Muscle fatigue is an exercise-induced reduction in maximal voluntary muscle force. It may arise not only because of peripheral changes at the level of the muscle, but also because the central nervous system fails to drive the motoneurons adequately. Evidence for "central" fatigue and the neural mechanisms underlying it are reviewed, together with its terminology and the methods used to reveal it. Much data suggest that voluntary activation of human motoneurons and muscle fibers is suboptimal and thus maximal voluntary force is commonly less than true maximal force. Hence, maximal voluntary strength can often be below true maximal muscle force. The technique of twitch interpolation has helped to reveal the changes in drive to motoneurons during fatigue. Voluntary activation usually diminishes during maximal voluntary isometric tasks, that is central fatigue develops, and motor unit firing rates decline. Transcranial magnetic stimulation over the motor cortex during fatiguing exercise has revealed focal changes in cortical excitability and inhibitability based on electromyographic (EMG) recordings, and a decline in supraspinal "drive" based on force recordings. Some of the changes in motor cortical behavior can be dissociated from the development of this "supraspinal" fatigue. Central changes also occur at a spinal level due to the altered input from muscle spindle, tendon organ, and group III and IV muscle afferents innervating the fatiguing muscle. Some intrinsic adaptive properties of the motoneurons help to minimize fatigue. A number of other central changes occur during fatigue and affect, for example, proprioception, tremor, and postural control. Human muscle fatigue does not simply reside in the muscle.

1. Voluntary activation of elbow flexor muscles can be optimal during brief maximal voluntary contractions (MVCs), although central fatigue, a progressive decline in the ability to drive the muscle maximally, develops during sustained or repeated efforts. We stimulated the motor cortex and motor point in human subjects to investigate motor output during fatigue. 2. The increment in force (relative to the voluntary force) produced by stimulation of the motor point of biceps brachii increased during sustained isometric MVCs of the elbow flexors. Motoneuronal output became suboptimal during the contraction, i.e. central fatigue developed and accounted for a small but significant loss of maximal voluntary force. During 3 min MVCs, voluntary activation of biceps fell to an average of 90.7% from an average of > 99%. 3. The increment in force (relative to the voluntary force) produced by magnetic cortical stimulation was initially small (1.0%) but also increased during sustained MVCs to 9.8% (with a 2 min MVC). Thus, cortical output was not optimal at the time of stimulation nor were sites distal to the motor cortex already acting maximally. 4. A sphygmomanometer cuff around the upper arm blocked blood supply to brachioradialis near the end of a sustained MVC and throughout subsequent brief MVCs. Neither maximal voluntary force nor voluntary activation recovered during ischaemia after the sustained MVC. However, fatigue‐induced changes in EMG responses to magnetic cortical stimulation recovered rapidly despite maintained ischaemia. 5. In conclusion, during sustained MVCs, voluntary activation becomes less than optimal so that force can be increased by stimulation of the motor cortex or the motor nerve. Complex changes in excitability of the motor cortex also occur with fatigue, but can be dissociated from the impairment of voluntary activation. We argue that inadequate neural drive effectively ‘upstream’ of the motor cortex must be one site involved in the genesis of central fatigue.

of exercise. Obesity. 2006;14:345-356. Voluntary physical activity and exercise training can favorably influence brain plasticity by facilitating neurogenerative, neuroadaptive, and neuroprotective processes. At least some of the processes are mediated by neurotrophic factors. Motor skill training and regular exercise enhance executive functions of cognition and some types of learning, including motor learning in the spinal cord. These adaptations in the central nervous system have implications for the prevention and treatment of obesity, cancer, depression, the decline in cognition associated with aging, and neurological disorders such as Parkinson's disease, Alzheimer's dementia, ischemic stroke, and head and spinal cord injury. Chronic voluntary physical activity also attenuates neural responses to stress in brain circuits responsible for regulating peripheral sympathetic activity, suggesting constraint on sympathetic responses to stress that could plausibly contribute to reductions in clinical disorders such as hypertension, heart failure, oxidative stress, and suppression of immunity. Mechanisms explaining these adaptations are not as yet known, but metabolic and neurochemical pathways among skeletal muscle, the spinal cord, and the brain offer plausible, testable mechanisms that might help explain effects of physical activity and exercise on the central nervous system.

We investigated the reproducibility of measurements of maximal voluntary torque and maximal voluntary activation using twitch interpolation. On 5 days, each of 5 subjects performed 10 maximal voluntary isometric contractions of their elbow flexors. Single supramaximal stimuli were delivered over biceps brachii at the measured peak torque during each effort, and in the relaxed muscle 5 s later. A voluntary activation score was calculated from the size of twitches evoked by the stimuli (resolution < 0.15 Nm). Although all subjects were able to drive the stimulated elbow flexor muscles maximally in some trials, they did not do so in 75% of all contractions. Maximal voluntary torques did not vary significantly within a subject between sessions. There were consistent differences in the level of maximal voluntary activation between subjects (P < 0.01), but no differences in voluntary activation within an individual across days in 4 of 5 subjects. Failure to drive the stimulated elbow flexor muscles maximally was not associated with inadvertent co-contraction of the antagonist muscles.

1. The excitability of the motor cortex was investigated during fatiguing contractions of the elbow flexors in human subjects. Although the silent period following cervicomedullary stimulation lengthened, it remained substantially shorter than the cortically evoked silent period. 5. The altered EMG responses to transcranial stimulation during fatigue suggest both increased excitation and increased inhibition in the motor cortex. As these changes were unaffected by manipulation of afferent input they presumably result from intrinsic cortical processes and/or altered voluntary drive to the motor cortex.Transcranial magnetic stimulation can be used to examine the motor output in human subjects. Stimulation over the motor cortex evokes both excitatory and inhibitory responses in the EMG of contracting muscle. The shortlatency motor-evoked potential (MEP) is a compound muscle action potential with an onset latency consistent with a rapidly conducting monosynaptic pathway. It is believed to arise from direct and trans-synaptic activation of corticospinal neurones and is influenced by the excitability of the motor cortex and the a-motoneurone pool (Amassian,

Electrical stimulation over human muscle can generate force directly by activation of motor axons and indirectly by ‘reflex’ recruitment of spinal motoneurones. These experiments were designed to define the properties of the centrally generated ‘reflex’ force, including the optimal stimulus conditions for producing it in tibialis anterior (TA) and triceps surae (TS), and its interaction with volition. Subjects (n= 21) were seated with their foot strapped to an isometric myograph. Surface EMG was recorded from TS and TA. High‐frequency electrical stimulation (100 Hz) of TS and TA with wide pulse widths (1 ms) was most effective to evoke the sustained centrally generated forces. The maximal force evoked by this mechanism during stimulation of TA for 40 s was ∼42 % of that produced by a maximal voluntary contraction. For both muscle groups, ramp increases and decreases in stimulus frequency (from ∼4 to 100 Hz and back to 4 Hz over 6 s) resulted in marked hysteresis in the force‐frequency plot. After a single ‘burst’ of 100 Hz stimulation during prolonged stimulation at 25 Hz, force remained elevated. Repeated bursts often generated progressively larger force increments. These behaviours were abolished by an anaesthetic nerve block proximal to the stimulation site, confirming the central origin for the ‘extra’ force. After a brief voluntary contraction was performed during 25 Hz stimulation, force remained elevated, and this showed some gradation with voluntary contraction amplitude. Sometimes voluntary contractions alone initiated the sustained central motor output. Involuntary contractions often persisted for many seconds after electrical stimulation ceased. These were not terminated by brief inhibitory inputs to the active motoneurones but could be stopped by the voluntary command to ‘relax completely’. Overall, these centrally generated contractions are consistent with activation of plateau potentials in motoneurones innervating the ankle dorsiflexors and plantarflexors. Large forces can be produced through this mechanism. The interaction with volitional drives suggests that plateau behaviour may contribute significantly to the normal output of human motoneurones.

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 Ϯ 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.

The deep and superficial fibers of the multifidus are differentially active during single and repetitive movements of the arm. The data from this study support the hypothesis that the superficial multifidus contributes to the control of spine orientation, and that the deep multifidus has a role in controlling intersegmental motion.