Muscle Fatigue Signals Start in the Brain

[Valentijn]

http://www.prohealth.com/library/showarticle.cfm?libid=16687

It's a series of three studies done by the same group.

In the initial study(1), the researchers showed that nerve impulses from the muscle - much like pain information - inhibit the primary motoric area during a tiring, energy-demanding exercise.

In a second step, using functional magnetic resonance imaging, the researchers were able to localize the brain regions that exhibit an increase in activity shortly before the interruption of a tiring, energy-demanding activity and are thus involved in signalizing the interruption.(2)

This is already showing up on smaller news sources in the context of CFS.

I'm a little confused, but I don't think it's a strong argument for a neurological cause of the fatigue. It sounds like the brain tells the muscle to stop working, but the brain bases that decision on information from the muscles. So the muscles could still be the source of the problem?

 

[Zee]

How muscle fatigue originates in the head (as opposed to is all in the head).

Posted on the ME Associations site,

How muscle fatigue originates in the head, University of Zurich press release, 5 December 2011
by Tony Britton on December 5, 2011
From the University of Zurich media office, 5 December 2011

Researchers from the University of Zurich have now studied in detail what sportsmen and women know from experience: The head plays a key role in tiring endurance performances. They have discovered a mechanism in the brain that triggers a reduction in muscle performance during tiring activities and ensures that ones own physiological limits are not exceeded. For the first time, the study demonstrates empirically that muscle fatigue and changes in the interaction between neuronal structures are linked.

The extent to which we are able to activate our muscles voluntarily depends on motivation and will power or the physical condition and level of fatigue of the muscles, for instance. The latter particularly leads to noticeable and measurable performance impairments. For a long time, the research on muscle fatigue was largely confined to changes in the muscle itself. Now, a joint research project between the University of Zurich and ETH Zurich has shifted the focus to brain research. Headed by neuro-psychologist Kai Lutz from the University of Zurich in collaboration with Urs Boutellier from the Institute of Human Movement Sciences and Sport at ETH Zurich, the researchers discovered neuronal processes for the first time that are responsible for reducing muscle activity during muscle-fatiguing exercise. The third and final part of this series of experiments, which was conducted by Lea Hilty as part of her doctoral thesis, has now been published in the European Journal of Neuroscience.

Muscles nerve impulses inhibit motoric area in the brain

In the initial study, the researchers showed that nerve impulses from the muscle much like pain information inhibit the primary motoric area during a tiring, energy-demanding exercise. They were able to prove this using measurements in which study participants repeated thigh contractions until they could no longer attain the force required. If the same exercise was conducted under narcotization of the spinal chord (spinal anesthesia), thus interrupting the response from the muscle to the primary motoric area, the corresponding fatigue-related inhibition processes became significantly weaker than when the muscle information was intact.

In a second step, using functional magnetic resonance imaging, the researchers were able to localize the brain regions that exhibit an increase in activity shortly before the interruption of a tiring, energy-demanding activity and are thus involved in signalizing the interruption: the thalamus and the insular cortex both areas which analyze information that indicates a threat to the organism, such as pain or hunger.

Neuronal system has regulating effect on muscle performance

The third study has now shown that the inhibitory influences on motoric activity are actually mediated via the insular cortex: In tests using a bicycle ergometer, the researchers determined that the communication between the insular cortex and the primary motoric area became more intensive as the fatigue progressed. This can be regarded as evidence that the neuronal system found not only informs the brain, but also actually has a regulating effect on motoric activity, says Lea Hilty, summing up the current result. And Kai Lutz points to the new research field that now opens up with these results: The findings are an important step in discovering the role the brain plays in muscle fatigue. Based on these studies, it wont just be possible to develop strategies to optimize muscular performance, but also specifically investigate reasons for reduced muscular performance in various diseases. Prolonged reduced physical performance is a symptom that is frequently observed in daily clinical practice. It can also appear as a side effect of certain medication. However, so-called chronic fatigue syndrome is often diagnosed without any apparent cause.

Literature:

Lea Hilty, Lutz Jncke, Roger Luechinger, Urs Boutellier, and Kai Lutz. Limitation of Physical Performance in a Muscle Fatiguing Handgrip Exercise Is Mediated by Thalamo-Insular Activity. Human Brain Mapping. December 10, 2010. doi: 10.1002/hbm.21177

Lea Hilty, Kai Lutz, Konrad Maurer, Tobias Rodenkirch, Christina M. Spengler, Urs Boutellier, Lutz Jncke, and Markus Amann. Spinal opioid receptor-sensitive muscle afferents contribute to the fatigue-induced increase in intracortical inhibition in healthy humans. Experimental Physiology. February 11, 2011. doi: 10.1113/expphysiol.2010.056226

Lea Hilty, Nicolas Langer, Roberto Pascual-Marqui, Urs Boutellier, and Kai Lutz. Fatigue-induced increase in intracortical communication between mid ?anterior insular and motor cortex during cycling exercise. European Journal of Neuroscience. November 21, 2011. doi: 10.1111/j.1460-9568.2011.07909.x
.

 

[Nielk]

Hi Zee,

Thank you for this interesting study.

I am not surprised by the outcome at all since we are learning every day how the body is regulated by the brain. It seems that so many studies now are
focused on the brain and neurons as the "director" of al bodily functions.

I don't get the last sentence: "However, so-called chronic fatigue syndrome is often diagnosed without any apparent cause."
It just doesn't fit here. Why mention this?

 

[Zee]

Hi Neilk,
Haven't really had time to digest it yet but my take on that sentence was that the researcher / researchers were trying to justify the work by suggesting in what areas it might practically be applied, of course I may be wrong and yes, the comment seems bolted on.

Trying to look at how this work might be positioned I can see it potentially being used in argument against interventions such as GET since if the brain is stopping muscle function due to existing fatiuge then forcing the muscle to do more work, I guess, is only going to lock that instruction in. I'd also suggest that for anyone arguing in favour of CBT, and on the surface I can see this study appealing to them, that you would then have to prove CBT was capable of affecting physical brain change rather than change in illness perception.

 

[Desdinova]

Hi Zee,

Thank you for this interesting study.

I am not surprised by the outcome at all since we are learning every day how the body is regulated by the brain. It seems that so many studies now are
focused on the brain and neurons as the "director" of al bodily functions.

I don't get the last sentence: "However, so-called chronic fatigue syndrome is often diagnosed without any apparent cause."
It just doesn't fit here. Why mention this?

No surprise here either.

Based on these studies, it wont just be possible to develop strategies to optimize muscular performance, but also specifically investigate reasons for reduced muscular performance in various diseases.

Multiple Sclerosis sounds like a good candidate since it's well established and accepted as a purely physical disorder. Studying MS and one or two other well established physical disorders would serve as good set points for comparisons for those disorders such as ours ME, CFS and FM that are embroiled in controversy and debate.

Prolonged reduced physical performance is a symptom that is frequently observed in daily clinical practice. It can also appear as a side effect of certain medication. However, so-called chronic fatigue syndrome is often diagnosed without any apparent cause.

It is a rather open and short statement. Purely speculating, perhaps they are stating that since CFS has no obvious clear cause that by showing physiological impact on the bodies performance and response it may point further towards it being a physiological disorder and not psychological one.

 

[Snow Leopard]

As far as I know, (I did a quick search of the articles for the keyword chronic), none of them explicitly mention CFS.

I'm a little confused, but I don't think it's a strong argument for a neurological cause of the fatigue. It sounds like the brain tells the muscle to stop working, but the brain bases that decision on information from the muscles. So the muscles could still be the source of the problem?

You are right, it isn't a strong argument. They've shown in the first study that by inhibiting the ?-opioid receptor (a key pain receptor, the one that morphine acts on) after a fatiguing activity, the maximal voluntary contraction does not change (compared to placebo), but the cortical silent period did not increase (compared to the pre-excercise baseline) when Fentanyl was used, compared to an increase in the cortical silent period (compared to pre-exercise baseline) when a placebo was used instead of Fenatyl.

Straightforward conclusion: pain receptors play a role in the perception of fatigue.

I guess the hypothesis in terms of CFS would be that there is a dysfunction in ether the ?-opioid receptors or downstream in the brain where this signal is received. But very speculative at this point.

 

[*GG*]

Hi Zee,
I don't get the last sentence: "However, so-called chronic fatigue syndrome is often diagnosed without any apparent cause."
It just doesn't fit here. Why mention this?

Yeah, I see your point. It seems like they could go either way with this. "So-called" makes it sound like they don't believe or they do not like the name?

I guess CFS could be non "apparent" depending upon the definition that you use? Mine was sudden onset (Mono), so I usually think of it as an apparent cause, but I know many have had a gradual case (Not sure of what percentage that is. Anyone know? I don't think I have read anything on that). A viral assault, and my immune system did not bounce back!

GG

PS I didn't take much away from this write up.

 

[oceanblue]

This study is fascinating, though I was too ill to comment when it came out.

One of the problems in researching CFS is that we don't properly understand how healthy fatigue works, so we don't know where to look to see if the normal fatigue mechanism is broken. These studies indicate that normal fatigue is influenced, at least in part, by the brain, which takes at least some of its cues from nerve signals coming from the muscles.

Crucially, these studies support a theory that's been developed over the last decade or so that "human muscle fatigue does not simply reside in the muscle" and there is a 'central governor' in the brain for physical activity, with "with the sensation of fatigue being the conscious interpretation of these homoeostatic, central governor control mechanisms." This fatigue mechanism serves the purpose of protecting the body from damage, as opposed to fatigue simply being the biological exhaustion of muscles.

This theory (free pdf, which is unusually short and readable) seems particularly relevant to ME/CFS. Basically, the system measures current demands on the body (eg the sensory nerve signals coming from working muscles), and anticipates future demands using 'neural calculations using afferent sensory inputs that detect current metabolic rate, fuel reserves, and rates of heat production among many other biological changes'. This leads to a 'robust, self sustaining mechanism that maintains homoeostasis by ensuring that no system is ever overwhelmed or used to absolute maximal capacity'

On CFS:
...the sensations of fatigue can be present at rest when no work is being performed, as is found in the chronic fatigue syndrome and other chronic diseases; or they may begin shortly after the onset of exercise, or they may peak even as the work output increases further, as in the case of the end spurt in the world record 10 000m running performances...

According to the predictions of the central governor model, the presence of fatigue at rest in chronic disease can be best understood as part of a protective mechanism to ensure that the metabolic rate cannot be elevated excessively through the recruitment of too large a muscle mass during activity, as this would overwhelm those homoeostatic mechanisms that have been impaired by the presence of disease.

So it's saying that fatigue is there in CFS to protect us from harm, though I don't think they have any specific evidence for this. However, it would tie in with the problems of PEM on over-exertion.

The Light's work on gene expression in response to exercise is also ties in. They found a rise in expression of the genes for a number of muscle-metabolite sensing receptors. It is stimulation of these receptors by rising metabolites that triggers a nerve signal to the brain (exactly the same type of signal that was blocked in the Hilty paper just published). There are two possibilities here:

1. Metabolite levels rise very fast in CFS patients due to abnormal muscle physiology, gene expression rises in response to this
2. Metabolite levels are normal, but gene expression of receptors increases - possilby as the primary defect in CFS - presumably leading to greater signalling by receptors and so a greater perception of fatigue.

There's no good evidence as to which is right: a recent Julia Newton study did find abnormal muscle pH on exercising in a sub-group of CFS patients but there were only 8 subjects with poorly-matched controls so the finding needs replicating.

It would be extremely interesting to study the biology of 'bad day'/PEM, to see what's going on - could this be the (partial) breakdown in homeostatis due to over-exertion, as implied by the central governor model? The Light work is an example of this, and Nancy Klimas et al is tracking cytokine/immune profiles in individuals over time, which will be able to examine the differences betwen good and bad days.

The third and final possible dysfunction in CFS implied by this theory is dysfunction of the fatigue-generating 'central governor' in the brain, i.e. normal muscle physiology, normal signalling of metabolites etc but abnormal interpretation of the signals. This dysfucntion of the brain's fatigue centre could be meditated by cytokines. Interferon-alpha treament leads to marked fatigue in Hepatitis C and cancer patients, and the Dubbo Study Team (looking at CFS that develops after specific infections eg glandular fever) have suggested that an initial over-strong cytokine response to infections is important in developing CFS. Their latest paper finds a strong link between having a particularly active version of the Interferon-gamma gene and fatigue as a symptom in response to infection.


Sorry, too lazy to include all the references but will if anyone is interested

 

[SOC]

I don't get the last sentence: "However, so-called chronic fatigue syndrome is often diagnosed without any apparent cause."
It just doesn't fit here. Why mention this?

I agree it sounds odd. My wild guess is that it's an awkward translation or imperfect use of English. If we look at the sentence along with the previous couple,

Prolonged reduced physical performance is a symptom that is frequently observed in daily clinical practice. It can also appear as a side effect of certain medication. However, so-called chronic fatigue syndrome is often diagnosed without any apparent cause.

Perhaps what was meant was closer to "On the other hand, so-called chronic fatigue syndrome has no known cause." They might have been trying to say that prolonged reduced physical performance could be a side effect of certain drugs, but there are also cases, diagnosed as "chronic fatigue syndrome" that have no known cause. Maybe....?

 

[biophile]

I have wondered if the baseline symptoms are a form of chronic post-exertional phenomenon arising from the body keeping itself "idling" in the presence of ME/CFS pathology. Extra exertion just makes matters worse and causes deeper dysfunction. In the more severely affected, merely being awake is extremely demanding.

 

[alex3619]

The counter argument is this. So much evidence now points to us getting a much stronger fatigue signal from the body. So what if the brain says stop? It does so because the body says to. Bye, Alex

 

[RustyJ]

I'd also suggest that for anyone arguing in favour of CBT, and on the surface I can see this study appealing to them, that you would then have to prove CBT was capable of affecting physical brain change rather than change in illness perception.

Zee, I believe you have hit the nail on the head. The CBT mob will see this as justification for their work. This study, when related to me/cfs is not about causes, but mechanisms - it is an observation, or an interpretation of an observation, not a determination of initial cause. In the case of me/cfs too little focus on these iffy mechanisms even within the me/cfs community, and not enough on causes.