Nicolas T. Petersen

The effect of sustained low‐intensity contractions on supraspinal fatigue in human elbow flexor muscles

Subjects quickly fatigue when they perform maximal voluntary contractions (MVCs). Much of the loss of force is from processes within muscle (peripheral fatigue) but some occurs because voluntary activation of the muscle declines (central fatigue). The role of central fatigue during submaximal contractions is not clear. This study investigated whether central fatigue developed during prolonged low‐force voluntary contractions. Subjects (n= 9) held isometric elbow flexions of 15% MVC for 43 min. Voluntary activation was measured during brief MVCs every 3 min. During each MVC, transcranial magnetic stimulation (TMS) was followed by stimulation of either brachial plexus or the motor nerve of biceps brachii. After nerve stimulation, a resting twitch was also evoked before subjects resumed the 15% MVC. Perceived effort, elbow flexion torque and surface EMG from biceps, brachioradialis and triceps were recorded. TMS was also given during the sustained 15% MVC. During the sustained contraction, perceived effort rose from ∼2 to ∼8 (out of 10) while ongoing biceps EMG increased from 6.9 ± 2.1% to 20.0 ± 7.8% of initial maximum. Torque in the brief MVCs and the resting twitch fell to 58.6 ± 14.5 and 58.2 ± 13.2% of control values, respectively. EMG in the MVCs also fell to 62.2 ± 15.3% of initial maximum, and twitches evoked by nerve stimulation and TMS grew progressively. Voluntary activation calculated from these twitches fell from ∼98% to 71.9 ± 38.9 and 76.9 ± 18.3%, respectively. The silent period following TMS lengthened both in the brief MVCs (by ∼40 ms) and in the sustained target contraction (by ∼18 ms). After the end of the sustained contraction, the silent period recovered immediately, voluntary activation and voluntary EMG recovered over several minutes while MVC torque only returned to ∼85% baseline. The resting twitch showed no recovery. Thus, as well as fatigue in the muscle, the prolonged low‐force contraction produced progressive central fatigue, and some of this impairment of the subjects ability to drive the muscle maximally was due to suboptimal output from the motor cortex. Although caused by a low‐force contraction, both the peripheral and central fatigue impaired the production of maximal voluntary force. While central fatigue can only be demonstrated during MVCs, it may have contributed to the disproportionate increase in perceived effort reported during the prolonged low‐force contraction.

Suppression of EMG activity by transcranial magnetic stimulation in human subjects during walking

1 The involvement of the motor cortex during human walking was evaluated using transcranial magnetic stimulation (TMS) of the motor cortex at a variety of intensities. Recordings of EMG activity in tibialis anterior (TA) and soleus muscles during walking were rectified and averaged. 2 TMS of low intensity (below threshold for a motor‐evoked potential, MEP) produced a suppression of ongoing EMG activity during walking. The average latency for this suppression was 40.0 ± 1.0 ms. At slightly higher intensities of stimulation there was a facilitation of the EMG activity with an average latency of 29.5 ± 1.0 ms. As the intensity of the stimulation was increased the facilitation increased in size and eventually a MEP was clear in individual sweeps. 3 In three subjects TMS was replaced by electrical stimulation over the motor cortex. Just below MEP threshold there was a clear facilitation at short latency (≈28 ms). As the intensity of the electrical stimulation was reduced the size of the facilitation decreased until it eventually disappeared. We did not observe a suppression of the EMG activity similar to that produced by TMS in any of the subjects. 4 The present study demonstrates that motoneuronal activity during walking can be suppressed by activation of intracortical inhibitory circuits. This illustrates for the first time that activity in the motor cortex is directly involved in the control of the muscles during human walking.

Impaired response of human motoneurones to corticospinal stimulation after voluntary exercise

1 Activation of descending corticospinal tracts with transmastoid electrical stimuli has been used to assess changes in the behaviour of motoneurones after voluntary contractions. Stimuli were delivered before and after maximal voluntary isometric contractions (MVCs) of the elbow flexor muscles. 2 Following a sustained MVC of the elbow flexors lasting 5–120 s there was an immediate reduction of the response to transmastoid stimulation to about half of the control value. The response recovered to control levels after about 2 min. This was evident even when the size of the responses was adjusted to accommodate changes in the maximal muscle action potential (assessed with supramaximal stimuli at the brachial plexus). 3 To determine whether the post‐contraction depression required activity in descending motor paths, motoneurones were activated by supramaximal tetanic stimulation of the musculocutaneous nerve for 10 s. This did not depress the response to transmastoid stimulation. 4 Following a sustained MVC of 120 s duration, the response to transcranial magnetic stimulation of the motor cortex gradually declined to a minimal level by about 2 min and remained depressed for more than 10 min. 5 Additional studies were performed to check that the activation of descending tracts by transmastoid stimulation was likely to involve excitation of direct corticospinal paths. When magnetic cortical stimuli and transmastoid stimuli were timed appropriately, the response to magnetic cortical stimulation could be largely occluded. 6 This study describes a novel depression of effectiveness of corticospinal actions on human motoneurones. This depression may involve the corticomotoneuronal synapse.

Investigating human motor control by transcranial magnetic stimulation

In this review we discuss the contribution of transcranial magnetic stimulation (TMS) to the understanding of human motor control. Compound motor-evoked potentials (MEPs) may provide valuable information about corticospinal transmission, especially in patients with neurological disorders, but generally do not allow conclusions regarding the details of corticospinal function to be made. Techniques such as poststimulus time histograms (PSTHs) of the discharge of single, voluntarily activated motor units and conditioning of H reflexes provide a more optimal way of evaluating transmission in specific excitatory and inhibitory pathways. Through application of such techniques, several important issues have been clarified. TMS has provided the first real evidence that direct monosynaptic connections from the motor cortex to spinal motoneurons exist in man, and it has been revealed that the distribution of these projections roughly follows the same proximal–distal gradient as in other primates. However, pronounced differences also exist. In particular, the tibialis anterior muscle appears to receive as significant a monosynaptic corticospinal drive as muscles in the hand. The reason for this may be the importance of this muscle in controlling the foot trajectory in the swing phase of walking. Conditioning of H reflexes by TMS has provided evidence of changes in cortical excitability prior to and during various movements. These experiments have generally confirmed information obtained from chronic recording of the activity of corticospinal cells in primates, but information about the corticospinal contribution to movements for which information from other primates is sparse or lacking has also been obtained. One example is walking, where TMS experiments have revealed that the corticospinal tract makes an important contribution to the ongoing EMG activity during treadmill walking. TMS experiments have also documented the convergence of descending corticospinal projections and peripheral afferents on spinal interneurons. Current investigations of the functional significance of this convergence also rely on TMS experiments. The general conclusion from this review is that TMS is a powerful technique in the analysis of motor control, but that care is necessary when interpreting the data. Combining TMS with other techniques such as PSTH and H reflex testing amplifies greatly the power of the technique.

Ischaemia after exercise does not reduce responses of human motoneurones to cortical or corticospinal tract stimulation

1 Motor unit firing rates and voluntary activation of muscle decline during sustained isometric contractions. After exercise, the responses to motor cortical and corticospinal stimulation are reduced. These changes may reflect motoneuronal inhibition mediated by group III and IV muscle afferents. To determine whether the post‐contraction depression of the responses to corticospinal or motor cortical stimulation could be maintained by continued firing of ischaemically sensitive group III and IV muscle afferents, we examined responses in muscles that were held ischaemic after exercise. 2 Following a sustained maximal voluntary contraction (MVC) of the elbow flexors lasting 2 min, the response to stimulation of the corticospinal tract was reduced but the usual recovery (over ∼2 min) was not delayed when the muscles were maintained ischaemic for 2 min after the contraction. 3 Following a sustained MVC, the time course of the reduction in the response to motor cortical stimulation (a gradual decrease over ∼2 min, maintained for > 10 min) was also not altered if the muscle was held ischaemic. 4 Mean arterial blood pressure rose to 155 ± 12 mmHg during the 2 min MVC, declined to 125 ± 9 mmHg immediately after it, but remained at this level without returning to pre‐exercise levels (102 ± 10 mmHg) until circulation to the arm was restored. This confirms that the sustained MVC activated a reflex dependent on group III and IV muscle afferents. 5 This study shows that ischaemically sensitive group III and IV muscle afferents do not mediate depression of responses to motor cortical or corticospinal stimulation after fatiguing exercise. It also suggests that firing of such afferents does not directly inhibit motoneurones or motor cortical output cells.

The effect of a contralateral contraction on maximal voluntary activation and central fatigue in elbow flexor muscles

A long-duration, submaximal contraction of a hand muscle increases central fatigue during a subsequent contraction in the other hand. However, this cross-over of central fatigue between limbs is small and the location within the central nervous system at which this effect occurs is unknown. We investigated this cross-over by measurement of the force and EMG responses to transcranial magnetic stimulation of the motor cortex (TMS). To produce central fatigue, we used sustained maximal voluntary contractions (MVCs). In the first study, subjects (n=10) performed four 1-min sustained MVCs of the elbow flexors, alternating between the left and right arms (two MVCs per arm). The sustained MVCs were performed consecutively with no rest periods. In the second study, the same subjects made two sustained 1-min MVCs with the same arm with a 1-min rest between efforts. During each sustained MVC, a series of TMS and brachial plexus stimuli were delivered. Surface EMG was recorded from biceps brachii and brachioradialis muscles bilaterally. Voluntary activation was estimated during each MVC using measurement of the force increments to TMS. On average during each sustained MVC, voluntary activation declined by 7–12% (absolute change, P<0.001) and voluntary force declined by 35–45% MVC (P<0.001), whereas the cortical motor-evoked potential increased (P<0.001) and the subsequent silent period lengthened (P<0.001). The average voluntary activation and voluntary force were similar during two sustained MVCs performed by the same arm, when separated by 1xa0min of rest. However, when the 1-min rest interval was replaced with a sustained contraction performed by the other arm, the average voluntary activation was 2.9% worse in the second contraction (absolute change, P<0.05), while it did not alter voluntary force production or the EMG responses to TMS. Therefore, in maximal exercise of 4xa0min duration, the cross-over of central fatigue between limbs is small in the elbow flexors and has a minor functional effect. Our data suggest that voluntary drive from the motor cortex is slightly less able to drive the muscle maximally after a fatiguing voluntary contraction on the contralateral side.

The effect of electrical stimulation of the corticospinal tract on motor units of the human biceps brachii

In healthy human subjects, descending motor pathways including the corticospinal tract were stimulated electrically at the level of the cervicomedullary junction to determine the effects on the discharge of motoneurones innervating the biceps brachii. Post‐stimulus time histograms (PSTHs) were constructed for 15 single motor units following electrical stimulation of the corticospinal tract and for 11 units following electrical stimulation of large diameter afferents at the brachial plexus. Responses were assessed during weak voluntary contraction. Both types of stimulation produced a single peak at short latency in the PSTH (mean 8.5 and 8.7 ms, respectively) and of short duration (< 1.4 ms). In separate studies, we compared the latency of the responses to electrical stimulation of the corticospinal tract in the relaxed muscle with that in the contracting muscle. The latency was the same in the two conditions when the intensity of the stimulation was adjusted so that responses of the same size could be compared. Estimates of the descending conduction velocity and measurements of presumed peripheral conduction time suggest that there is less than 0.5 ms for spinal events (including synaptic delays). We propose that in response to electrical stimulation of the descending tract fibres, biceps motoneurones receive a large excitatory input with minimal dispersion and it presumably contains a dominant monosynaptic component.

Interaction of transcranial magnetic stimulation and electrical transmastoid stimulation in human subjects

Transcranial magnetic stimulation activates corticospinal neurones directly and transsynaptically and hence, activates motoneurones and results in a response in the muscle. Transmastoid stimulation results in a similar muscle response through activation of axons in the spinal cord. This study was designed to determine whether the two stimuli activate the same descending axons. Responses to transcranial magnetic stimuli paired with electrical transmastoid stimuli were examined in biceps brachii in human subjects. Twelve interstimulus intervals (ISIs) from −6 ms (magnet before transmastoid) to 5 ms were investigated. When responses to the individual stimuli were set at 10‐15 % of the maximal M‐wave, responses to the paired stimuli were larger than expected at ISIs of −6 and −5 ms but were reduced in size at ISIs of −2 to 1 ms and at 3 to 5 ms. With individual responses of 3‐5 % of maximal M‐wave, facilitation still occurred at ISIs of −6 and −5 ms and depression of the paired response at ISIs of 0, 1, 4 and 5 ms. The interaction of the response to transmastoid stimulation with the multiple descending volleys elicited by magnetic stimulation of the cortex is complex. However, depression of the response to the paired stimuli at short ISIs is consistent with an occlusive interaction in which an antidromic volley evoked by the transmastoid stimulus collides with and annihilates descending action potentials evoked by the transcranial magnetic stimulus. Thus, it is consistent with the two stimuli activating some of the same corticospinal axons.

The nature of corticospinal paths driving human motoneurones during voluntary contractions

The properties of the human motor cortex can be studied non‐invasively using transcranial magnetic stimulation (TMS). Stimulation at high intensity excites corticospinal cells with fast conducting axons that make direct connections to motoneurones of human upper limb muscles, while low‐intensity stimulation can suppress ongoing EMG. To assess whether these cells are used in normal voluntary contractions, we used TMS at very low intensities to suppress the firing of single motor units in biceps brachii (n= 14) and first dorsal interosseous (FDI, n= 6). Their discharge was recorded with intramuscular electrodes and cortical stimulation was delivered at multiple intensities at appropriate times during sustained voluntary firing at ∼10 Hz. For biceps, high‐intensity stimulation produced facilitation at 17.1 ± 2.1 ms (lasting 2.4 ± 0.9 ms), while low‐intensity stimulation (below motor threshold) produced suppression (without facilitation) at 20.2 ± 2.1 ms (lasting 7.6 ± 2.2 ms). For FDI, high‐intensity stimulation produced facilitation at 23.3 ± 1.2 ms (lasting 1.8 ± 0.4 ms), with suppression produced by low‐intensity stimulation at 25.2 ± 2.6 ms (lasting 7.5 ± 2.6 ms). The difference between the onsets of facilitation and suppression was short: 3.1 ± 1.2 ms for biceps and 2.0 ± 1.5 ms for FDI. This latency difference is much less than that previously reported using surface EMG recordings (∼10 ms). These data suggest that low‐intensity cortical stimulation inhibits ongoing activity in fast‐conducting corticospinal axons through an oligosynaptic (possibly disynaptic) path, and that this activity is normally contributing to drive the motoneurones during voluntary contractions.

Presynaptic control of transmission along the pathway mediating disynaptic reciprocal inhibition in the cat

1 In cat lumbar motoneurones, disynaptic inhibitory postsynaptic potentials (IPSPs) evoked by stimulation of antagonist motor nerves were depressed for at least 150 ms following conditioning stimulation of flexor (1.7‐2 times threshold (T)) and ankle extensor (5T) nerves. The aim of the present study was to investigate the possibility that this depression is caused by presynaptic inhibitory mechanisms acting at the terminals of group I afferent fibres projecting to the Ia inhibitory interneurones and/or the terminals of these interneurones to the target motoneurones. 2 Conditioning stimulation of flexor, but not ankle extensor, nerves evoked a depression of the monosynaptic Ia excitatory postsynaptic potentials (EPSPs) recorded intracellularly in Ia inhibitory interneurones. This depression lasted between 200 and 700 ms and was not accompanied by a depression of the monosynaptic EPSPs evoked by stimulation of descending pathways. These results suggest that flexor, but not ankle extensor, group I afferent fibres can modulate sensory transmission at the synapse between Ia afferent fibres and Ia inhibitory interneurones. 3 Conditioning stimulation of flexor muscle nerves, extensor muscle nerves and cutaneous nerves produced a long‐lasting increase in excitability of the terminals of the Ia inhibitory interneurones. The increase in the excitability of the terminals was not secondary to an electrotonic spread of synaptic excitation at the soma. Indeed, concomitant with the excitability increase of the terminals there were signs of synaptic inhibition in the soma. 4 The unitary IPSPs induced in target motoneurones following the spike activity of single Ia inhibitory interneurones were depressed by conditioning stimulation of muscle and cutaneous nerves. Since the conditioning stimulation also evoked compound IPSPs in those motoneurones, a firm conclusion as to whether unitary IPSP depression involved presynaptic inhibitory mechanism of the terminals of the interneurones could not be reached. 5 The possibility that the changes in excitability of the Ia interneuronal terminals reflect the presence of a presynaptic inhibitory mechanism similar to that operating at the terminals of the afferent fibres (presynaptic inhibition) is discussed.1. In cat lumbar motoneurones, disynaptic inhibitory postsynaptic potentials (IPSPs) evoked by stimulation of antagonist motor nerves were depressed for at least 150 ms following conditioning stimulation of flexor (1.7‐2 times threshold (T)) and ankle extensor (5T) nerves. The aim of the present study was to investigate the possibility that this depression is caused by presynaptic inhibitory mechanisms acting at the terminals of group I afferent fibres projecting to the Ia inhibitory interneurones and/or the terminals of these interneurones to the target motoneurones.