Exercise Induced Fatigue: Neural Mechanisms

Amerigo Rossuello

Brain and Behavior I

Final Paper
August 13, 2009
Introduction

Exercise induced fatigue has been defined as an inability to sustain a given level of power

output during repetitive or continuous muscular contractions . The failure to maintain power

output during exercise is most likely multifactorial and may be caused by central factors, which

decrease the body’s ability to maximally stimulate the muscle, or peripheral factors, which

decrease the ability of the muscle to produce maximal force . The relative contributions of

central and peripheral factors to exercise induced fatigue are still a cause for debate . Several

studies have attempted to answer this question via the twitch interpolation technique, whereby

the motor nerve is artificially stimulated while the subject is maximally contracting the

innervated muscle. If the force increases during the twitch interpolation, than the central drive

was insufficient and central fatigue is likely a cause of the fatigue; if no increase in force occurs,

then the fatigue is likely completely peripheral. Recent advances have allowed researchers to

also use targeted transcranial magnetic stimulation during muscle contractions to also asses

central drive deficiencies in fatigue.

These types of studies are typically done using isometric contractions to enable optimal

assessment of force and EMG, and the results generally indicate that central fatigue accounts for

10-25% of total fatigue . The goal of this paper will be to explain the most probable supraspinal

and spinal changes that occur during exercise to cause a reduction in neural drive. Some

particular attention will also be given to any relative changes in central fatigability that may

occur with aging.

This paper will also attempt to differentiate and find commonalities between the various

causes of fatigue due to the three primary modes of fatiguing exercise; 1. Repeated or sustained

maximal contractions in which EMG remains relatively constant while force decreases. 2.

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Repeated or sustained submaximal muscle contractions in which force is maintained as long as

possible while EMG gradually increases until failure. 3. Dynamic whole body endurance

exercise in which power output is maintained until failure.

Supraspinal fatigue

Supraspinal fatigue can be quantified by administering TMS to the motor cortex with a

simultaneous maximal voluntary effort. The difference between the last maximal voluntary

contraction and the subsequent contraction with TMS supplementation is considered to be the

amount of fatigue that is due to supraspinal processes. Supraspinal fatigue has been

demonstrated to be approximately ¼ of the total central fatigue during repeated maximal exercise

and ½ of the total during submaximal exercises .

Preventing the recovery of a newly fatigued muscle by limiting blood flow does not

affect the recovery of excitability in the motor cortex from central fatigue, as evidenced by TMS

activation. However, supraspinal fatigue remains evident until blood flow is restored to the

fatigued muscle due to maintained activation of group III and IV muscle afferents , suggesting

that these neurons inhibit maximal motor cortical output when metabolic factors indicate muscle

fatigue. This evidence should somewhat moderate the weight of the conclusions achieved in

fatigue studies that use sustained contractions, maximal or sub-maximal, of a small muscle group

because of the potential for the exercise to unnaturally occlude blood flow.

The actual changes in neurotransmitter release, reuptake and breakdown during fatiguing

exercise are still mostly theoretical because it has been difficult to assess brain neurotransmitter

activity in vivo. However, based on the recent advances using the microdialysis technique and

accumulated knowledge of neurotransmitter function, several theories have strong evidential

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support, primarily focused on exercise induced changes in the dopaminergic, noradrenergic and

serotonergic systems .

The neurotransmitter implicated in the predominant central fatigue theory has been

serotonin. The theory is based on research showing that free tryptophan and branched chain

amino acids (BCAA) compete for a transporter to cross the blood brain barrier . During

endurance exercise, the human body progressively utilizes more BCAAs, allowing more

tryptophan to cross the blood brain barrier. Because tryptophan is a precursor to serotonin, this

sequence leads to higher than normal concentrations of serotonin in the brain, causing fatigue

symptoms like irritability and increased level of perceived exertion. However, if the process

were this simple, then BCAA supplementation, which elevates blood BCAA concentration would

improve exercise performance by delaying fatigue; but the results have been equivocal .

Furthermore, because studies that were able to selectively increase brain serotonin concentration

did not consistently improve exercise , it is more likely that the interactions between several

neurotransmitters actually influence the development of fatigue during exercise.

A revised central fatigue hypothesis contends that, because of the well-known properties

of dopamine in feeling motivated, the ratio between brain serotonin and dopamine is probably a

better indicator of fatigue . High ratios (serotonin to dopamine) are associated with fatigue, and

low ratios are associated with motivation. Because mood and exercise tolerance are strongly

based on brain neurotransmitter activity, it is more likely that central fatigue is caused by

changes in serotonin and dopamine concentration than by serotonin alone. More research needs

to be done to determine the exact changes in neurotransmitter activity in the brain during

exercise and to what degree they cause fatigue.

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 Endurance exercise in a hot and humid environment, when body temperature cannot be

controlled, causes fatigue more quickly than in cooler temperatures, which may indicate a

thermal limit (~40˚C) to exercise performance, although the mechanism is unclear . Though

some of the fatigue associated with high body heat may be due to reduced blood volume

associated with dehydration, part of it can be attributed to central fatigue based on the activity of

the hypothalamus in core temperature regulation. Therefore, exercise induced functional

changes in the serotonergic and catecholaminergic projections to the hypothalamus may alter its

function. Seven out of 9 subjects who were administered bupropion, a norepinephrine and

dopamine reuptake inhibitor, were able to achieve core temperatures above 40˚C, while only 2

out of 9 in the placebo trial . Furthermore, endurance performance was significantly better in the

experimental trail, indicating that neurotransmitter activity at high temperatures affects the

hypothalamus’ control of body temperature, and subsequently rate of fatigue.

Another possible cause of the reduced supraspinal capacity during maximal repeated

contractions is intracortical inhibition, caused by GABAB receptor activation , although some

evidence suggests a much more complex system of inhibition and excitation controlled by both

GABAA and GABAB receptor activation . It is still unclear, however, exactly how this

mechanism is controlled during fatiguing exercise.

Spinal fatigue

One of the most well known causes of central fatigue during maximal sustained or

repeated exercise and repeated submaximal contractions is the slowing of motor unit firing rates .

Slowed motor unit firing rates may cause some muscle fibers to not fully contract, reducing the

force output and causing fatigue. Three general changes to the motor neuron are most likely

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responsible for the slowing of motor neuron firing rate; increased inhibitory input, reduced

excitatory input, and decreased responsiveness to excitatory stimuli. It is likely that all three

contribute to central fatigue , but their relative contributions to the slowing of maximal motor

unit firing rate remain unknown.

Nociceptive stimulation incurred during fatiguing exercise most likely stimulates the

activity of inhibitory interneurons which reduce the excitability of motor neurons . Furthermore,

group III and IV afferent nerves, which are sensitive to the accumulation of metabolites, increase

in heat, and mechanical stresses may also inhibit motor neuron activity during maximal exercises

. It has been shown that a sustained contraction as small as 5% of maximal voluntary contraction

can sufficiently increase the arteriovenous K+ difference to stimulate group IV afferent neurons

which many also slow neuron firing rate (spinal fatigue) and reduce motor cortical drive

(supraspinal fatigue).

Motor neuron firing rate may also decrease due to a reduction in muscle spindle firing,

causing a decrease in the muscle spindle contraction facilitation . Macefield, et al. observed a ½

reduction in muscle spindle activity after 1 minute of isometric contraction, likely leading to a

reduction in excitatory input during and immediately after fatiguing exercise.

Andersen, et al. measured maximal force output following a fatiguing exercise of the

abductor digiti minimi muscle. They also measured the fatigued force output while

supplemented with TMS, and the force with simultaneous TMS and direct motor nerve

stimulation. The findings showed that TMS failed to activate all of the motor neurons following

the fatiguing exercise, indicating that a reduction in the motor neuron responsiveness to an

excitatory stimulus was the primary cause of central fatigue.

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Older Adults and Aging

Although older adults produce less maximal force than their young counterparts, older

adults experience less fatigue during repetitive or sustained maximal contractions when the last

contraction is expressed as a percentage of maximal voluntary contractile force . Because the

fatigability is apparently different between young and older adults, it can be supposed that the

mechanisms that cause central fatigue may be different or differentially influential in older

adults.

One of the mechanisms of central fatigue in young, healthy adults is a slowing of the

maximal firing rate of the motor neurons. Older adults have approximately 30-35% slower

maximal motor unit firing rates than young adults when unfatigued . Furthermore, it has been

well documented that older adults have a relatively higher percentage of slower, type I motor

neurons than young adults, and an increased threshold for motor cortex excitability . However, it

is unclear whether the slower baseline firing rates changes differently during fatiguing exercise.

Kent-Braun, et al. found no difference in the rate of force development between young and old

adults during repeated maximal contractions. Similarly, young and older adults are both able to

voluntarily activate more than 99% of their target muscle fibers at baseline and fatigue. A recent

study, however, observed a decrease in maximal voluntary activation following a submaximal

fatiguing protocol (20% MVC) in older adults , although the difference was not present at 80%

MVC.

The motor neurons of older adults may have a lower concentration of acetylcholine , less

synaptic vesicles and altered sodium-potassium transport capabilities , suggesting

neuromuscular propagation should be lower in older adults. The M-wave amplitude is, in fact,

approximately 20-40% lower in older adults, depending on the muscle group, and progressively

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declines with age . Although the older motor neurons are clearly functionally different, fatiguing

exercise has not had any consistent differential effects on M-wave characteristics in older adults

compared to young adults.

The results from the relatively few studies that have been done comparing the

mechanisms of central fatigue in young and older adults (or animals) have been inconclusive .

At this time, it does not appear that the causes of central fatigue change with age, but future

research may clarify whether the proportional influence of each aspect changes over time.

Conclusion

The central mechanisms of exercise induced fatigue remain relatively unknown because

of the inherent difficulties in assessing neural changes during exercise performance. However,

decades of arduous work and ingenuity have led the scientific field to a basic understanding of

several causes of a reduced capacity to maximally stimulate muscle during exhaustive exercise.

One of the most likely causes of supraspinal fatigue during exercise is the inhibitory

effect of afferent group III and IV neurons, which sense fatigue and may be a safety negative

feedback loop to make sure humans do not pass their limit of exercise tolerance. Endurance

exercise is also limited in the brain by the contrasting affects of serotonin and dopamine. High

serotonin concentration may lead to fatigue unless there is a concurrent increase in dopamine

concentration to counteract the affects of serotonin. High dopamine concentrations may

stimulate the hypothalamus to disregard the exercise related increase in core temperature, which

also may delay fatigue during endurance exercise in the heat.

There is a broad consensus that the most prominent portion of central fatigue is caused by

a decrease in the maximal firing rate of fatigued motor neurons. The reduction in firing rate is

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caused by increased inhibitory input, reduced excitatory input and responsiveness to excitatory

input.

Older adults fatigue at a slower rate than young adults during maximal or submaximal

exercise protocols, but the mechanism causing the difference has yet to be discovered, although

one likely cause is a decrease in maximal voluntary activation.

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References

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