It's not quite that simple. The perception of fatigue or pain involves signals from sensors, and communication through the nerves, and processing. Problems can arise in any of those links. Neuropathic pain, as I understand it, involves normal levels of sensor signals, but the processing cells overrespond to those normal signals, giving the perception of pain.
Neuropathic pain conditions are due to incomplete recovery of damaged nerves. Often this is due to peripheral neuropathies (they usually arise after various severe injuries or neurological diseases). But they can in principle be due to central causes, such as multiple sclerosis, strokes, spinal cord injuries as well.
I can accept that a person might have normal muscle energy, yet have problems in the signal feedback from those muscles which give the perception of lack of energy. You could do an fMRI of the muscles, and EEG of the nerves involved, and see nothing abnormal, yet the patient might still have a very real perception of muscle fatigue.
There is no EEG of peripheral nerves and peripheral (non-brain) fMRI doesn't have the resolution to measure small fibre neuropathy.
The patient could also have a psychological disorder convincing them of severe fatigue. AFAIK, there's no way to properly measure perception of fatigue.
The problem is that symptoms associated with fatigue (pain, stiffness etc) are bundled in with fatiguability, when they are two related, but separate phenomena. Fatigability can be measured, with spinal, supraspinal, peripheral nerve and peripheral metabolic components separated out using a variety of exercise protocols and a combination of measuring force, along side EMG and TMS targeting motor nerves at spinal and supraspinal levels, as well as pharmacological blockades of afferent function at the local and spinal levels.
The research into ME/CFS has been a bit haphazard, but the research so far, combined with the underlying research in healthy people, provides strong evidence for central fatigability (which is attenuation of output - the opposite of sensitisation), driven by muscular afferents.
The primary purpose of these afferents is not to signal danger, nor to prevent further activity (task failure), but to modulate the balance between motor unit drive and ventilatory activity as muscle fibres fatigue, so that there is lower hysteresis of (expected) force output due to varying metabolic demands. So although maximal performance is decreased, sustainable performance is improved. The various sensations we associate with fatigue - the mild muscle pain, stiffness, sense of weakness when doing strenuous activities is the warning that there is a reduction in performance.
A notable consequence of this afferent feedback is the reduction in the ventilatory threshold on the 2-Day CPET, found in over 10 studies so far. This also shows that the effect is dynamic - it is not simply a constant sensation due to "normal signals".
Now one key point that I'd like to make is that many parts of the brain are involved, with a variety of functions - the supplementary motor areas that model limb function (which process the 'efferent copy'/corollary discharge, to provide a comparison with proprioceptive afferents), the motor cortex, the parts of the brain that sense pain etc. The key point is that in ME/CFS that upon processing a variety of sensory inputs in several different parts of the brain, all agree that there is a problem. Hence any model analogous to central pain sensitisation will necessarily need to be much more complex than simple examples of spinal or supraspinal sensitisation to normal signals.
Of course, we still don't know if the peripheral afferents are being stimulated by aberrant metabolic signals, or whether this is a unique form of neuropathy (or both could be true, in different groups of patients).
@Hutan
The Sci-American article is a bit... Incomplete. That view seems to be that of neurologists who think that fatigue is a loss of maximal force output and this fatigue is caused by motor units not firing at all. This view tends to neglect the metabolic factors as well as the ways that the brain and spinal reflexes compensate.
While a motor unit might still fire, the force generated might be lower due to metabolic factors. So it is not simply a function of whether the motor unit fires or not. The brain also modulates both the amplitude and frequency of descending drive to optimise force output. In addition, there is "muscle wisdom effect", where the motor contractile frequency tends to match the descending signal over time.
The brain also pays attention to peripheral afferents to attenuate descending drive "central fatigue" to modulate the balance between ventilatory drive and peripheral fatigue due to limitations of metabolic kinetics.
But a surprising point that is often over looked is that there are spinal mechanisms that
increase the motor unit sensitivity due to fatigue - this is called "reflex compensation". Hence some motor units may actually be
more likely to fire when an individual is suffering from muscle fatigue!
https://journals.physiology.org/doi/abs/10.1152/jn.1987.57.6.1893
I suspect these spinal reflex effects are what leads to the sensation of stiffness in a fatigued muscle.
So in summary, a trembling effect in fatigued muscles is not simply due to a drop-out of motor units, but a failure of the brain to optimise the descending drive as the model of limb function is no longer accurate as the sensitivity of the motor units no longer follows the assumptions of the model in the brain (eg higher threshold motor units will provide higher force output).
