Motoneurone excitability after fatiguing exercise in subjects with ME/CFS


Wood L, Sutherland G, Day L, Paul L


Department of Biological and Biomedical Sciences, Glasgow Caledonian University, Glasgow, UK


Muscle fatigue is a complex and multifactorial phenomenon which affects the ability of individuals to maintain adequate force during voluntary contraction following a period of exercise. The physiological mechanisms responsible for this decline in force production may be peripheral in origin, related to factors within the muscle itself, or central, related to extra-muscular (neural) factors which influence how the muscle contracts. The central neural drive for muscle contraction is finally transmitted to the muscle via the spinal motoneurones and these are subject to various descending inputs arising in the higher elements of the CNS, and also by reflex afferents arising from peripheral sensory receptors.  Subjects with ME/CFS have previously been shown to demonstrate delayed recovery from fatiguing contractions in knee extensor muscles (Paul, Wood, Behan & MacLaren, 1999) although the reasons for this delay are not known. This study aimed therefore to investigate the effects of skeletal muscle fatigue on the excitability of spinal motoneurones in subjects with ME/CFS utilising the Hoffmann reflex (H-reflex) as a measure of this.

The H-reflex is a non-invasive neurophysiological tool which allows the overall excitability of the motoneurones (or more accurately, the excitability of the monosynaptic reflex arc involving these motoneurones) to be monitored. Variations in H-reflex amplitude reflect changes in motoneuronal excitabiltity and is easily measured by electromyography. Inhibition of the H-reflex with fatigue is thought to be due to the effects of group III and group IV muscle afferents activated by pain and metabolic factors during fatigue. We have previously demonstrated that recovery of generation of muscle force following fatiguing exercise in subjects with ME/CFS is delayed (Paul et al, 1999) and therefore postulated that there may be a link to differences in motoneuronal excitability controlling muscle contraction in these subjects.


Experiments were performed on 8 subjects (age 44 – 62, mean 50.8 ± 3.0 years) with ME/CFS satisfying the diagnostic criteria set out by the Centre for Disease Control (Fukuda et al, 1994). In addition, subjects were assessed using the Canadian criteria for ME/CFS (Carruthers, 2003). The mean duration of the condition in these subjects was 14.7 ± 2.2 years. Control experiments were performed on age- and sex-matched sedentary controls. H-reflexes were elicited by surface electrical stimulation of the posterior tibial nerve in the popliteal fossa utilising 1 millisecond stimulus pulses at a constant voltage and current set to 1.1 – 1.2 x threshold for eliciting the reflex. Subsequent changes in H-reflex amplitude were expressed as percentages of the mean of these pre-fatigue reflexes. Following a warm-up period and practice contractions, subjects undertook a fatiguing test consisting of a series of 40 maximal voluntary contractions (MVCs) of the triceps surae muscle group. This test involved making plantar flexion movements of the ankle joint against a custom-built footplate with inbuilt force transducer. Force of contraction was measured for each of the 40 MVCs and calculated as a percentage of the mean of the initial three MVC contractions (taken as 100%).


During the fatigue test, subjects demonstrated a general decline in the force produced by maximal voluntary contraction over the course of the 40 contractions. There was, however, wide variability in the response of subjects to the fatiguing contractions. During the 40 MVC fatigue test, the mean force produced by the control subjects did not decline to any great extent, and the force at the end of the fatigue test was not significantly different from that at the beginning (p>0.05). During the recovery phase control subjects demonstrate a trend of increasing force though this is also not significantly different from initial levels (p>0.05). For the subjects with ME/CFS there was a decline in force during the fatigue test to around 75% of initial force levels. This was significantly different from initial force levels (p<0.05). During the recovery phase, force levels continue to decrease up to 240 minutes post-exercise, remaining significantly different from initial force levels, but not from the force levels at the end of the fatigue test. In all cases the size of the error bars was large, reflecting the large degree of variability in the responses of individual subjects. However, in both subjects with ME/CFS and in control subjects there were no significant changes in H-reflex amplitude post-exercise (p<0.05). As with the changes in force, there was a wide variability in the response of individual subjects and the amplitude of the H-reflex fluctuated considerably during the recovery period. Such fluctuations are not uncommon, but, overall, there was little change in mean amplitude during this time.


The overall conclusion from this pilot study was that fatigue of ankle plantar flexors did not affect the excitability of the motoneurones supplying these muscles. However, the degree of fatigue induced in these muscles in the current study may not have been sufficient to unmask any such effects. Similarly, there were no effects on the M-wave produced by direct muscle stimulation, though, again, this may have been due to the level of fatigue induced.

Publication & Dissemination

International Colloquium on ME/CFS Biomedical Research, Glasgow Caledonian University, July 2006

New Horizons International Conference on ME/CFS Biomedical Research, Friday 25th May 2007, Edinburgh Conference Centre, Heriot-Watt University, Edinburgh

Comment by ME Research UK

Historically, one of the cardinal signs of ME was marked muscle “fatigability” or loss of power,  often in response to quite minor degrees of exercise. Muscle cramps, twitching and extreme muscle tenderness were also common findings. Today, how many ME patients have had a proper clinical examination of their affected muscles? Very few, in fact, but patient reports suggest that observable muscle abnormalities might be more common that is often supposed, and there is some evidence in the modern literature of anomalies in the muscles and nerves of patient. For example, muscle fatigue has been shown to produce alterations in muscle membrane excitability in ME patients, possibly associated with increased muscle oxidative stress (Jammes et al, 2005).

Building on their investigation of pain in ME patients, Dr Les Wood and Dr Lorna Paul at Glasgow Caledonian University designed this study to look at how nerves control the calf muscles in the leg and what happens to this control after exercise. To do this, they stimulated one of the nerves in the back of the leg behind the knee using a short, non-painful electric shock and at the same time recorded what happens to the muscle when this occurs. They did this about ten times initially and then, after a short warm-up period, they asked the patient to undertake a short exercise designed to fatigue the calf muscles. This exercise involved pointing the toes to push as hard as possible against a footplate which records the force, and the patient did this for ten seconds followed by ten seconds rest and then repeated the test up to a total of twenty times. As Dr Wood explained, “What we were doing was investigating the effects of fatiguing contractions on the excitability of spinal motoneurone pools using the Hoffmann reflex (H-reflex) as a tool to measure this. Following this exercise, we stimulated the nerve again to observe any effects of the exercise on nerve control. This nerve stimulation was repeated at several time intervals (initially every ten minutes) for up to four hours after the exercise had finished, and we invited the patient to come back to the lab for a short time the next day to repeat the nerve stimulation.

The overall conclusion from the pilot study was that fatigue of ankle plantar flexors did not affect the excitability of the motoneurones supplying these muscles. However, the degree of fatigue induced in these muscles in the study may not have been sufficient to unmask any such effects. Similarly, there were no effects on the M-wave produced by direct muscle stimulation, though, again, this may have been due to the level of fatigue induced. One solution – for future studies – would be to use an alternative plantar flexion fatiguing exercise, such as the use of heel-lifts as a means of fatiguing the triceps surae muscle group. This technique involves subjects raising the heel by a set height (by effectively standing on tip-toe) and repeating these contractions until fatigue occurs. This is a more strenuous exercise, which has previously been shown to be able to modulate H-reflex excitability in triceps surae; however it has the potential to lead to excessive post-exercise muscle pain, and so care would have to be taken to ensure no long-lasting damage in subjects with ME/CFS. Another option for future studies would be to use trans-cranial magnetic stimulation (TMS) to investigate changes in cortical and spinal motoneurone activity after fatigue in subjects with ME/CFS. This technique has the advantage that no electrical stimulation is involved, therefore  potentially allowing for following-day measurements to be obtained. This technique also allows for monitoring of changes in motoneurone excitability both during as well as after exercise.

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