreceptors. An alternative hypothesis for the reduction in diaphragmatic activation during expulsive efforts is that substantial contractile fatigue developed in the abdominal muscles. Given that the abdominal muscles and diaphragm act mechanically in series to elevate abdominal pressure it follows that both muscles cannot be fully activated during a 'static' manoeuvre (cf. Hershenson et al. 1988). We have documented that the abdominal muscles are not fully activated during maximal expulsive efforts commenced at the resting end-expiratory level (Gandevia et al. 1990) and that the diaphragm, rather than the abdominal muscles, fatigues during a prolonged static expulsive effort of % of MVC (Gandevia & McKenzie, 1988 b). However, the stronger expulsive manoeuvres studied here required relatively greater activation of abdominal muscles. Thus it is possible that the relatively fatigue-resistant diaphragm eventually matched the pressure-generating capacity of the abdominal muscles. Thereafter, maximal activation of the diaphragm would not have been required in a 'static' manoeuvre. The present studies provide no support for the concept that the diaphragm is especially susceptible to central fatigue when tested with maximal static inspiratory efforts. This study was supported by the National Health and Medical Research Council of Australia, the Asthma Foundation of New South Wales and USPHS Grant HL We are grateful to Professor D. Burke for comments on the manuscript. 655 REFERENCES ALDRICH, T. K. (1987). Transmission fatigue of the rabbit diaphragm. Respiration Physiology 69, BELANGER, A. Y. & MCCOMAS, A. J. (1981). Extent of motor unit activation during effort. Journal of Applied Physiology 51, BELLEMARE, F. & BIGLAND-RITCHIE, B. (1984). Assessment of human diaphragm strength and activation using phrenic nerve stimulation. Respiration Physiology 58, BELLEMARE, F. & BIGLAND-RITCHIE, B. (1987). Central components of diaphragmatic fatigue assessed from bilateral phrenic nerve stimulation. Journal of Applied Physiology 62, BELLEMARE, F. & GRASSINO, A. (1982). Effect of pressure and timing of a contraction on human diaphragm fatigue. Journal of Applied Physiology 53, BELLEMARE, F., WOODS, J. J., JOHANSSON, R. & BIGLAND-RITcHIE, B. (1983). Motor-unit discharge rates in maximal voluntary contractions of three human muscles. Journal of Neurophysiology 50, BIGLAND-RITCHIE, B., FURBUSH, F. & WOODS, J. (1986). Fatigue of intermittent, submaximal voluntary contractions: central and peripheral factors. Journal of Applied Physiology 61, BUCHLER, B., MAGDER, S., KATSARDIS, H., JAMMES, Y. & Roussos, C. (1985). Effects of pleural pressure and abdominal pressure on diaphragmatic blood flow. Journal ofapplied Physiology 58, DECRAMER, M., JIANG, T.-X. & REID, M. B. (1990). Respiratory changes in diaphragmatic intramuscular pressure. Journal of Applied Physiology 68,

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