Acta Physiol Scand 1998, 162, 275±283

Neural control in human muscle fatigue: changes in muscle

afferents, moto neurones and moto cortical drive

S. C. GANDEVIA
Prince of Wales Medical Research Institute and University of New South Wales, Sydney, Australia

ABSTRACT
To understand the neural factors which contribute to fatigue, it is not satisfactory to regard fatigue as
occurring only when a task can no longer be performed. Changes in muscle afferent feedback, moto
neuronal discharge, moto cortical output, and perceived effort develop well before an endurance limit
in limb muscles. During sustained maximal contractions the discharge of moto neurones declines,
commonly to below the level required to produce maximal force from the muscle whose contractile
speed is usually slowed. Thus, some `central' fatigue develops. Recent findings using transcranial
stimulation have revealed that the moto cortex is one site at which suboptimal output develops
during human muscle fatigue. There is a need to study the reflex effects on moto neurones and the
excitability of the moto cortex in experimental animals, as well as to apply rigorous methods to
assess these processes in voluntary exercise in human subjects.

Keywords central fatigue, cortical stimulation, fatigue, inhibition, moto neurones, moto cortex,
muscle spindles, re¯exes.

Received 2 April 1997, accepted 16 June 1997

Fatigue is a time-dependent exercise-induced reduction
in the maximal force generating capacity of a muscle.
During a maximal voluntary contraction fatigue begins
rapidly. It arises more slowly for weaker contractions
but occurs even if a submaximal voluntary force is
sustained. Manifestations of fatigue re¯ecting largely
peripheral factors include the reduction in maximal
force and power and also the slowing of muscle relax-
ation which often accompanies sustained high-intensity
effort. However, the central nervous system is involved
not only in driving moto neurones but also in the in-
creased tremor of the exercising limb, the recruitment
of muscles initially uninvolved in the task and the
subjective increase in effort. Some of these `central'
features may disrupt performance more than the re-
duction in maximal muscle force. The increased per-
ceived `effort', a signal requiring the moto cortex,
re¯ects the need to recruit more moto neurones and
muscles, and to drive them harder (for review see Jones
1995, Gandevia 1996). However, the interaction be-
tween re¯ex inputs, moto neuronal properties and su-
praspinal factors during fatigue is not well understood
(for review see Enoka & Stuart 1992, Fuglevand 1996).
There is a question as to what extent the available
moto neurones are recruited in fatigue. Studies using
sensitive forms of twitch interpolation (Hales &
Gandevia 1988) have not con®rmed the original pre-
diction of Merton (1954) that moto units are fully re-
cruited and discharging at rates suf®cient for fusion at
the onset of maximal voluntary isometric contractions.
For several muscles in which identical methods have
been used voluntary activation is usually above 85±90%
during attempted maximal voluntary isometric con-
tractions (including for the diaphragm) (e.g. Allen et al.
1993, Allen et al. 1995, Herbert & Gandevia 1996, for
review see Gandevia et al. 1995). Averaged across one
fatiguing `maximal' contraction in several subjects, or
several contractions in one subject, voluntary activation
declines signi®cantly. This is de®ned as `central fatigue'
(Gandevia et al. 1995). Its development should con-
tribute to the decline in discharge rate of moto neu-
rones during fatigue.
For maximal voluntary isometric contractions the
moto neurone discharge rates after the initial peak force
are about 20±50 Hz for upper limb muscles with
variation between subjects and muscles (e.g. Bellemare
et al. 1983). If the voluntary contraction continues for
more than a few seconds, discharge rates decline and
approach a plateau towards 60 s (e.g. Grimby et al.
1981, Bigland-Ritchie et al. 1983a, Gandevia et al. 1990).

Correspondence: Professor S. C. Gandevia, Prince of Wales Medical Research Institute, High Street, Randwick, Sydney, NSW Australia 2031.

Ó 1998 Scandinavian Physiological Society 275

Neural control and muscle fatigue á S C Gandevia
This decline in rate assists the output from the muscle
because relaxation times for whole muscle usually
lengthen during strong isometric contractions and thus
lower discharge frequencies produce the same fraction
of maximal force (Bigland-Ritchie et al. 1983b). The
decline in moto unit rate has been called muscle `wis-
dom' (Marsden et al. 1983) but given that the ®ring may
fall too low to maintain full activation of the muscle
and that muscle relaxation rate sometimes increases in
fatigue (e.g. McKenzie & Gandevia 1991), the term is
not appropriate. More irregular ®ring of moto neurones
develops with fatigue (Gandevia et al. 1990, Garland
et al. 1994). In fatiguing anisometric contractions moto
units show variable discharge patterns (Miller et al.
1996).
An extreme example of the predominance of central
factors in fatigue occurs when a task cannot be con-
tinued (`task failure') but the muscles can produce the
required force when stimulated electrically. This pos-
sibility was recognized by Mosso, Waller, Lombard and
others last century and a recent report supports the
proposition: when subjects could no longer voluntarily
plantar¯ex the ankle at 30% maximum, the force could
be maintained by electrical stimulation of the nerve
innervating the plantar¯exors (Loescher et al. 1996a).
This phenomenon is likely to depend on the subjects,
the degree of maximal voluntary drive for the muscle
group, the peripheral muscle properties, and the in-
tensity of the fatiguing task.
In this brief review I consider the effects of feed-
back from muscle and the role of supraspinal sites on
the changing behaviour of moto neurones during fa-
tigue. Much of the data derive from isometric exercise
in which electrophysiological measures can be made
without interference from movement. De®ciencies in
techniques used to assess human muscle fatigue are
mentioned.
276
Acta Physiol Scand 1998, 162, 275±283
M U S CL E A F F E RE N T I N P UT S D U R I N G
M U S CL E F A T I G U E
During maximal voluntary contractions of a human
muscle, the input from specialized muscle mechanore-
ceptors (innervated by large-diameter afferents) and
from chemosensors and nociceptors (innervated by
small-diameter afferents) will change. Based largely on
data from animal studies, the probable changes in
muscle afferent input are shown in Figure 1.
Muscle spindle afferents
During isometric contractions the fusimotor system
recruits human muscle spindle endings but their dis-
charge frequency declines with time if the contraction is
sustained beyond 1±2 s and fatigue develops (e.g.
Mace®eld et al. 1991). Neglecting the effect of presyn-
aptic inhibition, spindle-mediated facilitation of moto
neurones will decline during a sustained isometric
contraction, i.e. disfacilitation develops. However, in
concentric contractions the spindle afferents' role will
differ because fusimotor drive may be insuf®cient to
overcome muscle shortening and spindle afferents in
the contracting muscle may fall silent (Burke et al. 1978,
Al Falahe et al. 1990). In eccentric contractions spindle
input may be accentuated as animal studies indicate that
spindle afferents increase their responsiveness to
stretch during fatigue (e.g. Nelson & Hutton 1985,
Hayward et al. 1991).
Golgi tendon organ afferents
Tendon organs respond to active muscle forces gen-
erated by the moto units which insert into them (Jami
1992, cf. Hulliger et al. 1995). However, their discharge
adapts during the ®rst seconds of force production.
Thereafter, the ensemble input from tendon organs is
Figure 1 Schematic representation of the
likely changes in muscle afferent input during a
sustained maximal voluntary contraction of a
limb muscle. Data compiled mostly from
studies in animals.
Ó 1998 Scandinavian Physiological Society
Acta Physiol Scand 1998, 162, 275±283
well suited to signal force produced by the muscle. The
stretch sensitivity of individual tendon organs varies
with fatigue (Hutton & Nelson 1986, Thompson et al.
1990, Hayward et al. 1991). The practical consequences
of changes in stretch sensitivity of muscle spindle and
tendon organ afferents during muscle fatigue are un-
certain, particularly as their re¯ex effects may be at-
tenuated at a spinal level, and because the effects are
small compared with those in the more numerous
group III and IV afferents (Hayward et al. 1991).
Non-spindle group II and groups III and IV muscle afferents
During muscle fatigue the discharge of small-diameter
muscle afferents (groups III and IV) increases accord-
ing to the temperature, chemical and the mechanical
environment of their free nerve endings (e.g. Paintal
1960, Kniffki et al. 1978, Kaufman et al. 1983, Hayward
et al. 1991). They have little or no background discharge
and, because they are so numerous, small changes in
their discharge will produce massive increases in their
ensemble input to the central nervous system (CNS).
Following fatiguing contractions most group II non-
spindle afferents and group III mechanosensitive af-
ferents have increased discharge rates, increased
sensitivity to stretch and palpation but reduced re-
sponsiveness to additional contractions (Hayward et al.
1991). Group III afferents increase their discharge by
about 1 Hz within the ®rst 10 s of an isometric con-
traction but this is not sustained (Sinoway et al. 1993).
Metabolites produced by prolonged muscle contraction
reduce the mechanical thresholds of group III and IV
afferents (e.g. Rotto et al. 1988). Some group III af-
ferents discharge during slow locomotion in decere-
brate cats (Pickar et al. 1994), but there are no data on
the discharge of human group III and IV afferents in
voluntary contractions. Some recordings in animals may
be of limited guidance because contractions are pro-
duced by electrical stimulation without distributing it in
a more natural asynchronous way to moto units.
C HA N G E S A T TH E MO T O N E U RO N AL
L E VE L D UR I N G M US CL E FA T I G UE
Intrinsic moto neuronal properties, re¯ex inhibition
and disfacilitation, Renshaw cell inhibition, and insuf-
®cient drive from supraspinal sites may all contribute to
the decline in moto unit ®ring rate in fatigue. Theo-
retically, it would be optimal if each moto neurone had
its output individually controlled to produce the highest
force from its muscle ®bres depending on their con-
tractile state. However, a compartmentalized re¯ex
machinery which modulates each moto neurone's out-
put based on local re¯ex inputs from group III and IV
afferents surrounding its muscle ®bres is highly un-
Ó 1998 Scandinavian Physiological Society
S C Gandevia á Neural control and muscle fatigue
likely. Systematic changes in the intrinsic properties of
moto neurones with increasing threshold and size
(Kernell & Monster 1982, Binder & Mendell 1990),
along with nonhomogeneous distribution of re¯ex in-
puts within the moto neurone pool, will aid optimiza-
tion of the whole pool's output.
An intrinsic property of moto neurones which could
mediate the decline in moto neuronal discharge rates
during fatigue is that ®ring rates adapt when moto
neurones are stimulated with intracellular or extracel-
lular current (e.g. Kernell & Monster 1982, Spielmann
et al. 1993, Sawcuk et al. 1995). The reduction in ®ring
rate (`late adaptation') is appropriately more pro-
nounced for type F than type S moto units. Additional
changes develop with repeated bursts of stimulation
(Spielmann et al. 1993). The precise pattern of moto
neuronal discharge can in¯uence the force produced
(see Bevan et al. 1992), but whether the observed in-
crease in irregularity of ®ring actually increases force
production in fatigue is unclear.
In intact preparations, moto neuronal behaviour
during fatigue will be modulated by: (i) supraspinal
commands to interneurones and moto neurones; (ii)
control by brainstem serotonergic pathways of the
`gain' and possible bistable behaviour of moto neurones
(e.g. Hultborn & Kiehn 1992); (iii) classical re¯ex and
recurrent inputs to a- and c-moto neurones; (iv) pre-
synaptic modulation speci®c classes of re¯ex inputs to
moto neurones (e.g. Jankowska 1992). Some of these
factors are shown in Figure 2. To determine how the
whole system will behave during fatigue is daunting
because of the many inputs to the moto neurone pool,
their combined monosynaptic and nonmonosynaptic
effects on moto neurones, and their changes in size
with time and with fatigue. Some re¯ex effects on moto
neurones are considered brie¯y below (see Windhorst
& Boorman 1995).
The connection between Ia afferents and the moto
neurone is well studied but its behaviour during fatigue
is not established. Indirect evidence reveals that muscle
afferents provide signi®cant excitation to the moto
neurone pool (up to 30%) during sustained fatiguing
isometric contractions (e.g. Gandevia et al. 1990,
Mace®eld et al. 1993). However, presynaptic inhibition
will attenuate the re¯ex effectiveness of any Ia input in
some movements, at least in the lower limb (e.g.
Capaday & Stein 1987, Meunier & Pierrot-Deseilligny
1989). Effective transmitter depletion at the Ia-moto
neurone synapse (homosynaptic depression) may also
develop (e.g. Curtis & Eccles 1960, Bongiovanni &
Hagbarth 1990, Lev-tov & Pinco 1992).
As indicated earlier, muscle spindle discharge de-
creases during fatiguing static contractions in human
subjects (Mace®eld et al. 1991), irrespective of any re-
¯ex excitation of fusimoto neurones (e.g. Ljubisavljevic
277
Neural control and muscle fatigue á S C Gandevia
et al. 1992, Ljubisavljenc & Anastasijevic 1994,
Ljubisavljevic et al. 1995). It is not established whether
late increases in fusimotor ®ring in the cat are relevant
to voluntary fatigue of human muscles. As the un-
loading re¯ex seems reduced in fatigue of human ®nger
extensor muscles, any excitation of homonymous
fusimotor neurones is insuf®cient to maintain the
prefatigue levels of spindle-mediated facilitation. Any
attenuation of `stretch' re¯exes will reduce the ability of
spinal re¯exes to oppose length changes (e.g. Hagbarth
et al. 1995). However, methodological dif®culties
abound in the interpretation of studies of human re-
¯exes in fatigue (see below).
Golgi tendon organ afferents are traditionally be-
lieved to re¯exly reduce moto neurone output (Jami
1992). The picture is more complex in fatigue because
of spindle afferent convergence on Ib inhibitory inter-
neurones (see Jankowska 1992), such that Ib effects can
be excitatory (e.g. Pratt 1995). In a sustained contrac-
tion, the Ib inhibitory postsynaptic potentials in moto
neurones decline so that the gain of force feedback is
reduced (Zytnicki et al. 1990, see also Kirsch & Rymer
1987).
While there seems no doubt that inputs from small-
diameter muscle afferents re¯exly alter moto outputs,
the way it is achieved in fatiguing voluntary contrac-
tions is unresolved. The inputs will act at spinal and
supraspinal sites. In the anaesthetized cat the spinal
machinery exists to mediate inhibition among synergist
muscles during fatigue (Hayward et al. 1988). Many
have implied that these afferents exert their inhibitory
effects at a spinal level (e.g. Bigland-Ritchie et al. 1986,
see also Garland & McComas 1990) but the evidence is
circumstantial. The decline in moto neurone discharge
in strong contractions is present when muscles contract
voluntarily after fatigue produced by electrical stimu-
lation (Garland & McComas 1990), but absent when
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Acta Physiol Scand 1998, 162, 275±283
Figure 2 A simpli®ed representation of some re¯ex
pathways affecting a- and c-moto neurones. Renshaw
cells and presynaptic inhibition are included. Filled cells
are inhibitory. No afferent input reaches moto neurones
exclusively by a monosynaptic path and all
interneurones in the re¯ex circuits are probably
in¯uenced by descending commands.
muscle afferents are blocked by local anaesthesia
(Gandevia et al. 1990, Mace®eld et al. 1993).
Additional inhibition of moto neurones derives
from Renshaw cells which receive excitatory inputs
from moto neurones, particularly those of high
threshold (Hultborn et al. 1988) as well as descending
and peripheral inputs. In the cat the rapid discharge of
Renshaw cells declines nonlinearly when moto neurone
frequency declines so that their output can contribute
to the adaptation of moto neurone rates during fatigue
(Windhorst & Boorman 1995). Studies using indirect
H-re¯ex methods in humans suggest that recurrent
inhibition (and/or prolongation of the after-hyperpo-
larization) increases in maximal efforts (Kukulka et al.
1986), but declines in submaximal ones (Loescher et al.
1996b).
M O TO R CO R T I CA L A N D S U PR A S PI N A L
F A CT O R S I N M US CL E FA T I G U E
In fatiguing exercise, there are changes in central en-
kephalinergic, dopaminergic and serotonergic systems
(e.g. Hoffman et al. 1990, Bailey et al. 1993, Persson
et al. 1993, cf. van Hall et al. 1995). These presumably
control vigilance and motivation, pain and its tolerance,
while other neuroendocrine changes alter availability of
substrates for muscle contraction. Manipulation of
these factors should alter centrally mediated compo-
nents of fatigue. A challenge is to isolate direct roles for
these systems in both central fatigue and subsequent
task failure.
Given the behavioural changes that accompany
muscle fatigue (including changes in subjective effort,
attention and pain), there must be many associated
supraspinal changes measurable at an electrophysio-
logical and biochemical level, but, as for events at a
spinal level, it is dif®cult to determine which are sec-
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Acta Physiol Scand 1998, 162, 275±283
ondary to peripheral fatigue and which contribute to
central fatigue and eventual task failure. As indicated
earlier, intrinsic moto neuronal, spinal and supraspinal
factors could all generate central fatigue. However, we
must examine the roles the moto cortex and supraspi-
nal drive play in the decline in moto neurone ®ring
frequency in fatigue. Particularly in humans, cortical
output monosynaptically excites most spinal moto nu-
clei (e.g. Porter & Lemon 1993) without the effects of
presynaptic inhibition (Nielsen & Petersen 1994).
Hence supraspinal centres which alter corticomoto
neuronal output will affect moto neurones in a most
direct way.
Some recent studies have focused on the develop-
ment of changes in the corticospinal system during fa-
tigue. In monkeys trained to fatigue their elbow ¯exors
there were variable changes in the discharge of cor-
ticomotor neuronal cells (Maton et al. 1994). In humans
performing repetitive submaximal contractions, the size
and area of electromyographic (EMG) responses to
transcranial magnetic stimulation of the cortex decline
after cessation of exercise (Brasil Neto et al. 1993,
McKay et al. 1995, Zanette et al. 1995). We recently
examined the changes in the EMG and force responses
to transcranial stimulation of the motor cortex during
sustained maximal voluntary isometric contractions of
the elbow ¯exors lasting 1±3 min (Figure 3). Voluntary
activation was monitored during exercise with twitch
interpolation from the moto point and by measurement
of force twitches evoked by transcranial stimulation
(Gandevia et al. 1996, Taylor et al. 1996).
The silent period in the EMG following high-in-
tensity cortical stimulation lengthened by about 50 ms
from its control value (see also McKay et al. 1996)
within 30 s of a maximal voluntary contraction or when
Figure 3 (a) Biceps brachii EMG during maximal
voluntary contractions (MVCs) of elbow ¯exors. Upper
®ve traces during brief control MVCs. Middle traces
during a sustained 2 min MVC and lower traces during
recovery. The ®rst vertical dashed line shows time of the
transcranial magnetic stimulation. Second vertical dotted
line shows the time of return of continuous EMG and
marks the end of the silent period in control trials. This
lengthens during the sustained MVC and recovers
quickly. The moto evoked potential (MEP, just right of
dashed line) is variable but grows during the sustained
contraction and recovers rapidly. (From Taylor et al.
1996.) (b) Force during the sustained MVC shown in
panel (a). Arrows indicates the time of a cortical
stimulus. Corresponding force increments are shown
sequentially in a raster below. (Panel (b), unpublished
records from Gandevia et al. 1996.
Ó 1998 Scandinavian Physiological Society
S C Gandevia á Neural control and muscle fatigue
an initially submaximal contraction later required
maximal effort. The short-latency excitatory response
to cortical stimulation appeared to increase in maximal
contractions by about 50% (Figure 3a). One factor
which could underlie this is the recruitment of addi-
tional corticospinal cells, not simply those with a pro-
jection to the elbow ¯exors, but others with a divergent
projection to several arm muscles including the elbow
¯exors (Mills and Thomson 1995). If present, such
progressive spread of recruitment would lead to the
contraction of additional related muscles during the
task, a phenomenon commonly observed with strong
isometric efforts (Figure 4b).
Three pieces of evidence suggest that these changes
were focal cortical events. Firstly, the changes could not
be prevented by vibration of the muscles designed to
make up for diminished spindle input. Secondly, if the
sustained maximal contraction involved one muscle
group, the cortical `silent period' lengthened only in
that group and not in nearby muscles. Finally, the
growth of the excitatory response to cortical stimula-
tion was not present when the corticospinal axons were
stimulated distal to the cortex at the cervicomedullary
junction.
Despite their robustness, changes in moto cortical
excitability probed by arti®cial stimulation do not di-
rectly affect the central fatigue during sustained efforts.
First, these changes in cortical excitability recovered
within 30 s, even when the contracting elbow ¯exors
were maintained ischaemic, a manoeuvre assumed to
maintain the chemically mediated input via group III
and IV afferents (see above). However, during is-
chaemia maintained after a sustained maximal con-
traction with a sphygmomanometer cuff, central fatigue
persisted. Thus, moto cortical stimulation at the start of
279
Neural control and muscle fatigue á S C Gandevia
the maximal contraction increased ongoing voluntary
force by about 1%, but as central fatigue evolved, the
same cortical stimulus produced progressively more
force (Figure 3b). Hence, the voluntary moto output
became progressively less than optimal. The evoked
force increments were followed immediately by a de-
crement: its duration increased with that of the silent
period but its amplitude diminished due to the slowing
in muscle relaxation rate. The presence of cortically
evoked `twitches' late in the prolonged contractions
show that no site distal to the moto cortex was working
at its absolute maximum. The most parsimonious ex-
planation for the development of central fatigue is not
that it re¯ects changes in moto cortical excitability, but
that drive effectively `upstream' of cortical output de-
clined (such that it could be augmented by superim-
posed arti®cial stimulation). This reduction in drive may
be mediated by supraspinal effects of group III and IV
afferents. If so, a crucial question is not why moto
neurones fail to ®re fast enough but why the moto
cortex does not work as hard as it could. The failure of
moto cortical drive to remain suf®cient during fatigue
raises questions about the role of the cortical and
subcortical areas projecting to the primary moto cortex
and other cortical areas with direct corticospinal pro-
jections.
T E CH N I C AL LI MI T A T I O N S TO T H E
S T UD Y O F HU MA N MU S C LE F AT I G U E
Experimental methods are no better than their weakest
link. Because it is dif®cult to make the `cleanest' mea-
surements to deduce changes in neural control during
strong contractions, experimenters have often accepted
conditions which are not ideal. Three examples are
given to highlight problems that occur in measurements
of force, EMG, and moto neuronal `excitability'. Any
conclusions about central control of muscle during
280
Acta Physiol Scand 1998, 162, 275±283
Figure 4 Schematic representation of sites at
which changes occur during maximal
isometric contractions. Filled cells are
inhibitory. (a) (1) indicates apparently
increased excitability of the moto cortex, (2)
increased intracortical inhibition responsible
for silent period prolongation, and (3) the
corticospinal synapses and a-moto neurones.
(b) Extended view of moto cortex to show
the progressive recruitment of additional
corticospinal outputs to elbow ¯exor muscles
and related muscles during fatigue, that is,
from the `central' region to the peripheral
region within the box enclosing moto cortical
output cells. This would lead to progressive
contraction of `synergist' muscles during
fatigue.
fatigue must survive rigorous assessment of the meth-
ods on which they are based.
(i) Twitch responses to electrical stimulation are
used to monitor peripheral fatigue. The twitch is very
susceptible to the `history' of contraction with fatigue
usually reducing the twitch more than tetanic force (e.g.
Edwards et al. 1977). If submaximal stimulus intensities
are used (e.g. with knee extensors) the same moto units
are not tested with each stimulus. Furthermore, with
fatigue, such a stimulus will activate fewer motor axons
because of activity-dependent reductions in axonal ex-
citability (Bergmans 1973). Hence, for force measure-
ments in fatigue stimulus intensities must be
supramaximal.
(ii) Levels of EMG are commonly used as surrogate
measurements of neural drive to the fatiguing muscle.
Problems arise because the size of the intracellular ac-
tion potential is not constant with fatigue (Sandercock
et al. 1985): maximal compound muscle action poten-
tials initially grow and then decline during a sustained
contraction (Hicks et al. 1989, see also Fuglevand et al.
1993). The latter change re¯ects slowing in the con-
duction velocity of muscle ®bres. Furthermore, surface
EMG will not necessarily measure `drive' to one muscle
as it is easily contaminated by activity in nearby mus-
cles.
(iii) Tests of moto neuronal excitability can only be
conducted indirectly with H-re¯exes and stretch and
unloading responses. None of these re¯exes is purely
monosynaptic in humans (Burke et al. 1984) and re¯ex
size must therefore depend on the activity of inter-
neurones. These re¯exes could only provide valid tests
of moto neurone behaviour if exactly the same afferent
volley were evoked and all other re¯ex and descending
inputs were unaltered. These conditions are not easily
achieved. Ideally the re¯ex behaviour of single moto
units should be tested, as has been done for ®ring
properties during fatigue (e.g. Enoka et al. 1989, Gar-
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Acta Physiol Scand 1998, 162, 275±283
land et al. 1994). Finally, any apparent change in re¯ex
behaviour must be interpreted in the light of the known
reduction in moto neurone ®ring rate during sustained
isometric contractions.
C O N CL U S I O N S
With intense brief exercise, force is likely to depend
largely on muscle and biomechanical factors. If maxi-
mal exercise continues beyond about 10 s, central fac-
tors including de®cient drive `upstream' of moto
cortical output attenuate performance and eventually
stop it. If contractions are suf®ciently intense, the
threshold of the moto cortex appears reduced for both
inhibitory and excitatory processes. There is a need to
study in experimental animals the neural processes
controlling activity of moto neurones and moto cortical
neurones, and to apply rigorous methods to assess
these processes in voluntary exercise in humans.
The author's laboratory is supported by the National Health and
Medical Research Council and the Asthma Foundation of New South
Wales. Comments on the manuscript by Janet Taylor, Jane Butler and
Gabrielle Allen are gratefully acknowledged. I regret that space limi-
tations prevented citation of additional references.
R E FE RE N CE S
Al-Falahe, N.A., Nagaoka, M. & Vallbo, A Ê .B. 1990. Response
pro®les of human muscle afferents during active ®nger
movements. Brain 113, 325±346.
Allen, G.M, Gandevia, S.C. & McKenzie, D.K. 1995.
Reliability of measurements of muscle strength and
voluntary activation using twitch interpolation. Muscle Nerve
18, 593±600.
Allen, G.M., McKenzie, D.K., Gandevia, S.C. & Bass, S. 1993.
Reduced voluntary drive to breathe in asthmatic subjects.
Resp Physiol 93, 29±40.
Bailey, S.P., Davis, J.M., Ahlborn, E.N. 1993. Neuroendocrine
and substrate responses to altered brain 5-HT activity
during prolonged exercise to fatigue. J Appl Physiol 74,
3006±3012.
Bellemare, R., Woods, J.J., Johansson, R. & Bigland-Ritchie,
B. 1983. Motor-unit discharge rates in maximal voluntary
contractions of three human muscles. J Neurophysiol 50,
1380±1392.
Bergmans, J. 1973. Physiological observations on single
human nerve ®bres. In: J.E. Desmedt (Ed) New
Developments in Electromyography and Clinical Neurophysiology,
Vol. 2,
pp 89±127. Karger, Basel.
Bevan, L., Laouris, Y., Reinking, R.M. & Stuart, D.G. 1992.
The effect of the stimulation pattern on the fatigue of
single moto units in adult cats. J Physiol (Lond) 449,
85±108.
Bigland-Ritchie, B., Dawson, N.J., Johansson, R.S. & Lippold,
O.C. 1986. Re¯ex origin for the slowing of motoneurone
®ring rates in fatigue of human voluntary contractions.
J Physiol (Lond) 379, 451±459.
Ó 1998 Scandinavian Physiological Society
S C Gandevia á Neural control and muscle fatigue
Bigland-Ritchie, B., Johansson, R., Lippold, O.C.J., Smith, S.
& Woods, J.J. 1983a. Changes in motoneurone ®ring rates
during sustained maximal voluntary contractions. J Physiol
(Lond) 340, 335±346.
Bigland-Ritchie, B., Johansson, R., Lippold, O.C. & Woods,
J.J. 1983b. Contractile speed and EMG changes during
fatigue of sustained maximal voluntary contractions.
J Neurophysiol 50, 313±324.
Binder, M.D. & Mendell, L.M. (Eds). 1990. The Segmental Motor
System. Oxford University Press, New York.
Bongiovanni, L.G. & Hagbarth, K.-E. 1990. Tonic vibration
re¯exes elicited during fatigue from maximal voluntary
contractions in man. J Physiol (Lond) 423, 1±14.
Brasil-Neto, J.P., Pascual-Leone, A., Valls-SoleÂ, J.,
Cammarota, A., Cohen, L.G. & Hallet, M. 1993. Post
exercise depression of moto evoked potentials: a measure
of central nervous system fatigue. Exp Brain Res 93,
181±184.
Burke, D., Hagbarth, K.-E. & LoÈfstedt, L. 1978. Muscle
spindle activity in man during shortening and lengthening
contractions. J Physiol (Lond) 277, 131±142.
Burke, D., Gandevia, S.C. & McKeon, B. 1984. Monosynaptic
and oligosynaptic contributions to human ankle jerk and
H-re¯ex. J Neurophysiol 52, 435±448.
Capaday, C. & Stein, R.B. 1987. Difference in the amplitude
of the human soleus H re¯ex during walking and running.
J Physiol (Lond) 392, 513±522.
Curtis, D.R. & Eccles, J.C. 1960. Synaptic action during and
after repetitive stimulation. J Physiol (Lond) 150, 374±398.
Edwards, R.H., Hill, D.K., Jones, D.A. & Merton, P.A. 1977.
Fatigue of long duration in human skeletal muscle after
exercise. J Physiol (Lond) 272, 769±778.
Enoka, R.M., Robinson, G.A. & Kossev, A.R. 1989. Task and
fatigue effects on low-threshold moto units in a human
hand muscle. J Neurophysiol 62, 1344±1359.
Enoka, R.M. & Stuart, D.G. 1992. Neurobiology of muscle
fatigue. J Appl Physiol 72, 1631±1648.
Fuglevand, A.J. 1996. Neural aspects of fatigue. Neuroscientist
2, 203±206.
Fuglevand, A.J., Zackowski, K.M., Huey, K.A. & Enoka, R.M.
1993. Impairment of neuromuscular propagation during
human fatiguing contractions at submaximal forces.
J Physiol (Lond) 460, 549±572.
Gandevia, S.C. 1996. Kinaesthesia: roles for afferent signals
and moto commands. In: Handbook of Physiology Section 12,
pp 128±172. American Physiological Society.
Gandevia, S.C., Mace®eld, G., Burke, D. & McKenzie, D.K.
1990. Voluntary activation of human moto axons in the
absence of muscle afferent feedback. Brain 113, 1563±1581.
Gandevia S.C., Allen G.M., Butter J.-E., Taylor J.L. 1996.
Supraspinal factors in human muscle fatiques. Evidence for
subspinal output from the motor cortex. J Physiol (Lond)
490, 529±536.
Gandevia, S.C., Allen, G.M. & McKenzie, D.K. 1995. Central
fatigue: critical issues, quanti®cation and practical
implications. Adv Exp Med Biol 384, 281±294.
Garland, S.J., Enoka, R.M., Serrano, L.P. & Robinson, G.A.
1994. Behavior of moto units in human biceps brachii
during a submaximal fatiguing contraction. J Appl Physiol
76, 2411±2419.
281
Neural control and muscle fatigue á S C Gandevia
Garland, S.J. & McComas, A.J. 1990. Re¯ex inhibition of
human soleus muscle during human muscle fatigue.
J Physiol (Lond) 401, 547±558.
Grimby, L., Hannerz, J. & Hedman, B. 1981. The fatigue and
voluntary discharge properties of single moto units in man.
J Physiol (Lond) 316, 545±554.
Hagbarth, K.-E., Bongiovanni, L.G. & Nordin, M. 1995.
Reduced servo-control of fatigued human ®nger extensor
and ¯exor muscles. J Physiol (Lond) 485, 865±872.
Hales, J.P. & Gandevia, S.C. 1988. Assessment of maximal
voluntary contraction with twitch interpolation: an
instrument to measure twitch responses. J Neurosci Meth 25,
97±102.
Hayward, L., Breitbach, D. & Rymer, W.Z. 1988. Increased
inhibitory effects on close synergists during muscle fatigue
in the decerebrate cat. Brain Res 440, 199±203.
Hayward, L., Wesselmann, U. & Rymer, Z. 1991. Effects of
muscle fatigue on mechanically sensitive afferents of slow
conduction velocity in the cat triceps surae. J Neurophysiol
65, 360±370.
Herbert, R.D. & Gandevia, S.C. 1996. Muscle activation in
unilateral and bilateral efforts assessed by moto nerve and
cortical stimulation. J Appl Physiol 80, 1351±1356.
Hicks, A., Fenton, J., Garner, S. & McComas, A.J. 1989. M
wave potentiation during and after muscle activity.
J Appl Physiol 66, 2606±2610.
Hoffman, P., Terenius, L. & ThoreÂn, P. 1990. Cerebrospinal
¯uid immunoreactive b-endorphin concentration is
increased by voluntary exercise in the spontaneously
hypertensive rat. Regul Pept 28, 233±239.
Hulliger, M., SjoÈlander, P., Windhorst, U.R. & Otten, E. 1995.
Force coding by populations of cat golgi tendon organ
afferents. In: A. Taylor, M.H. Gladden & R. Durbaba (Eds)
Alpha and Gamma Motor Systems, pp. 302±308. Plenum Press,
New York.
Hultborn, H., & Kiehn, O. 1992. Neuromodulation of
vertebrate moto neuron membrane properties. Curr Opin
Neurobiol 2, 770±775.
Hultborn, H., Lipski, J., Mackel, R. & Wigstrom, H. 1988.
Distribution of recurrent inhibition within a moto nucleus.
I. Contribution from slow and fast moto units to the
excitation of Renshaw cells. Acta Physiol Scand 134, 347±361.
Hutton, R.S. & Nelson, D.L. 1986. Stretch sensitivity of Golgi
tendon organs in fatigued gastrocnemius muscle. Med Sci
Sports Exerc 18, 69±74.
Jami, L. 1992. Golgi tendon organs in mammalian skeletal
muscle: functional properties and central actions. Physiol Rev
72, 623±666.
Jankowska, E. 1992. Interneuronal relay in spinal pathways
from proprioceptors. Progr Neurobiol 38, 335±387.
Jones, L.A. 1995. The senses of effort and force during
fatiguing contractions. In: Gandevia, S.C., Enoka, R.M.,
McComas, A.J., Stuart, D.G. & Thomas, C.K (Eds) Fatigue:
Neural and Muscular Mechanisms, Plenum Press, New York.
Adv Exp Med Biol 384, pp 305±313.
Kaufman, M.P., Longhurst, J.C., Rybicki, K.J., Wallach, J.H.
& Mitchell, J.H. 1983. Effects of static muscular
contraction on impulse activity of groups III and IV
afferents in cats. J Appl Physiol 55, 105±112.
282
Acta Physiol Scand 1998, 162, 275±283
Kernell, D. & Monster, A.W. 1982. Time course and
properties of late adaptation in spinal motoneurones of the
cat. Exp Brain Res 46, 191±196.
Kirsch, R.F. & Rymer, W.Z. 1987. Neural compensation for
muscular fatigue evidence for signi®cant force regulation in
man. J Neurophysiol 57, 1893±1910.
Kniffki, K.D., Mense, S. & Schmidt, R.F. 1978. Responses of
group IV afferent units from skeletal muscle to stretch,
contraction and chemical stimuli. Exp Brain Res 31, 511±522.
Kukulka, C.G., Moore, M.A. & Russell, A.G. 1986. Changes
in human a-motoneuron excitability during sustained
maximum isometric contractions. Neurosci Lett 68, 327±333.
Lev-Tov, A. & Pinco, M. 1992. In vitro studies of prolonged
synaptic depression in the neonatal rat spinal cord.
J Physiol (Lond) 447, 149±169.
Ljubisavljevic, M., Jovanovic, K. & Anastasijevic, R. 1992.
Changes in discharge rate of fusimoto neurones provoked
by fatiguing contractions of cat triceps surae muscles.
J Physiol (Lond) 445, 499±513.
Ljubisavljevic, M. & Anastasijevic, R. 1994. Fusimoto-
induced changes in muscle spindle out¯ow and
responsiveness in muscle fatigue in decerebrate cats.
Neurosci 63, 339±348.
Ljubisavljevic, M., Anastasijevic, R. & Trifunjagic, D. 1995.
Changes in fusimoto discharge rate provoked by isotonic
fatiguing muscle contractions in decerebrate cats. Brain Res
673, 126±132.
LoÈescher, W.N., Cresswell, A.G. & Thorstensson, A. 1996a.
Central fatigue during a long-lasting submaximal
contraction of the triceps surae. Exp Brain Res 108,
305±314.
LoÈescher, W.N., Cresswell, A.G. & Thorstensson, A. 1996b.
Recurrent inhibition of soleus alpha-motoneurons during a
sustained submaximal plantar ¯exion. Electroencephalogr clin
Neurophysiol 101, 334±338.
Mace®eld, V.G., Hagbarth, K.-E., Gorman, R., Gandevia,
S.C. & Burke, D. 1991. Decline in spindle support to a
motoneurones during sustained voluntary contractions.
J Physiol (Lond) 440, 497±512.
Mace®eld, V.G., Gandevia, S.C., Bigland-Ritchie, B.,
Gorman, R.B. & Burke, D. 1993. The ®ring rates of
human motoneurones voluntarily activated in the absence
of muscle afferent feedback. J Physiol (Lond) 471,
429±443.
Marsden, C.D., Meadows, J.C. & Merton, P.A. 1983.
`Muscular wisdom' that minimized fatigue during
prolonged effort in man: peak rates of motoneuron
discharge and slowing of discharge during fatigue.
Adv Neurol 39, 169±211.
Maton, B., Fourment, A. & Belhaj-Saif, A. 1994. Changes in
precentral moto cortical cells activity during fatigue induced
by submaximal isometric intermittent contractions. Neural
and Neuromuscular Aspects of Muscle Fatigue: Satellite
Symposium to the Society for Neuroscience B13.
McKenzie, D.K. & Gandevia, S.C. 1991. Recovery from
fatigue of human diaphragm and limb muscles. Respir
Physiol 84, 49±60.
Merton, P.A. 1954. Voluntary strength and fatigue.
J Physiol (Lond) 123, 553±564.
Ó 1998 Scandinavian Physiological Society
Acta Physiol Scand 1998, 162, 275±283
Meunier, S. & Pierrot-Deseilligny, E. 1989. Gating of the
afferent volley of the monosynaptic stretch re¯ex during
movement in man. J Physiol (London) 419, 753±763.
Miller, K.J., Garland, S.J., Ivanova, T. & Ohtsuki, T. 1996.
Motor-unit behavior in humans during fatiguing arm
movements. J Neurophysiol 75, 1629±1636.
Mills, K.R. & Thomson, C.C.B. 1995. Human muscle fatigue
investigated by transcranial magnetic stimulation.
Neuroreport 6, 1966±68.
McKay, W.B., Stokic, D.S., Sherwood, A.M., Vrbova, G. &
Dimitrijevic, M.R. 1996. Effect of fatiguing maximal
voluntary contraction on excitatory and inhibitory
responses elicited by transcranial magnetic moto cortex
stimulation. Muscle Nerve 19, 1017±1024.
McKay, W.B., Tuel, S.M., Sherwood, A.M., Stokic, D.S. &
Dimitrijevic, M.R. 1995. Focal depression of cortical
excitability induced by fatiguing muscle contraction: a
transcranial magnetic stimulation study. Exp Brain Res 105,
276±282.
Nelson, D.L. & Hutton, R.S. 1985. Dynamic and static stretch
responses in muscle spindle receptors in fatigued muscle.
Med Sci Sports Exerc 17, 445±450.
Nielsen, J. & Petersen, N. 1994. Is presynaptic inhibition
distributed to corticospinal ®bres in man? J Physiol (Lond)
477, 47±58.
Paintal, A.S. 1960. Functional analysis of group III afferent
®bres of mammalian muscle. J Physiol (Lond) 152, 250±270.
Persson, S., Jonsdottir, I., ThoreÂn, P., Post, D., Nyberg, F. &
Hoffmann, P. 1993. Cerebrospinal ¯uid dynorphin-
converting enzyme activity is increased by voluntary
exercise in the spontaneously hypertensive rat. Life Sci 53,
643±652.
Pickar, J.G., Hill, J.M. & Kaufman, M.P. 1994. Dynamic
exercise stimulates group III muscle afferents. J Neurophysiol
71, 753±760.
Porter, R. & Lemon, R. 1993. Corticospinal Function and
Voluntary Movement. Clarendon Press, Oxford.
Pratt, C.A. 1995. Evidence of positive force feedback among
hindlimb extensors in the intact standing cat. J Neurophysiol
73, 2578±2583.
Ó 1998 Scandinavian Physiological Society
S C Gandevia á Neural control and muscle fatigue
Rotto, D.M. & Kaufman, M.P. 1988. Effect of metabolic
products of muscular contraction on discharge of group III
and IV afferents. J Appl Physiol 64, 2306±2313.
Sandercock, T.G., Faulkner, J.A., Albers, J.W. & Abbrecht,
P.H. 1985. Single moto unit and ®ber action potentials
during fatigue. J Appl Physiol 58, 1073±1079.
Sawcuk, A., Powers, R.K. & Binder, M.D. 1995. Spike
frequency adaptation studied in hypoglossal motoneurons
of the rat. J Neurophysiol 73, 1799±1810.
Sinoway, L.I., Hill, J.M., Pickar, J.G. & Kaufman, P. 1993.
Effects of contraction and lactic acid on the discharge of
group III muscle afferents in cats. J Neurophysiol 69,
1053±1059.
Spielmann., J.M., Laouris, Y., Nordstrom, M.A., Robinson,
G.A., Reinking, R.M. & Stuart, D.G. 1993. Adaptations of
cat motoneurons to sustained and intermittent extracellular
activation. J Physiol (Lond) 464, 75±120.
Taylor, J.L., Butler, J.E., Allen, G.M. & Gandevia, S.C. 1996.
Changes in moto cortical excitability during human muscle
fatigue. J Physiol (Lond) 490, 519±528.
Thompson, S., Gregory, J.E. & Proske, U. 1990. Errors in
force estimation can be explained by tendon organ
desensitization. Exp Brain Res 79, 365±372.
van Hall, G., Raaymakers, J.S., Saris, W.H. &
Wagenmakers, A.J. 1995. Ingestion of branched-chain
amino acids and tryptophan during sustained exercise in
man: failure to affect performance. J Physiol (Lond) 486,
789±794.
Windhorst, U. & Boorman, G. 1995. Overview: potential role
of segmental motor circuitry in muscle fatigue. Adv Exp
Med Biol 384, 241±258. Plenum Press, New York.
Zanette, G., Bonato, C., Polo, A., Tinazzi, M., Manganotti, P.
& Fiaschi, A. 1995. Long-lasting depression of motor-
evoked potentials to transcranial magnetic stimulation
following exercise. Exp Brain Res 107, 80±86.
Zytnicki, D., La¯eur, J., Horcholle-Bossavit, G., Lamy, F. &
Jami, J. 1990. Reduction of 1b autogenetic inhibition in
motoneurons during contractions of an ankle extensor
muscle in the cat. J Neurophysiol 64,
1380±1389.
283