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Recently, transcranial magnetic stimulation of the motor cortex (TMS) revealed impaired voluntary activation of muscles during maximal efforts. Hence, we evaluated its use as a measure of voluntary activation over a range of contraction strengths in both fresh and fatigued muscles, and compared it with standard twitch interpolation using nerve stimulation. Subjects contracted the elbow flexors isometrically while force and EMG from biceps and triceps were recorded. In one study, eight subjects made submaximal and maximal test contractions with rests to minimise fatigue. In the second study, eight subjects made sustained maximal contractions to reduce force to 60 % of the initial value, followed by brief test contractions. Force responses were recorded following TMS or electrical stimulation of the biceps motor nerve. In other contractions, EMG responses to TMS (motor evoked potentials, MEPs) or to stimulation at the brachial plexus (maximal M waves, Mmax) were recorded. During contractions of 50 % maximum, TMS elicited large MEPs in biceps (> 90 % Mmax) which decreased in size (to ≈70 % Mmax) with maximal efforts. This suggests that faster firing rates made some motor units effectively refractory. With fatigue, MEPs were also smaller but remained > 70 % Mmax for contractions of 50–100 % maximum. For fresh and fatigued muscle, the superimposed twitch evoked by motor nerve and motor cortex stimulation decreased with increasing contraction strength. For nerve stimulation the relation was curvilinear, and for TMS it was linear for contractions of 50-100 % maximum (r2= 1.00). Voluntary activation was derived using the expression: (1 – superimposed twitch/resting twitch) × 100. The resting twitch was measured directly for nerve stimulation and for TMS, it was estimated by extrapolation of the linear regression between the twitch and voluntary force. For cortical stimulation, this resulted in a highly linear relation between voluntary activation and force. Furthermore, the estimated activation corresponded well with contraction strength. Using TMS or nerve stimulation, voluntary activation was high during maximal efforts of fresh muscle. With fatigue, both measures revealed reduced voluntary activation (i.e. central fatigue) during maximal efforts. Measured with TMS, this central fatigue accounted for one-quarter of the fall in maximal voluntary force. We conclude that TMS can quantify voluntary activation for fresh or fatigued muscles at forces of 50–100 % maximum. Unlike standard twitch interpolation of the elbow flexors, voluntary activation measured with TMS varies in proportion to voluntary force, it reveals when extra output is available from the motor cortex to increase force, and it elicits force from all relevant synergist muscles.
The level of neural drive to muscle during exercise is termed voluntary activation (Gandevia et al. 1995) and is commonly estimated by interpolation of a single supramaximal electrical stimulus to the motor nerve during an isometric voluntary contraction (‘twitch interpolation’; Merton, 1954). If extra force is evoked at an appropriate latency by the ‘superimposed’ stimulus then either the stimulated axons were not all recruited voluntarily or they were discharging at sub-tetanic rates. Hence, voluntary activation must have been less than maximal (Merton, 1954; Belanger & McComas, 1981; Herbert & Gandevia, 1999; for review see Gandevia, 2001). To quantify voluntary activation, the amplitude of the superimposed twitch is expressed as a fraction of the twitch evoked by the same stimulus in the potentiated relaxed muscle (Thomas et al. 1989).
The amplitude of the superimposed twitch decreases with increasing voluntary force (e.g. Merton, 1954; Belanger & McComas, 1981; Allen et al. 1998). During brief maximal voluntary contractions (MVCs), the superimposed twitch is small or absent, suggesting that it is possible to drive motoneurones voluntarily to produce maximal force from appropriate muscles (e.g. Belanger & McComas, 1981; McKenzie et al. 1988; Gandevia et al. 1990; Herbert & Gandevia, 1996; Lyons et al. 1996; Thomas et al. 1997; Allen et al. 1998; Behm et al. 2002). Herbert & Gandevia (1999) developed, for adductor pollicis, a realistic model of twitch interpolation which incorporated axonal factors such as refractoriness and antidromic collision. The model revealed a linear relation between voluntary force and the superimposed twitch, and it accurately predicted small superimposed twitches during maximal voluntary efforts. In the elbow flexor muscles, the relationship between the amplitude of the superimposed twitch and voluntary force appears linear until high effort where increases in voluntary force occur with little or no change in size of the superimposed twitch (e.g. Dowling et al. 1994; Allen et al. 1998; De Serres & Enoka, 1998). This non-linearity may be due to differential voluntary activation of the synergistic muscles and lengthening of active muscles at high voluntary forces (Allen et al. 1998). Furthermore, excessive currents used to stimulate nerves to the biceps brachii and brachialis muscles may inadvertently contract antagonist elbow extensor muscles and reduce the superimposed twitch (Awiszus et al. 1997).
Muscle fatigue, the decline in voluntary force during sustained maximal efforts, is caused by both central and peripheral mechanisms (Bigland-Ritchie et al. 1978, 1995; Gandevia et al. 1995). Much of the fatigue arises from processes occurring within the muscle such as disturbances in the excitation-contraction coupling, depletion of muscle glycogen and accumulation of metabolites (for review see Fitts, 1994). These changes reduce the resting muscle twitch. However, during fatiguing exercise, changes in the central nervous system also reduce force output (e.g. Reid, 1928; Bigland-Ritchie et al. 1978; for review see Gandevia, 2001). For instance, during a sustained maximal effort, or a series of brief maximal efforts, the amplitude of the superimposed twitch evoked by motor nerve stimulation progressively increases when expressed relative to the amplitude of the resting muscle twitch evoked by the same stimulus (e.g. Thomas et al. 1989; Lloyd et al. 1991). This decline in voluntary activation in maximal efforts is the hallmark of ‘central fatigue’ (Gandevia et al. 1995). Its development is accompanied by changes within the motor cortex, which increase the size of the motor evoked potential (MEP) and lengthen the EMG silence (‘silent period’) to transcranial magnetic stimulation of the motor cortex (TMS) (Taylor et al. 1996, 1999; for review see Gandevia, 2001).
Stimulation of the motor cortex has also revealed submaximal activation of muscles during maximal voluntary efforts of respiratory muscles (Gandevia et al. 1990) and subsequently of thenar (Herbert & Gandevia, 1996) and elbow extensor muscles (Thomas et al. 1997). It has also revealed central fatigue of the elbow flexor muscles (Gandevia et al. 1996; Taylor et al. 2000). However, quantification of voluntary activation with motor cortical stimulation is difficult. It is inappropriate to normalise the superimposed twitch evoked by TMS to the resting twitch evoked by the same stimulus because the motoneuronal output evoked by the cortical stimulus at rest is not the same as during a contraction. This reflects the increase in motor cortical and motoneuronal ‘excitability’ with activity (Hess et al. 1987; Ugawa et al. 1995; Di Lazzaro et al. 1998; for review see Rothwell et al. 1991).
The present study was designed to compare the superimposed twitches evoked with motor cortical stimulation and motor nerve stimulation across the full range of voluntary force, and uses a new method for normalisation of the superimposed twitch evoked by TMS to quantify voluntary activation. In addition, comparison of the MEP during strong voluntary contractions with its evoked superimposed twitch gives insight into the extent to which motoneurones are driven by volition. With the muscle fatigued, both TMS and motor nerve stimulation demonstrate central fatigue but they provide different information about its cause. Preliminary data has been previously published in abstract form (Russell et al. 2001, 2003).
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The present study has used motor cortical stimulation to define the extent to which the CNS has activated a muscle group across a wide range of contraction strengths. Results with this new method have been compared with those obtained with twitch interpolation which has long been the conventional method to calculate voluntary activation (Merton, 1954; Belanger & McComas, 1981; Thomas et al. 1989; see also Gandevia et al. 1996; Herbert & Gandevia, 1999). Three aspects of the results will be discussed in detail. First, the estimates of voluntary activation obtained with cortical stimulation follow the line of identity when plotted against voluntary force between 50 and 100 % MVC. Second, at 50 % MVC, the MEP evoked by cortical stimulation is near maximal compared to Mmax, and it diminishes progressively as force increases towards 100 % MVC. This finding may provide insight into the extent to which motoneurones are driven by volition. Third, when maximal voluntary force is reduced by 40 % by fatigue, about one-quarter of this reduction is due to a failure to drive the muscle optimally (i.e. central fatigue develops). Both types of stimulation (motor cortex and motor nerve) reveal central fatigue but they provide different information about its causes.
Voluntary activation in the unfatigued muscles
Between 50 and 100 % of maximal effort, voluntary activation increases linearly with increasing voluntary contraction strength when derived using cortical stimulation (see Fig. 6A). This is consistent with the idea that the superimposed twitch evoked by cortical stimulation reflects the ‘extra’ force obtained from motor units that voluntary effort did not recruit or did not discharge at a sufficiently fast rate. To allow direct comparison with results obtained with motor nerve stimulation, we derived the ‘resting twitch’ evoked by cortical stimulation by extrapolation and used this value in the conventional formula for voluntary activation (see Methods and Fig. 2B). This approach seems justified given the strong linear relation between voluntary force and voluntary activation measured with cortical stimulation.
In contrast to motor cortical stimulation, there is a non-linear relationship between voluntary activation estimated by motor nerve stimulation and voluntary force. At high forces, smaller changes in activation occur for a given change in voluntary force. Previous studies have also identified this non-linearity with stimulation over the biceps/brachialis muscles (Allen et al. 1998; see also De Serres & Enoka, 1998). One reason for the non-linearity is that the elbow flexor muscles innervated by the radial nerve (brachioradialis) are less well activated during maximal voluntary efforts (based on twitch interpolation) than those innervated by the musculocutaneous nerve (biceps and brachialis, Allen et al. 1998; for review Gandevia, 2001). Thus, the balance of force generated by the different elbow flexor muscles varies over the range of voluntary forces. In contrast, voluntary activation measured with cortical stimulation reveals the net output from all muscles that generate elbow flexion force. Consistent with this, the size of the superimposed twitch evoked by motor cortical stimulation is more than double that produced by motor nerve stimulation in the studies described here.
During brief efforts at 50 % MVC, the MEP was about the same size as a maximal motor response evoked by peripheral nerve stimulation. This suggests that under these conditions most motoneurones were activated by the motor cortical stimulus. In some contractions, the size of the MEP was slightly greater than Mmax suggesting that some motoneurones may have fired more than once as a result of the motor cortical stimulus. Similar conclusions have been reached for intrinsic muscles of the hand (Merton et al. 1982; Day et al. 1989). At lower voluntary forces, the MEP was much smaller than at 50 % MVC, presumably because of reduced ‘excitability’ at cortical and spinal sites (Kischka et al. 1993; Taylor et al. 1997). At forces above 50 % MVC, the MEP decreased progressively to 77 ± 14 % of Mmax during maximal efforts. As the MEP was normalised to Mmax recorded during a contraction of similar strength, our method accounts for any activity-dependent changes in the muscle fibre action potential (Taylor et al. 1999). Mmax did decrease slightly with increasing force (Fig. 5A), presumably more axons and muscle fibres were refractory as their firing rates increased. Thus, the decrease in MEP size implies a decrease in motoneuronal output in response to the stimulus. We suggest that the reduction reflects the inability of some motoneurones to fire in response to the excitatory input. They may be effectively ‘refractory’ due to intrinsic motoneuronal factors and the trajectory of the after-hyperpolarisation (see Matthews, 1999). Consistent with this we have found that the response to transmastoid stimulation (which activates corticospinal axons) is smaller during maximal than submaximal contractions (J. L. Taylor, J. E. Butler, N. T. Petersen and S. C. Gandevia, unpublished observations).
Although the MEP is reduced above 50 % MVC it is still more than 70 % of Mmax. This implies that many motoneurones are not firing ‘maximally’ during brief maximal efforts because they can fire in response to the synaptic input from the descending corticospinal volleys. Furthermore, the firing rate of motoneurones is not ‘optimal’ because the increased activity brought about by the descending volleys produces a small increase in muscle force.
Behaviour during muscle fatigue
When the elbow flexor muscles were fatigued by prior sustained maximal contractions so that maximal voluntary force dropped by 40 %, there was evidence of peripheral fatigue. The resting twitch evoked by motor nerve stimulation declined. There was also evidence of central fatigue. During brief maximal efforts, motor nerve stimulation evoked larger superimposed twitches than when the muscles were not fatigued. Thus, the ability of subjects to drive the muscle voluntarily was impaired. Increases also occurred in the superimposed twitches evoked by motor cortical stimulation during brief maximal efforts. While this also indicates development of central fatigue, it adds information on the site of impairment within the central nervous system. A larger superimposed twitch after motor nerve stimulation implies that even though the axons of the motoneurones are capable of increased firing rates and the muscle fibres could produce more force, motoneurone firing has slowed, or some motor units have been derecruited (Peters & Fuglevand, 1999). With motor cortical stimulation, the larger superimposed twitch is produced through synaptic activation of the motoneurones and demonstrates that the fall in motoneurone activity is not because the motoneurones are unresponsive to extra input. Motor cortical stimulation does not identify the mechanisms for the decrease in motoneurone activity with fatigue. Such mechanisms include decreased responsiveness of the motoneurones through changes in their intrinsic properties or through inhibitory afferent input, or disfacilitation through decreased excitatory afferent or descending input. Despite this, stimulation of the motor cortex produces extra output and this is sufficient to evoke a MEP, which is similar in size to that in the unfatigued muscle. There is presumably some as yet untapped cortical drive that can increase motoneurone firing and produce additional force. When fatigue had reduced the maximal voluntary force by 40 %, voluntary activation (measured with responses to motor cortical stimulation) fell by 14 % (in absolute terms). If we calculate the force that could have been produced by the fatigued muscle if voluntary activation had not fallen, the difference between the calculated force and the measured force is about 10 % MVC. This indicates that central fatigue accounts for approximately one-quarter of the 40 % fall in maximal voluntary force produced by sustained maximal contractions.
Although unchanged at higher contraction strengths, the size of the MEP in biceps was reduced at 25 and 50 % MVC when the muscle was fatigued. This decrease is difficult to interpret but may be due in part to the lower levels of voluntary activation, and consequent decreased excitability of motor cortical neurones and/or the motoneurones, needed to reach these target forces during fatigue. The activation needed to reach the target forces is low because the targets are set as percentages of a maximal effort in which there is central fatigue and poor voluntary activation. Other mechanisms including changes in the intrinsic properties of motoneurones or alterations in afferent input could also decrease the gain of the motoneurone pool, while a decreased response to stimulation of the motor cortex could also reduce MEP size. In contrast to the current findings, we have previously reported that MEPs in biceps get larger during fatiguing maximal efforts and have attributed this growth to increased cortical excitability (Taylor et al. 1996, 1999). However, the growth of MEPs occurred during sustained contractions and had recovered in brief MVCs performed after 15 s rest. Here, brief MVCs were performed 8 s after sustained MVCs of various durations and this period may be sufficient to allow recovery from any increase in excitability of the motor cortex.
For motor cortical stimulation, the plot of voluntary activation against force production remained linear when the elbow flexors were fatigued so the method of estimation of voluntary activation remained valid, and may remain so for other changes in peripheral force-generating capacity. Thus, a contraction to the target of 50 % of the fatigued MVC has a voluntary activation of approximately half that of a maximal effort. For nerve stimulation with the unfatigued and the fatigued muscles, the curves were also similar in shape. Hence, if there is preferential activation of biceps and brachialis rather than other elbow flexors, this does not appear to be changed by fatigue during maximal contractions. It is superficially attractive to compare the measures of voluntary activation produced by cortical and nerve stimulation, to identify the ‘site’ of failure of voluntary drive. Unfortunately, direct quantitative comparison is problematic because the two types of stimuli can activate different muscles and the shapes of the voluntary activation-voluntary force curves for motor cortical and motor nerve stimulation are different.
Estimation of voluntary activation of the elbow flexor muscles through superimposed twitches evoked by motor cortical stimulation provides a measure which is linearly related to the strength of contraction, whether of unfatigued or fatigued muscles. It can demonstrate central fatigue and shows that, when central fatigue is present after sustained MVCs, it is not due to a lack of responsiveness of the motoneurones to input or to an inability of motor cortical neurones to produce additional output.