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The Journal of Neuroscience, June 1, 2001, 21(11):4059-4065
Large Involuntary Forces Consistent with Plateau-Like Behavior of
Human Motoneurons
D. F.
Collins,
D.
Burke, and
S. C.
Gandevia
Spinal Injury Research Centre, Prince of Wales Medical Research
Institute and University of New South Wales, Randwick, Sydney,
Australia 2031
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ABSTRACT |
When electrical stimulation is applied over human muscle, the
evoked force is generally considered to be of peripheral origin. However, in relaxed humans, stimulation (1 msec pulses, 100 Hz) over
the muscles that plantarflex the ankle produced more than five times
more force than could be accounted for by peripheral properties. This
additional force was superimposed on the direct response to motor axon
stimulation, produced up to 40% of the force generated during a
maximal voluntary contraction, and was abolished during anesthesia of
the tibial nerve proximal to the stimulation site. It therefore must
have resulted from the activation of motoneurons within the spinal
cord. The additional force could be initiated by stimulation of
low-threshold afferents, distorted the classical relationship between
force and stimulus frequency, and often outlasted the stimulation. The
mean firing rate of 27 soleus motor units recorded during the sustained
involuntary activity after the stimulation was 5.8 ± 0.2 Hz. The
additional force increments were not attributable to voluntary
intervention because they were present in three sleeping subjects and
in two subjects with lesions of the thoracic spinal cord. The
phenomenon is consistent with activation of plateau potentials within
motoneurons and, if so, the present findings imply that plateau
potentials can make a large contribution to forces produced by the
human nervous system.
Key words:
human; motoneuron; muscle force; spinal cord; reflex; muscle contraction; plateau potential
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INTRODUCTION |
The discharge of motoneurons is
essential for all purposive movements. Traditionally, motoneurons are
believed to summate linearly the various descending and reflex inputs
that they receive (Eccles, 1957 ; Granit et al., 1966). However, some
behavior of motoneurons does not easily fit within this view. First,
there are situations in which motoneuronal discharge is excessively prolonged or inappropriately timed for the stimulus that initiated it.
For example, soleus motoneurons in the cat may show prolonged self-sustained firing after activation of muscle spindle endings (Granit et al., 1957; Hultborn et al., 1975; Wada et al., 1989). In
human subjects, motoneuron discharge may not be temporally locked to a
large reflex input from muscle spindle afferents, despite the ability
of monosynaptic pathways to phase-lock the discharge of motoneurons
under other circumstances (Lang and Vallbo, 1967; Burke and Schiller,
1976). Second, animal experiments have demonstrated that motoneurons
can develop plateau potentials that distort the relationship between
input current and firing rate and can also produce self-sustained
firing (Schwindt and Crill, 1980; Hounsgaard et al., 1988; Hounsgaard
and Kiehn, 1989; Bennett et al., 1998a; Carlin et al., 2000) (for
review, see Kiehn and Eken 1998; Hultborn, 1999; Hornby et al., 2000).
There is indirect evidence that these mechanisms may influence
motoneuron activity in conscious human subjects (Kiehn and Eken, 1997;
Gorassini et al., 1998, 2000) and unrestrained animals (Eken and Kiehn,
1989; Gorassini et al., 1999). However, the potential "power" of
any such assistance to the forces produced by human muscle has been difficult to gauge, partly because it is not possible to record intracellularly from human motoneurons in vivo and possibly
because the conditions under which plateau potentials develop in
experimental animals are dependent on the type and "state" of the
experimental preparation (Wada et al., 1989). In humans, possible
plateau activation must be inferred from more indirect measures such as
single motor unit recordings (Kiehn and Eken, 1997; Gorassini et al.,
1998, 2000).
Percutaneous electrical stimulation of human muscle is used extensively
in both clinical and experimental settings. Such stimulation activates
the muscle by directly stimulating the terminal branches of the
motoneurons, and the resulting forces are thought to depend on the
peripheral properties of the muscle and nerves under the stimulating
electrodes. However, the stimulation will also activate sensory axons
that can produce a "reflex" response in motoneurons with
similarities to the tonic vibration reflex (De Gail et al., 1966; Lang
and Vallbo, 1967). We have found that similar stimulation can produce
surprisingly large forces and substantial distortions in the
"normal" relation between stimulus frequency and the evoked force.
This behavior cannot be explained by either peripheral properties of
nerve and muscle or volitional drive to the motoneurons, and we propose
the involvement of plateau-like properties of human motoneurons.
Some of these data have been presented in abstract form (Collins and
Gandevia, 2000; Gandevia et al., 2001).
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MATERIALS AND METHODS |
Studies were performed on 15 able-bodied subjects (nine males,
six females; age range, 24-56 years) and two paraplegic subjects with
traumatic spinal cord lesions at the thoracic level (ages 39 and 43 years) studied 3 and 6 months after their accident. The procedures were
approved by the local human research ethics committee. Subjects sat
with the hips and knees comfortably flexed and the right foot strapped
to a myograph to record torque about the ankle joint (hip, knee, and
ankle 90-110°). Throughout the study subjects were reminded to
relax, disregard the stimulation, and were encouraged to read.
Sometimes the subjects were asked to confirm that they were relaxed,
and they were often asked to "relax completely", although they
received no feedback about their performance during the experiment.
Three subjects slept during parts of the experiment. Before the study,
the maximal voluntary force (MVC) of ankle plantarflexion was measured
in several attempts lasting 2-4 sec.
Electrical stimulation was applied over the calf muscles (triceps
surae) via two flexible strip electrodes (10- to 18-cm-long × 3.5-cm-wide) positioned ~10 and 20 cm distal to the popliteal fossa.
Pulses of 1 msec duration were delivered from a stimulator that could
be driven by a computer. The electrodes were positioned (with the
cathode proximal) such that the stimuli produced minimal local
discomfort. Stimulation intensity was adjusted based on the response to
"test" trains (5 pulses; 1 msec duration; 100 Hz) producing 2-7%
MVC. Several protocols were used in which trains of stimuli were
delivered at constant intensity. (1) Trains at constant frequency:
stimuli at 100 Hz for  7 sec with the trains separated by >1 min with
the 5-pulse test trains before and after the long train. (2) Trains at
low frequency with one or more abrupt intermittent periods of
high-frequency stimulation (e.g., 2 sec at 25 Hz, then 100 Hz for 2 sec
and finally 25 Hz for 3 sec). Control trains were delivered at 25 Hz
only. (3) Trains with linearly changing frequencies (rising from
~10-100 Hz over 10 sec and declining over 10 sec).
In many studies surface electromyographic (EMG) activity was recorded
from medial gastrocnemius (MG) and lateral gastrocnemius (LG), soleus
(Sol), and tibialis anterior (TA) muscle (sampling rate 1 kHz; bandpass
16 Hz-1 kHz). Torque, EMG, and stimulus parameters were recorded to
disc. In seven subjects the activity of single motor units in soleus
was recorded during self-sustained plantarflexion contractions via the
surface EMG or a monopolar needle electrode (sampling rate 10 kHz;
bandpass 16 Hz-3 kHz).
In two subjects the tibial nerve was blocked in the popliteal fossa
(with 12-15 ml of 2% lidocaine with adrenaline). The nerve was
initially localized with stimulation through a monopolar electrode, and
the block was monitored clinically and by electrical stimulation. In
one subject the block was complete, and in the other it reduced the
force of maximal voluntary plantar flexion to <10% of control and
abolished the Sol H reflex.
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RESULTS |
In all subjects electrical stimulation over the calf muscles
produced an additional reflex-like plantarflexion force
superimposed on the force arising from stimulation of the motor axons
beneath the stimulating electrodes. This "additional" force could
be evoked with a range of stimulus intensities, even below motor
threshold. An example of the force that developed during a long
stimulus train (100 Hz) delivered at motor threshold is shown for one
subject in Figure 1A.
When the stimulation was applied above motor threshold, the extra force
that arose in addition to the direct response to motor axon stimulation
could reach >40% MVC. Examples are shown in Figure 1, B
and C, for trains of stimuli lasting 60 and 7 sec, respectively. The additional force arose at a variable latency after
the onset of the trains and could be evoked using a variety of
stimulation protocols. Across eight subjects the maximal force in a
prolonged train lasting >10 sec (as in Fig. 1B)
increased 1.6-5.7 fold over the force 0.5 sec into the train. This
represented a mean increase of 21 ± 6% MVC (mean ± SEM;
range, 7-43% MVC). Peak force occurred 44 ± 11 sec after
stimulus onset (range, 8-106 sec). This additional force occurred even
though the force due to the direct stimulation of motor axons declined.
This is shown in Figure 1B by the reduction in the
amplitude of the response to the brief test train (five stimuli at 100 Hz; mean reduction across the eight subjects, 56%). This decrease
presumably reflects a reduced number of stimulated motor axons
(Bergmans, 1970; Vagg et al., 1998) and peripheral fatigue in the
muscle fibers activated by the stimulated motor axons. Sometimes the
stimulation induced a cramp in the calf muscles that could be avoided
by moving the stimulating electrodes or reducing the stimulus
intensity.
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Figure 1.
Forces during 100 Hz stimuli over the calf muscles
in relaxed subjects. A, Force during a stimulation for
55 sec delivered at the threshold for motor axon stimulation for one
subject. B, Force during a train lasting 60 sec
delivered above motor threshold for one subject. Note the gradual
increase in force to ~30% MVC and the reduction in response to the
test train after the prolonged stimulation. C, Mean
responses (± SEM) to five stimulus trains of 7 sec duration in one
subject before and during a complete anesthetic block of the tibial
nerve. Error bars (shown at 0.5 sec intervals throughout the
stimulation) are very small on the "nerve block" trace.
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To exclude the possibility that these unexpected forces reflected an
odd peripheral property of the stimulated motor axons and the
innervated muscle fibers, we assessed responses during block of the
tibial nerve in two subjects. This prevented activation of motoneurons
via reflex or antidromic paths and the resulting forces could only
arise from peripheral properties of the motor axons and muscle fibers
beneath the stimulating electrodes. When muscles below the knee were
paralyzed and "disconnected" from the CNS in this way, the
additional forces associated with sustained high-frequency stimulation
were absent (Fig. 1C), and the evoked forces were much more
consistent and predictable.
The relationship between stimulus frequency and the evoked force was
investigated with a triangular pattern of stimulation with increasing
then decreasing stimulus frequencies (Fig.
2). The evoked force remained abnormally
high or even increased as the stimulus frequency declined. In some
instances a prominent "take off" for the extra force was identified
(Fig. 2, arrow), although the stimulus frequency when this
occurred was variable across subjects (between ~30 and 100 Hz). This
resulted in a marked distortion of the relationship between stimulus
frequency and evoked force clearly evident by the hysteresis in the
force-frequency plot in Figure 2B. This distortion
was abolished during the tibial nerve block, thus confirming that the
additional force arose from within the CNS.
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Figure 2.
Responses to "triangular-shaped" changes in
stimulus frequency for one subject before and during complete tibial
nerve block. A, Responses to trains of increasing then
decreasing frequency (between 10 and 100 Hz) over ~20 sec. The
arrow marks the onset of the "extra" force.
B, Corresponding force-frequency relationship.
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To assess the force increments that arose during the high-frequency
(100 Hz) stimulation, we delivered brief periods (~2 sec) of such
stimulation during longer trains of stimuli at 25 Hz. These 100 Hz
"bursts" not only increased the force much more than expected from
the direct stimulation of motor axons, but when the frequency of
stimulation returned to 25 Hz, the force remained inappropriately high.
This is shown for one subject in Figure 3A in which there was a clear
take off in the force (arrow) during the 100 Hz burst, after
which the force remained elevated compared to the same point during the
two control stimulus trains. Figure 3B shows 10 superimposed
responses (five control, five test) from a different subject, and the
mean across the group of seven subjects is shown in Figure
3C. For the group, the average force 3 sec after the end of
the 100 Hz train was 188 ± 31% of that at the same time in the
control train.
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Figure 3.
Forces during control trains (25 Hz) and during
trains with additional 100 Hz stimulation. A, Force
responses from one subject to three successive stimulus trains.
B, Superimposed responses (n = 10)
to control (thin lines) and test trains (thick
lines) for one subject. C, Average responses for
seven subjects (mean ± SEM). Data expressed relative to the force
0.5 sec after stimulus onset in control trains.
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Figure 4A shows force
and the activity of a single motor unit in Sol evoked by two successive
25 Hz stimulus trains with bursts at 100 Hz (as in Fig. 3). The initial
100 Hz burst (during the first stimulus train) resulted in only a small
increase in force. In contrast, much more force was evoked during and
after the 100 Hz burst of the second stimulation. Similarly, the
sustained force and EMG that remained after the stimulation was turned
off was much larger after the second stimulus train than the first.
Figure 4B shows the EMG data on an expanded time
scale (200 msec sections) from the four points indicated by the
arrows in A. The large vertical lines in the
first four traces show the truncated stimulus artifacts from the
stimulation at 25 Hz. The first trace shows the EMG activity before the
first 100 Hz burst (Fig. 4A, point 1). The
only EMG activity present was time-locked to each stimulus pulse and
reflected muscle activation caused by the direct stimulation of the
motor axons. Part of this direct response was truncated with the
stimulus artifact. The second trace is taken after the first 100 Hz
burst (point 2) and shows the direct EMG response to the stimulation as
well as the recruitment of other small motor units whose discharge was
not time-locked to the stimulation. The data from the period after the
second 100 Hz burst (Fig. 4A, point 3) show that a
motor unit was recruited (at the arrow; note the reduction
in gain). Trace 4 comprises the 400 msec period (in two parts)
beginning with the last five pulses of the second stimulus train and
shows that the large unit recruited at point 3 remained active
throughout the remainder of the stimulus train. This unit also fired
after the stimulus was turned off, initially at ~10-12 Hz, and then the frequency declined to ~6-8 Hz. The insert at the bottom of the
Figure shows six superimposed spikes from the unit highlighted by the
arrows in B (three recorded during the
stimulation and three after).
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Figure 4.
Force and EMG activity during two successive
stimulus trains of 25 Hz stimulus with a 100 Hz burst. A
shows the force and EMG activity (recorded with a monopolar recording
electrode) before, during, and after the stimuli. B
shows the unitary activity at the four points (1-4) during the
stimulation shown by the arrows in A.
Note the change in gain. The data from point 4 encompass the last five
stimulus pulses and the period immediately after that. The
inset at the bottom of B
shows the morphology of the spike highlighted by the
arrows in traces 3 and 4
(6 superimposed spikes, 3 during the stimulation and 3 after).
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In all subjects there were instances when force was maintained after
the stimulation was turned off. This sustained force could last for
minutes and occurred although, when questioned, the subjects confirmed
that they were "relaxed." This occurred commonly when one or more 1 sec bursts of 100 Hz stimulation was delivered during 25 Hz trains and
reflected the development of continuous EMG activity in the
plantarflexor muscles, activity that had not been present before the
stimulus train that evoked it (Figs.
4-6). The
mean firing rate of 27 single motor units in Sol during such sustained
involuntary activity was 5.8 ± 0.2 Hz (coefficient of variation;
12.9 ± 1.1%). An example of the force and EMG activity that
remained after a triangular pattern of stimulation is shown in Figure
5. In this example, brief voluntary dorsiflexion efforts failed to
eliminate the sustained contraction of the plantarflexor muscles.
Similar contractions (up to 10% maximum) also did not eliminate this
activity in three of three subjects tested. Interestingly, if the
sustained muscle contraction did not end spontaneously, a request to
concentrate and relax completely usually terminated it, although when
first asked subjects would typically state that they were relaxed.
Figure 5 shows that the command to relax completely was not associated
with activation of the antagonist muscles. No examples of sustained
discharges after the stimulation was turned off were observed during
the nerve blocks.
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Figure 5.
Recording from a subject during and after a train
of increasing then decreasing frequency (between ~4 and 100 Hz in 6 sec). Force continued to increase as the stimulus frequency declined,
and sustained plantarflexion force and Sol EMG remained after
stimulation. This persisted despite two brief efforts to dorsiflex the
ankle but disappeared when the subject was asked to relax completely.
EMG occurred in TA during the voluntary dorsiflexions but not when
asked to relax completely. Stimulus artifacts have been
truncated.
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Figure 6.
Recordings from a sleeping subject to a complex
stimulus train that included repeated bursts of 100 Hz stimulation
followed by a decline in frequency. Force did not decline smoothly
during the slow reduction in frequency and residual force developed
after the train (accompanied by EMG in Sol and MG and LG, but not TA).
Stimulus artifacts have been truncated. Instantaneous discharge rate of
a single motor unit in soleus is shown.
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The additional forces were not attributable to inadvertent volitional
descending drives to the motoneurons. They were recorded from subjects
who were relaxed and often distracted by reading. They were also
recorded in three subjects who went to sleep during the study (Fig. 6).
Here force and EMG continued after a complex stimulus train in which
the stimulus frequency declined slowly from 25 Hz after four 1 sec
bursts at 100 Hz. In two paraplegic subjects with thoracic spinal cord
lesions, the additional force responses were evident with the various
protocols used to evoke them (Fig. 7),
although these forces seemed smaller than in intact subjects.
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Figure 7.
Recordings from two patients with spinal cord
injury (mean ± SEM, n = 5). A,
Data from one subject with a complete spinal cord lesion at T12. Forces
during trains of stimuli with 2 sec at 25 Hz, 2 sec at 100 Hz, and then
3 sec at 25 Hz. For the control sequence stimulus rate was constant at
25 Hz. B, Data from a subject with an incomplete lesion
at T8. Force response to the triangular pattern of stimulation. Maximal
voluntary plantarflexion force was <10% predicted for healthy
subjects.
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DISCUSSION |
Electrical stimulation over the calf muscles at innocuous
intensities can evoke substantial plantarflexion force, much more than
attributable to direct stimulation of the motor axons. When this
developed the force could increase more than fivefold. Some of this
additional force often remained, despite lowering the stimulus
frequency or even cessation of the stimulation. This force occurred
despite activity-dependent hypoexcitability in the stimulated axons
(Bergmans, 1970; Vagg et al., 1998), and the peripheral fatigue
expected in the motor units with the largest (and most easily excited)
motor axons (Burke, 1981) as seen in the responses to test stimuli
before and after prolonged trains (Fig. 1B).
This behavior was of central origin because it was absent when the
nerve was blocked proximal to the stimulation site. During the nerve
block the evoked forces could only arise from direct activation of the
motor axons, and the resulting contraction forces were consistent and
predictable. The presence of the unexpected force increments during
stimulation at intensities below the threshold for motor axons (see
also De Gail et al., 1966; Lang and Vallbo, 1967) suggest that they
probably arose from stimulation of large-diameter afferents and that
the antidromic activation of motoneurons was not required. Muscle
rather than cutaneous afferents are likely to be important because the
behavior has been observed for muscles other than the calf such as
tibialis anterior (Collins and Gandevia, 2000; Gandevia et al., 2001)
and biceps brachii (D. F. Collins, and S. C. Gandevia,
unpublished observations) where stimulation evoked little or no
cutaneous sensation. When the stimulation was applied above motor
threshold, motoneurons with large-diameter axons would be
preferentially activated, and antidromic volleys traveling along those
axons would abolish any orthodromic action potentials arising within
the spinal cord. Thus, the additional force superimposed on the direct
motor response must arise from the recruitment of the smaller, more
fatigue-resistant, motoneurons.
The additional forces do not reflect voluntary drive to the motoneurons
because they were present in sleeping subjects and in patients with
spinal cord transection. We did not document sleep stage but expect
that the subjects were in non-REM sleep, a state in which voluntary
intent could not have interfered. The patient data also indicate that
supraspinal projections are not required, a finding consistent with
recent motor unit recordings from spinal cord-injured humans (Gorassini
et al., 2000) and rats (Bennett et al., 2000). However, in our
experiments these additional forces could be modified by descending
commands because the instruction to relax completely could abolish the
sustained involuntary activity that often remained after the
stimulation was turned off. Surprisingly, these self-sustained
contractions of the calf muscles were not abolished by brief isometric
voluntary contractions of the antagonistic muscles, demonstrating a
lack of responsiveness to a particular voluntary drive that is often
reciprocally organized.
The presence of these additional forces dramatically shifts the
force-frequency relation of the stimulated muscle and introduces nonlinearities far greater than known for "isolated" muscle
(Partridge, 1966; Binder-Macleod and Clamann, 1989). Furthermore, it
makes the responses to muscle stimulation more unpredictable because the size of the extra forces varies and the onset can be triggered at
different points in a stimulus train. This contrasts with the stability
of the responses to the different stimulus trains during the proximal
nerve block.
Given the widespread use of electrical stimulation of human muscle, it
is unclear why the potency of the phenomenon reported here has not been
reported previously. Our use of large surface electrodes over the
muscles, long-duration pulses that favor activation of afferent axons
(Veale et al., 1973; Mogyoros et al., 1996), high stimulation
frequencies, and the patterns of stimulation may account for this.
However, inspection of published records suggests that the additional
forces to electrical stimulation are present in some recordings
(Bigland-Ritchie, 1981; Rafolt et al., 1999).
Previous studies with electrical stimulation have revealed that the
discharge of human Sol motoneurons may be locked to the reflex stimulus
at very low frequencies in the presence or absence of a weak voluntary
contraction (as in the Hoffman or H reflex; Ashby and Zilm, 1982; Burke
et al., 1984). However, in relaxed subjects the H reflex declines with
increasing rates of stimulation (Burke and Schiller, 1976; Burke et
al., 1989; Crone and Nielsen, 1989; Hultborn et al., 1996). It is often
overlooked that at high stimulus frequencies this locking is absent and
that the discharge of recruited motoneurons is not locked to the
driving stimulus, as shown in Figure 4 (De Gail et al., 1966; Lang and
Vallbo, 1967; Burke and Schiller, 1976). One explanation for the
present results is that motoneurons are recruited by the high-frequency
afferent bombardment and their discharge is then sustained via
activation of plateau potentials within them. The motoneurons then
become temporally uncoupled from the reflex inputs which, under other conditions, can drive them through largely monosynaptic reflex paths
(Burke et al., 1984).
Plateau potentials leading to bistable states are generated in many
central neurons (Fraser and MacVicar, 1996; Morisset and Nagy, 1999)
and have been demonstrated in mammalian motoneurons (Schwindt and
Crill, 1980; Hounsgaard et al., 1988; Hounsgaard and Kiehn, 1989;
Bennett et al., 1998a; Lee and Heckman, 1998; Carlin et al., 2000) (for
review, see Hornby et al., 2000). Several features of the present
results are consistent with the involvement of plateau potentials in
motoneurons. First, the additional force depended on the activation of
the smaller, more fatigue-resistant motoneurons (Lee and Heckman, 1998,
2000) by high-frequency synaptic input from large-diameter afferents
(Hultborn et al., 1975; Bennett et al., 1998a; Lee and Heckman, 1998);
second, it often became more prominent with repeated bursts of
stimulation analogous to the "wind up" phenomenon (Bennett et al.,
1998b); third, it could generate self-sustained firing (Hounsgaard et
al., 1988; Wada et al., 1989; Kiehn and Eken, 1997; Gorassini et al.,
1998); fourth, it could often be terminated by particular "inputs"
to the motoneuron pool (Hultborn et al., 1975; Lee and Heckman, 1998),
and finally, motor unit discharge frequencies were similar to those in
a previous human study that probably involved plateau potentials (Kiehn
and Eken, 1997). Alternatively, the abnormal force increments may derive from plateau-like activity in spinal interneurons, or a "reverberating" spinal circuit (Hultborn et al., 1975), although there is currently little evidence for such a circuit.
Regardless of the underlying mechanism, stimulation applied over human
muscles can recruit motoneurons synaptically, presumably according to
their natural recruitment order (small to large; Henneman, 1957;
Henneman et al., 1965). This may have applications for functional
electrical stimulation in which muscle fatigue is often a problem
caused by the preferential activation of motoneurons with
large-diameter axons. The additional recruitment of the smaller motoneurons that innervate more fatigue-resistant muscle fibers may be
particularly useful for generating sustained contractions required for
tasks such as standing. Similarly, because the stimulation activates a
portion of the muscle not normally activated by direct motor axon
stimulation, it may have applications in reducing the muscle atrophy
resulting from disuse associated with acute or chronic injury conditions.
Plateau potentials have been invoked in other studies on human subjects
to explain cramp-like behavior (Baldissera et al., 1991, 1994),
self-sustained discharges (Kiehn and Eken, 1997; Gorassini et al.,
1998), and the potential discrepancy between the forces at recruitment
and derecruitment of motor units (Heckman and Lee, 1999). Whereas these
studies focused on EMG recordings and the properties of single motor
units, our study focused on the resulting forces and suggests that
these intrinsic mechanisms can generate large forces and thereby make a
substantial contribution to the control of voluntary movement. Thus,
present understanding of the in vivo operation of human
motoneuron pools may need revision.
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FOOTNOTES |
Received Jan. 29, 2001; revised March 13, 2001; accepted March 16, 2001.
This work was funded by the National Health and Medical Research
Council of Australia (Grant number 3206). D.F.C. was supported by the
National Sciences and Engineering Research Council of Canada and the
Alberta Heritage Foundation for Medical Research. We are grateful to
Drs. Elspeth McLachlan and James Brock for comments on this manuscript.
Correspondence should be addressed to S. C. Gandevia, Prince of
Wales Medical Research Institute, Barker Street, Randwick, New South
Wales, Australia 2031. E-mail: S.Gandevia{at}unsw.edu.au.
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ABSTRACT
INTRODUCTION
