The Dopamine Imbalance Hypothesis of Fatigue in Multiple Sclerosis

Marco

Marco

Senior Member (Voting Rights)
For those interested in these things this is a useful review (and hypothesis) of possible mechanisms for 'central fatigue' in MS and other neurological disorders (full paper).

Not directly relevant to ME/CFS although several ME/CFS studies are referenced.

Possibly the most interesting (and speculative) discussion is the possible influence of the immune system in dopaminergic dysregulation :

Based in large part on the evidence from the MS animal model, experimental autoimmune encephalomyelitis (EAE), MS is considered to be an autoimmune disorder of the CNS. To a large extent, the immune system depends on the functioning of the leukocytes or white blood cells. T cells are a type of white blood cell that produce an immune response, i.e., they are activated when the body needs to fight an infection. In autoimmune diseases, including MS, T cells proliferate and attack healthy cells (18), passing though the blood–brain barrier into the CNS. It has been shown that proliferating CD4+ cells (a type of T cells) express the D3 receptor that contributes to the destruction of dopamine neurons in the SN and generate interferon-γ, a compound that proliferates inflammation and prevents dopamine synthesis (11, 18, 70, 71). This potentially can result in decreased dopamine levels. Indeed, animal studies showed that CNS dopamine depletion by means of administration of the neurotoxin that kills dopamine cells in the SN leads to EAE exacerbation, while daily administration of a dopamine agonist, bromocriptine that has an affinity for D2 DRs (of which the striatum has a high concentration), has been shown to have beneficial effects on EAE. Treatment with bromocriptine has been shown to result in reduced severity and duration of relapses in rats with acute EAE. It also leads to the suppression of prolactin, a pituitary hormone that is inhibited by dopamine synthesized in the hypothalamus (see above) (10, 11, 17, 72). Though highly speculative, this line of reasoning suggests that fatigue might occur due to the dopamine imbalance that starts in the immune system, subsequently affecting the CNS.
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357260/
 
Interesting, but I just feel like they are trying to overextend the dopamine idea to explain fatigue. Since all the products of that overexcited immune system are running about the body as well as the brain, and since they interfere with energy production and impede functioning in all sorts of other ways, there are much simpler explanations for the fatigue.

Also, I suspect that fatigue associated with dopamine-related illnesses is kind of different from autoimmune fatigue. More "mental". People describe it more as a loss of initiative, and it seems to be most pronounced when you try to get started with an action plan (like walking up a footpath), and less pronounced once you've gotten into it.

One important factor is whether the fatigue fluctuates wildly or is permanent/predictable give the activity. If its peripherally induced, it is likely to vary massively with the level of circulating cytokines etc. If its CNS induced, it should be less variable.

I think we need a whole new vocabulary for understanding these various physical states that make it feel like doing things is an incredible effort and incredibly draining (i.e. fatigue). Until we find one, people will keep confusing chalk and cheese.

Dopamine could be of interest when it comes to explaining low mood, though.
 
Might be interesting -- whether as an endorsemennt or as a contradiction, I don't know, though:

Neural correlates of effort-dependent and effort-independent cognitive fatigue components in patients with multiple sclerosis


.entryAuthor" data-author-container-selector=".NLM_contrib-group"> Show all authors
Stefan Spiteri, Thomas Hassa, Dolores Claros-Salinas, ...
First Published November 21, 2017 Research Article
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Abstract
Background:
Among patients with multiple sclerosis (MS), fatigue is the most commonly reported symptom. It can be subdivided into an effort-dependent (fatigability) and an effort-independent component (trait-fatigue).

Objective:
The objective was to disentangle activity changes associated with effort-independent “trait-fatigue” from those associated with effort-dependent fatigability in MS patients.

Methods:
This study employed behavioral measures and functional magnetic imaging to investigate neural changes in MS patients associated with fatigue. A total of 40 MS patients and 22 age-matched healthy controls performed in a fatigue-inducing N-back task. Effort-independent fatigue was assessed using the Fatigue Scale of Motor and Cognition (FSMC) questionnaire.

Results:
Effort-independent fatigue was observed to be reflected by activity increases in fronto-striatal-subcortical networks primarily involved in the maintenance of homeostatic processes and in motor and cognitive control. Effort-dependent fatigue (fatigability) leads to activity decreases in attention-related cortical and subcortical networks.

Conclusion:
These results indicate that effort-independent (fatigue) and effort-dependent fatigue (fatigability) in MS patients have functionally related but fundamentally different neural correlates. Fatigue in MS as a general phenomenon is reflected by complex interactions of activity increases in control networks (effort-independent component) and activity reductions in executive networks (effort-dependent component) of brain areas.
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http://journals.sagepub.com/doi/10.1177/1352458517743090
 
@Marco

Please accept my apologies for the delayed response.

In MS, there are many different types of fatigue, too. Actually, some clinicians distinguish and are really interested in investigating the different forms. At least, they differentiate between "mental", "cognitive" and "motor" fatigue. The latter occurs during physical exertion.

I find these investigations done by a small research institute in Germany very interesting, and even though the preliminary results may not be applicable to ME (but perhaps there are overlapping mechanisms?), they could be inspiring for those who are striving to find objective measurements of ME related fatigue/ fatiguability (types).

Perhaps your question is better answered in one of the studies of the mentioned institute: http://www.kliniken-schmieder.de/lurija-institut.html

Unfortunately, there is no direct URL to the studies publihed in English. You have to navigate through "aktuelle Forschungsprojekte" -> "Fatigue and Fatiguability -> and then "Literatur" on the right side.

Thought about opening a new thread for discussion of these studies, but need a longer rest now.

(Have been made aware of the Lurija Intitut when spending several weeks in a neurological rehab facility linked to the institute. In addition, I was suspected to have MS more than once, and have encountered many MS patients, some of them also suffering from so called "PEM", some of cognitive fatigue, some of depressions, and some experience neither forms of fatigue/ "PEM", but this is another topic.)
 
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Thanks @MSEsperanza

Opening a new thread would be a good idea when you're feeling up to it as there may be a lot to learn about 'fatigue' (or loss of endurance as I personally experience it).

One field that particularly interests me is mild post traumatic brain injury where in a sub-set of cases 'post concussion syndrome' is a long term problem with many similarities to ME/CFS (and where similarly 'psychological' factors are assumed to play a role when the patient refuses to get better) that occurs when (unlike MS) the initial trauma is assumed to have fully healed.

This paper (abstract only) caught my eye in the link you provided :

Fatigue and fatigability in neurologic illnesses: proposal for a unified taxonomy.

https://www.ncbi.nlm.nih.gov/pubmed/23339207

Unfortunately when you check the included image they include CFS under psychological factors that influence fatigue perception. Too bad!

On the other hand this https://www.ncbi.nlm.nih.gov/pubmed/24952620 could be a useful approach to objectively measuring motor fatigue in ME/CFS that avoids possible response bias using questionnaires (although I'm not sure how you exclude the possibility that motivation affects gait?).
 
Alvin said:
No brain power to read the study but raising dopamine is only a Dexedrine or Levodopa tablet away
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I have tried Bromocriptine, which slows the breakdown of dopamine, and also tried a stimulant, Methylphenidate at a low dose which doesn’t overtax my system, and my conclusion is that the methylphenidate offers a degree of help for cognition as well as hypotension, but the Bromocriptine doesn’t help my brain function. These drugs do not begin to resolve the whole problem of ME/its many elements.

So, while I would concur that low dopamine is probably happening in us, adding or stimulating it alone doesn’t fix the whole system or ME brain.

Researchers like to focus on one element and in some illnesses, there is one element amiss, but the apparent low dopamine in us is, I expect, a downstream effect and only part of a complex picture of a different metabolism/system that has gone amiss.
 
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Sing said:
I have tried Bromocriptine, which slows the breakdown of dopamine, and also tried a stimulant, methylphenidate at a low dose which doesn’t overtax my system, and my conclusion is that they methylphenidate offers a degree of help for cognition as well as hypotension. However these drugs do not begin to resolve the problem of ME and its many features.

So, while I would concur that low dopamine may be happening, adding or stimulating it, doesn’t fix the system or ME brain. Researchers like to focus on one element and in some illnesses, there is one element amiss, but the apparent low dopamine in us I expect is a downstream effect and only part of a complex picture of a different metabolism/system going on.
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Dexedrine (dextroamphetamine) is used to increase energy (as well as wakefulness) and its a dopamine pumper. That said if our issues arise from pyruvate dehydrogenase inhibition then all the dopamine in the world is not likely to affect it, it would be like trying to fix a broken alternator by filling the gas tank.
The problem with fatigue is that it can have many causes, and targeting the wrong one won't get us very far. Some possibilities off the top of my head, low in ATP, muscle wasting disease, low blood glucose, etc.
 
MSEsperanza said:
Might be interesting -- whether as an endorsemennt or as a contradiction, I don't know, though:
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I just saw this article you posted, @MSEsperanza, and it's really interesting. A really good effort to try and identify subtypes of fatigue. We really need a system for describing and rating the different types that can be used across all illnesses where fatigue is a component.

The only reservation I had about the article is that they seem to continue to assume that all types of fatigue in MS must have a central nervous system origin. What if some types have a peripheral origin, and are primarily a function of levels of circulating peripheral cytokines or the like? That would sound more plausible to me, and it would help explain why some fatigue is effort-sensitive (if its going on in the periphery, its going to be influenced by all sort of things going on there).
 
I shall watch this thread with interest.

Thirty years ago good, experience, consultants considered that some of my symptoms, upon exhaustion, were similar to Parkinsonism-but without any particular tremor. It was the stooped, slow, shuffling gait together with a rigidity. The symptoms were, and still are transitory.

I always suspected the involvement of dopamine. I once got taken into my GP in that state. I mentioned the 'comment about Parkinsonism. Need I go on? You know the rest.
 
chrisb said:
I shall watch this thread with interest.

Thirty years ago good, experience, consultants considered that some of my symptoms, upon exhaustion, were similar to Parkinsonism-but without any particular tremor. It was the stooped, slow, shuffling gait together with a rigidity. The symptoms were, and still are transitory.

I always suspected the involvement of dopamine. I once got taken into my GP in that state. I mentioned the 'comment about Parkinsonism. Need I go on? You know the rest.
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Good grief (belatedy).

That sounds exactly like me and rather unlike what is reported for ME/CFS. I refer to them as 'stroke-like' episodes where amongst other things I have transient episodic ataxia.
 
Amantadine and L-carnitine treatment of Chronic Fatigue Syndrome.
https://www.ncbi.nlm.nih.gov/pubmed/9018019

Amantadine was poorly tolerated by the CFS patients. Only 15 were able to complete 8 weeks of treatment, the others had to stop taking the medicine due to side effects. In those individuals who completed 8 weeks of treatment, there was no statistically significant difference in any of the clinical parameters that were followed.
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Amantadine is a weak antagonist of the NMDA-type glutamate receptor, increases dopamine release, and blocks dopamine reuptake.[16] Amantadine probably does not inhibit MAO enzyme.[17] Moreover, the mechanism of its antiparkinsonian effect is poorly understood.[citation needed] The drug has many effects in the brain, including release of dopamine and norepinephrine from nerve endings. It appears to be a weak NMDA receptor antagonist[18][19] as well as an anticholinergic, specifically a nicotinic alpha-7 antagonist like the similar pharmaceutical memantine.
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https://en.wikipedia.org/wiki/Amantadine
 
I wonder which side-effects occurred, and whether those might give us clues. As always, I suspect it's a secondary consequence of CNS disruption, rather than a primary cause.
 
Dysautonomia is not very studied in MS. There are more than a dozen different types and most doctors don't have experience in this field. I think it is more than likely that the cognitive 'fatigue' we all suffer from is closely related.
 
More on the dopamine imbalance hypothesis of fatigue - this time in traumatic brain injury.

https://www.nature.com/articles/s41598-017-08846-6

Cognitive fatigue following traumatic brain injury appears to be mediated by dopamine signalling in the caudate nucleus of the basal ganglia with low dopamine associated with greater cognitive fatigue (both low dopamine and underactivation of the basal ganglia have been noted in ME/CFS).

Perhaps the U shaped nature of the effects of dopamine signalling on cognitive fatigue might explain negative results/side effects of dopamine agonists?

The negative relationships between activation in the caudate and self-reported fatigue are consistent with the Dopamine Imbalance Hypothesis46,47,48 that suggests a U-shaped relationship between the amount of dopamine in the brain (or activation in the structures enervated by dopamine) and levels of fatigue. That is, at low levels of dopamine, fatigue is high; as levels of dopamine increase, fatigue decreases; however, at high levels of dopamine, fatigue increases again. Indeed, it has been shown that dopamine agonists (e.g., methylphenidate) lead to fatigue reduction in individuals with TBI49 and other clinical populations50, 51
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