Preprint: Pharmacological blockade of muscle afferents and perception of effort: a systematic review with meta-analysis, 2021, Bergevin et al

Abstract

The perception of effort (PE) provides information on task difficulty and influences physical exercise regulation and human behavior. This perception differs from other-exercise related perceptions such as pain. There is no consensus on the role of group III-IV muscle afferents as a signal processed by the brain to generate PE. The aim of this meta-analysis was to investigate the effect of pharmacologically blocking muscle afferents on the PE. Six databases were searched to identify studies measuring the ratings of perceived effort (RPE) during physical exercise, with and without pharmacological blockade of muscle afferents. Articles were coded based on the operational measurement used to distinguish studies in which PE was assessed specifically (effort dissociated) or as a composite experience including other exercise-related perceptions (effort not dissociated). Articles that did not provide enough information for coding were assigned to the unclear group. The effort dissociated group (n=6) demonstrated a slight RPE increase with reduced muscle afferents feedback (standard mean change raw (SMCR), 0.39; 95%CI, 0.13 to 0.64). The group effort not dissociated (n=2) did not reveal conclusive results (SMCR, -0.29; 95%CI, -2.39 to 1.8). The group unclear (n=8) revealed a slight RPE decrease with reduced muscle afferents feedback (SMCR, -0.27; 95%CI, -0.50 to -0.04). The heterogeneity in results between groups reveals that the inclusion of other perceptions than effort in its rating influences the RPE scores reported by the participants. The absence of decreased RPE in the effort dissociated group suggests that muscle afferents feedback is not a sensory signal generating PE.

Open access, https://www.biorxiv.org/content/10.1101/2021.12.23.474027v1

 

We already knew this, in fact we have had evidence for over 140 years (Helmholz).

The sense of effort is determined by the signal generated upstream of the motor cortex and is independent of afferents. This sends two 'efferent copies' of the signal, one to the motor cortex and the other to the supplementary motor areas that have a model of limb function. The group I-II muscle afferents feed back into the supplementary motor areas and indicate a sense of weakness/fatigue if the muscle temporarily undershoots the expected result.

The type III-IV muscle afferents lead to the myalgia associated with intense exercise as well as inhibiting the output of the motor cortex, likely through GABAergic signalling. It is this inhibition that causes the main phenomena of "central fatigue".

The primary purpose of this "central fatigue" is not to indicate that the individual should stop exercising! The main result is that by inhibiting the motor cortex, this increases the relative amount of ventilation for a given level of motor force and hence should help increase oxygenation and hopefully reduce the amount of anaerobic metabolism.

Constant stimulation of this pathway partly explains the "unusual" CPET findings of Dane Cook as well as potentially explaining reduction in the power at the ventilatory threshold on the 2nd CPET of the 2 day CPET protocol.

 

Would other muscle diseases cause the same abnormalities on 2-day CPET?

Like for example mitochondrial myopathies or skeletal muscle channelopathies.

 

Maybe, but there can be differences in the kinetics of the effect eg if there is an acute affect of similar magnitude on both days during the test that limits performance similarly then perhaps the performance would be similarly limited on both days. But it would be interesting to find out. Patients with mitochondrial myopathies have been noted to have a "hypercirculatory" exercise response when approaching maximal VO2 on single date CPETs.

The mere stimulation of the group III/IV pathways during the test itself might not be the only thing going wrong in ME/CFS patients - the chronicicity for example suggests questions...

 

There seems to be an excess of what would be expected of people who have ME/CFS plus a skeletal muscle channelopathy or something that resembles both. Skeletal muscle channelopathies are said to be extremely rare but it's not difficult to find people in the ME/CFS community who appear to have both. A recent paper also reported a case of someone meeting the Canadian ME/CFS criteria who was found to have a pathogenic mutation in a muscle chloride ion channel.

The episodes of paralysis reported by some severely ill patients also suspiciously resemble what happens in periodic paralysis.

 

A new version of this preprint is available, https://www.biorxiv.org/content/10.1101/2021.12.23.474027v2 - I haven't looked to see what is different.