Effect of Melatonin Plus Zinc Supplementation on Fatigue Perception in ME/CFS: A Randomized, Double-Blind,Placebo-Controlled Trial,2021,Castro-Marrero

Don't tell my GP, i've had Circadin prescribed by them for a few years after a sleep specialist neurologist recommended it (in my 30s)

I'm definitely more drowsy for approx. 8hrs after taking Circadin (2mg slow release) and that can help me stay asleep a bit easier. But any significant waking event will overcome the effect fairly easily. A few weeks back I absentmindedly took Circadin instead of Ivabradine with my breakfast and couldn't bring it back up. Duvet day followed, feeling pretty spaced but I stayed awake.

Previously the neurologist did suggest that Circadin, being a bona fide pharmaceutical product, would be stronger and more reliable than supplement grade stuff... no idea how true that is. He did also suggest I come off it because the trial data only ever proved safety for short periods. Whenever I'm not using it though my sleep suffers and my pain levels rise, including a very specific waking ankle pain that i've never been able to pin down. So for now i'm not rocking the boat...

 

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. 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. The patient could also have a psychological disorder convincing them of severe fatigue. AFAIK, there's no way to properly measure perception of fatigue. It's a subject difficult to measure, so I wouldn't take questionnaire results about fatigue too seriously. A 'barely exceed the minimum statistical relevance' result doesn't have much meaning with such a shaky foundation.

 

I tried the supplement stuff...absolutely zero effect on me. A couple of people I know reckon it's brilliant though.

Having said that it doesn't have as strong an effect on me as it sounds like it has on you. I accidentally took it in the morning, realized what I'd done & had a cup of normal tea instead of decaff and was fine.

 

I know fatigue can be one of the symptoms of depression but are there psychological conditions where fatigue is the primary symptom?

I agree it's almost impossible to measure fatigue. What the heck woukd the unit of measurement be?

I don't get why the obsession with measurements of something immeasurable while at the same time not really acknowledging the many different types of fatigue & exploring the qualities of those different types.

 

Well, I wanted to principially say, that a supplement might induce a change in any functional unit (e.g. in a single pathway) without that the body suffers from any deficiency. Everything would have functioned as it has been purposely designed by nature.

Otherwise your post is sensible.

 

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.

There is no EEG of peripheral nerves and peripheral (non-brain) fMRI doesn't have the resolution to measure small fibre neuropathy.

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).

 

Could this be why some of us experience annoying muscle twitching or fasciculation when in PEM?

 

I'm not sure. The mechanism I was talking about involves spinal feedback loops related to proprioceptive afferents.

 

As far as I could tell, my ME didn't cause any effects on my muscles. I seemed to maintain the same level of strength and endurance. For me it's more of a limitation of willpower to make myself do physical or mental tasks. I'm just guessing that I wouldn't show the reduction in the ventilatory threshold on the 2-Day CPET. My guess is that the reduction is a common downstream effect of ME, but not core.

 

Well my experience is very different to yours and I'll leave it at that...

 

I frequently find myself, even with all I know about pacing myself, getting up to do something I really want to get done. Either because it's a chore I don't want to do and want it over with or because it's something I'm really looking forward to.

Then, thanks to factors beyond my control like the weather, a worse night's sleep than usual or maybe just the fluctuating nature of the illness itself, I find I am simply unable to start it, or I start &, having broken it into manageable stages, find I have to stop before it's done.

It's very, very frustrating. Frustration burns through energy very quickly. Depression is a terrible thing & I wouldn't want to have it or wish it in anybody, but sometimes I wish I was less motivated.

 

ME has nothing to do with willpower.

I've tried both Zinc and Melatonin, neither improved my symptoms. Complete waste of money.

 

For me it is. There are a bunch of tasks on my 'todo list' that I just don't feel like doing. However, if it became critical to do them, I could, even if it required strenuous physical work. The limitation seems cerebral: tasks requiring lots of cognitive effort, or ones with frustrating complications are the worst. To avoid them I might do some strenuous physical activity, such as digging soil or splitting/stacking firewood, since those are fairly mindless activities.

 

I take melatonin. It helps me sleep. It helps me fall asleep, specifically. It's been great from that point of view. I had a lot of sleep problems and melatonin was part of the solution in combination with something else, and of course improving sleep helped symptoms. I was really struggling.

I am not sure what else this is getting at? But to the extent that it helps some people get restorative sleep, seems like worth trying if that's a problem for the person? x

 

Of course ME is not a condition caused by a lack of willpower and a lack of willpower is not one of the symptoms. However, to give an example of where willpower is part of the picture for me personally:
As I tap out this post, I'm sitting up in bed mulling the walk to the greengrocer that I must do today if I'm to eat anything but cheese. I have nobody to help me and have 'only' moderate ME which I keep strictly to myself.
I know that as I stand up after tying my shoelaces, I'm going to feel dizzy and nauseated. Nasty but it passes.
After about 30 metres of walking, my legs will start to feel leaden. From here on my permanent headache starts to feel like an ever-tightening vice, my eyesight blurs even more, and if I tried to read at this point, I wouldn't be able to comprehend the simplest sentence.
Having started with a very significant level of overall pain, I arrive home and fall on the floor for 20 minutes until I'm back to baseline again because there are other things that need to be done before the day is over.
To put myself through this day in and day out requires a fair degree of determination - or willpower.

Oh, and I've been prescribed zinc supplements and melatonin, including slow release at various strengths, and I'm pretty sure they've made no difference to how I "perceive" fatigue - or anything else.

 

I can relate to needing willpower for cognitive tasks too. The symptom that causes me the most grief (literally) by far is 'brainfog'. To do something needing a fair bit of mental effort for me is so difficult, and requires so much determination/willpower to put myself through it, that I too tick off the mindless physical jobs on my to-do list first.

 

When my ME was less severe I definitely used minor, simple physical chores as a distraction from those more complex and long cognitive tasks that @Hutan describes as high friction tasks.

These days I tend not to have the capacity. I am also the type of person who hates having things hanging over me. So I know if I have a DWP form to fill in or some official stuff it will lurk in the back of my mind until I get to it anyway.

Plus I've learned it's extremely easy to let tasks like that build up until they seem quite insurmountable.

Even if I can't tackle the high friction task immediately I will have a look (& I do need someone to check things for me & help fill them in). So I will pencil in times specifically to get the job done, even if it's just an hour or two half hours every other day for a week or two or something. In the full knowledge and accepting that sometimes I'm just not going to be able to do anything at all.

I'll break it in to sections if I can. Before I start the task itself I'll gather any other documents or information that I need together into a folder and so on.

Once I've done that I find that instead of using a physical distraction as an excuse, I can (if I have the resources) do something else I would like to do as a reward.

This way I find each section I manage to complete or each time slot I manage to get something done in can be viewed as an achievement.