Muscles are richly innervated by group III and IV muscle
afferents. These afferents respond to a range of chemical and
mechanical changes within the muscle. In particular,
potassium, lactic acid, bradykinin and arachidonic acid
activate many group III and IV muscle afferents (e.g. Mense,
1977; Kniffki et al. 1978; Rotto & Kaufman, 1988) with
minimal effect on group I muscle afferents (e.g. Mense,
1977; Prochazka & Somjen, 1986). During a contraction, the
activity of many group IV afferents may take some seconds
to develop but it is enhanced by muscle ischaemia (e.g.
Kaufman et al. 1983, 1984; Mense & Stahnke, 1983;
Adreani & Kaufman, 1998).
It is widely believed that the central actions of group III and
IV muscle afferents involve direct inhibition of the activity
of human motoneurones during voluntary contractions,
although the mechanism through which this may be
achieved is poorly understood (for review see Garland &
Kaufman, 1995). If present, such an effect would limit the
firing frequencies of motor units during fatiguing
contractions and would reduce the effectiveness of voluntary
‘drive’ to motoneurones in fatigue. There is evidence that
these changes occur during sustained maximal voluntary
contractions (MVCs) in human subjects.
First, during sustained maximal isometric contractions the
discharge frequency of motor units declines (e.g. Marsden et
al. 1983; Bigland-Ritchie et al. 1983; Gandevia et al. 1990).
This decline occurs together with a slowing of contractile
speed of the whole muscle (e.g. Bigland-Ritchie & Woods,
1984). Importantly, if muscle ischaemia is maintained after
the effort with a sphygmomanometer cuff, the firing rates of
motoneurones do not recover (e.g. Bigland-Ritchie et al. 1986;
Woods et al. 1987). The decline in motoneuronal output is
absent when muscle afferent feedback is prevented from
reaching the spinal cord (Gandevia et al. 1990; Macefield et
al. 1993). In addition, the tendon jerk and H_reflex are
diminished in fatigue (Garland & McComas, 1990; Balestra
et al. 1992; Duchateau & Hainaut, 1993). Second, voluntary
activation of muscles during an isometric contraction
Journal of Physiology (2000), 525.3, pp.793—801
793
Ischaemia after exercise does not reduce responses of human
motoneurones to cortical or corticospinal tract stimulation
J. L. Taylor, N. Petersen, J. E. Butler and S. C. Gandevia
Prince of Wales Medical Research Institute and University of New South Wales,
Sydney, NSW 2031, Australia
(Received 26 November 1999; accepted after revision 20 March 2000)
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.
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Keywords:

declines despite being driven by ‘maximal’ effort. This has
been measured from force increments produced during the
effort by motor nerve stimulation (e.g. Woods et al. 1987;
McKenzie & Gandevia, 1987; McKenzie et al. 1992;
Gandevia et al. 1996). A plausible explanation for all these
findings is that the input from ischaemically sensitive group
III and IV afferents reduces motoneuronal output in fatigue.
There are observations which suggest that human muscle
fatigue is accompanied by a depression in the effectiveness
of descending outputs to motoneurones. Responses to
transcranial stimulation of the motor cortex are depressed
in relaxed muscles for many minutes after fatiguing exercise
(e.g. Brasil-Neto et al. 1993; Zanette et al. 1995; McKay et
al. 1995; Liepert et al. 1996; Gandevia et al. 1999), while
recent evidence shows that the responses to stimulation of
the corticospinal tract at the cervicomedullary junction are
depressed for about 2 min after a maximal contraction
(Gandevia et al. 1999).
We have previously demonstrated that EMG responses to
transcranial magnetic stimulation elicited during brief
maximal contractions after fatiguing exercise are not affected
by maintained firing of group III and IV afferents although
the force increments elicited by the stimulus are (Gandevia
et al. 1996; Taylor et al. 1996). We concluded that group III
and IV afferents acted ‘upstream’ of the motor cortex to
prevent 100% voluntary activation but did not affect motor
cortical or motoneuronal responses during MVC. However,
stimulation of the cortex during voluntary contraction is not
an adequate test of the actions of afferents at a segmental
level during fatigue. Neither the level of descending drive to
the motoneurones nor the corticofugal volleys evoked by
cortical stimulation can be controlled. Thus, increased
descending drive while insufficient to activate the muscle
fully could mask a reflex inhibition of the motoneurones.
The present studies were designed to look for an inhibition
of the motoneurones of elbow flexor muscles by group III
and IV muscle afferents excited by sustained voluntary
contractions. The responses of motoneurones were tested
during relaxation so that changes in descending input were
minimized while occlusion of the blood supply to and from
the muscle prevented recovery from fatigue. The metabolic
status of the muscle does not improve during post-
contraction ischaemia. Force output from the muscle does
not recover, neither does voluntary activation nor motor
unit firing rate. Firing of ischaemically sensitive muscle
afferents continues even with the muscle at rest (Kaufman et
al. 1984; see also McCloskey & Mitchell, 1972). Thus, a reflex
inhibition of motoneurones related to the fatigued state of
the muscle should be prolonged by ischaemia, and should
not recover until blood flow resumes.
There were two test inputs. The first was derived from an
electrical stimulus at the cervicomedullary junction, which
is likely to evoke a single excitatory corticospinal volley
(Ugawa et al. 1991; Gandevia et al. 1999). This input is not
subject to presynaptic inhibition (Nielsen & Petersen, 1994).
The second input was generated by transcranial magnetic
stimulation over the motor cortex. The effectiveness of these
inputs was assessed after a sustained MVC with the muscle
relaxed but held ischaemic, and the results compared with
those when there was no post-contraction ischaemia
(Gandevia et al. 1999). Because prior activity in muscle
fibres alters the size of their action potentials (e.g. Cupido et
al. 1996; Taylor et al. 1999), supramaximal stimuli to the
brachial plexus were also delivered to assess the relative size
of the test responses. Preliminary findings have been
reported previously (Petersen et al. 1998).
METHODS
Subjects
Seven healthy volunteers (3 females; age, 27—45 years) were
studied. Written informed consent was obtained from the subjects,
and the studies were approved by the local ethics committee and
conducted according to the Declaration of Helsinki. The subject sat
comfortably at a table with the shoulders flexed and the elbows
flexed to 90 deg (Fig. 1). During the experiment each subject
performed a single sustained maximal voluntary contraction (MVC)
of the right elbow flexor muscles. This maximal isometric elbow
flexion lasted 2 min and subjects received continuous visual
feedback and verbal encouragement throughout. No strong
contractions were undertaken by the subjects in the 1—2 h
preceding the studies. As many of the procedures were similar to
those recently described (Gandevia et al. 1999), only a brief
description is given below.
Recordings and stimulation
Surface electromyographic (EMG) activity was recorded with
electrodes overlying biceps brachii and brachioradialis (Ag—AgCl
discs, 10 mm diameter) firmly stuck to the skin (bandpass, 1·6 Hz
to 1 kHz). The isometric force produced by MVC of the right elbow
flexors was measured with a linear strain gauge (Xtran).
EMG responses to stimulation at three sites were measured: the
motor cortex, corticospinal tract and motor axons. Transcranial
magnetic stimuli were delivered via a circular coil (13·5 cm outer
diameter) positioned over the vertex (Magstim 200). The output was
usually set at 80—90% of maximal stimulator output. The direction
of current flow favoured activation of the left motor cortex.
Corticospinal stimulation was achieved with electrical shocks
between two 9 mm Ag—AgCl electrodes fixed over the left (cathode)
and right (anode) mastoid processes (100 ìs duration, up to 750 V;
Digitimer, D180). Such stimuli activate axons in the descending
motor tracts at the level of the cervicomedullary junction with a
large part of the evoked muscle response occurring through
activation of corticospinal axons (Gandevia et al. 1999; see also
Ugawa et al. 1991). The intensity of stimulation at the transmastoid
level was set while responses were monitored at high gain to assess
whether the onset latency of responses in the relaxed muscles was
reduced markedly (by •2 ms) with an increase in stimulus
intensity. Such a shift in latency indicated that stimulation was
inadvertently occurring distal, rather than proximal, to the
motoneurone cell bodies. With the subject instructed to relax, the
stimulus intensity was adjusted to produce a compound potential
(termed the cervicomedullary motor-evoked potential, CMEP) in
the right brachioradialis of 20—30% of the maximal M-wave. The
usual stimulus intensity was •500 V. Once this level had been
selected, the stimulus intensity was increased to check that a
shortening in latency occurred and thus confirm that the test
J. L. Taylor, N. Petersen, J. E. Butler and S. C. Gandevia
J. Physiol. 525.3
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