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Fatigue has been a mystery to the research world. Take multiple sclerosis (MS) – one of the most fatiguing diseases known. Fatigue is often one of the first symptoms that shows up in MS and it’s often the most troubling symptom MS patients experience, yet the fatigue in MS isn’t associated with the nerve lesions that cause the movement and other problems found in the disease.

microglia

The study authors proposed that microglial cell activation was causing the severe fatigue found in multiple sclerosis

Despite the lack of correlation between nerve lesion damage and fatigue, fatigue worsens as the disease progresses. It’s clear that several parts of the brain are affected in MS – the location of the lesions (usually in the supratentorial and perivenular areas and around the spinal cord in the neck) – and somewhere else.

Recently, Anthony Komaroff pointed to a possible fatigue center in the brain, elucidated by a multiple sclerosis study. The fact that the study, “Regional microglial activation in the substantia nigra is linked with fatigue in MS“, came from a now pretty familiar location – Harvard’s Brigham and Women’s hospital – which Ron Tompkins, David Systrom and other ME/CFS researchers are associated with – highlights again how useful it is to have ME/CFS researchers embedded in major medical centers.

This was kind of a hybrid hypothesis-driven exploratory study. Since all we know for sure, regarding the fatigue in MS, is that it’s not coming from the nerve lesions – the study needed to be exploratory. The study authors, though, had a hunch: microglial activation and the neuroinflammation it was causing was producing the fatigue. That idea, of course, fits right with similar speculations regarding ME/CFS/FM.

Because the site of the neuroinflammation was unclear, Medical Express reported that the researchers used what they called a “snooper” – a PET scan which used a radiolabeled “detective” or tracer  ([F-18]PBR06 radioligand) to bind to activated microglial cells. This was the first time microglial activation was assessed with regard to fatigue in MS. Not knowing where to look, they looked everywhere – and their finding, from an ME/CFS perspective, anyway – was astounding.

Results

The bright spots reflect correlations between fatigue and microglial activation. The bright spots in the middle are located in the substantia nigra of the basal ganglia

The main finding was a “strong correlation” between the amount of fatigue the MS patients were experiencing and the activation of microglial cells in a part of the brain called the substantia nigra. Secondary analyses found microglial activation in other parts of the brain (right precuneus, parahippocampal gyrus, putamen, thalamus, juxtacortical white matter) were also associated with increased fatigue.

All in all, the authors reported finding evidence of “widespread” microglial activation in the brains of MS patients with high rates of fatigue. Both Younger’s and Nakatomi’s ME/CFS study, and the recent fibromyalgia study, found evidence of “widespread” neuroinflammation as well.

The Basal Ganglia

The substantia nigra is part of the basal ganglia – a set of structures in the midbrain which affect “reward”, fatigue and movement. Damage to one part of the substantia nigra is responsible for the movement problems in Parkinson’s disease.  Without the substantia nigra, we couldn’t (subconsciously) “plan” movement – an essential part of being able to move at all.

The fatigue in MS isn’t totally mysterious – we just know that it isn’t associated with the amount of nerve damage present. Other studies have suggested that microstructural changes and abnormalities in various connections, networks and structures play a role, and several hypotheses (dopamine, neuroendocrine and functional disconnection) have been formed.

The cause behind these abnormalities has never been identified, but these authors proposed that the microglial activation they found could be the “unifying mechanism” driving the structural and other changes.

More pertinently for our case, though, they also suggested that the microglial activation might simply be causing fatigue in general – and jumped right into chronic fatigue syndrome (ME/CFS).

A Chronic Fatigue Syndrome (ME/CFS) Connection?

Given the similar findings in ME/CFS, I had been wondering, hoping, praying that ME/CFS findings would make their way into this paper and they did – in spades – a good sign that ME/CFS findings are getting around.

First they cited the 2014 Nakatomi ME/CFS neuroinflammation study. Then came Chaudhuri and Behan’s mammoth 2004 paper, “Fatigue in Neurological Disorders“, which proposed basal ganglia dysfunction was causing the fatigue in ME/CFS, and then came Komaroff’s 2019 JAMA paper, “Advances in Understanding the Pathophysiology of Chronic Fatigue Syndrome“,  one of the top visited papers from JAMA of 2019. They even cited a 1998 paper which compared post-polio syndrome to ME/CFS.

Findings suggesting that the activity of the default mode network was altered in more fatigued MS patients provided another potential connection between ME/CFS and fibromyalgia. One study in ME/CFS and many in FM have produced similar findings.

Miller’s 2014 Basal Ganglia ME/CFS Study

ME/CFS studies were thankfully well-represented. The authors didn’t cite, though, Andrew Miller’s 2014 study which explicitly linked reduced basal ganglia activation with fatigue in ME/CFS.

Miller, a psychoneuroimmunologist, came to his basal ganglia work in ME/CFS via a fascinating route. It turns out that giving an immune factor called interferon-alpha to hepatitis C patients knocks down their infection, but also produces an ME/CFS-like state (fatigue, fever, and other flu-like symptoms) in a large subset of patients.

Notice the concentration of dopamine in the midbrain (basal ganglia and hippocampus) and the prefrontal cortex. The Japanese believe dopamine reductions in these areas are producing fatigue in ME/CFS

It was the ability of interferon-alpha (IFN-a) – which is naturally produced by the body – to do this which clued researchers into the phenomena of “sickness behavior”; i.e. the deliberate production of symptoms to keep people with infections immobilized.

After studies suggested that this “sickness behavior” is being produced by the basal ganglia in hepatitis C, Miller used a functional MRI (fMRI) to measure the basal ganglia’s response to “reward” in ME/CFS patients and healthy controls.

Miller used “reward” because hepatitis C studies have shown that “reward” is strongly associated with fatigue, our mood and, interestingly, how well we move and react. In that vein, it’s interesting that ‘psychomotor’ slowing – one of the most consistent findings in ME/CFS – is also commonly found in people with basal ganglia dysfunction – and is also highly associated with fatigue severity.

Miller found that mental and physical fatigue and reduced activity in ME/CFS was correlated with reduced activation of the globus pallidus (GP) in the basal ganglia (BG). Reduced input from the striatum in the basal ganglia was also found.

The Gist

  • Severe fatigue is one of the most common symptoms in multiple sclerosis yet is not produced by the nerve lesions characteristic of the disease.
  • Proposing that microglial activation and neuroinflammation might be causing the fatigue M.S. researchers did an amall open-ended PET scan of the brain
  • They found widespread evidence of neuroinflammation with  a hotspot located in one a part of the basal ganglia called the substantia nigra.
  • Located in the midbrain the basal ganglia is involved in “reward”, movement, sleeping and wakefulness and others.
  • Researchers first learned of the connection between the basal ganglia and fatigue when hepatitis C patients given interferon alpha to fight their infection developed ME/CFS-like symptoms such as severe fatigue and other flu-like symptoms. Those patients were found to have reduced basal ganglia activation.
  • Since then reduced basal ganglia activity has been associated with fatigue in MS, ME/CFS and other groups.. Numerous studies have documented basal ganglia problems in ME/CFS, fibromyalgia and Gulf War Illness.
  • Low levels of dopamine, the main neurotransmitter serving the basal ganglia, can result in even small actions requiring large amounts of effort.
  • Miller’s findings suggest that low levels of dopamine may result in a hypersensitivity to inflammatory factors. (It was the hepatitis patients with low dopamine low levels who developed severe fatigue, etc. after taking IFN-a.)
  • A good deal of evidence suggests that dopamine levels may be low in fibromyalgia and could be contributing to the pain hypersensitivity found there.
  • The authors proposed that a microglial activation in the basal ganglia could be producing fatigue in a number of diseases including ME/CFS and urged more studies be done.
  • Finding a common “fatigue nucleus” in ME/CFS and other diseases would be a huge step forward.

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A Dopamine Connection?

That reduced input, Miller thought, was probably indicative of an under-functioning dopamine system. In fact, Miller suggested that problems with reduced dopamine functioning might be found across the brain in ME/CFS.

Dopamine plays a pivotal role in the regulation of mood, motivation, reward, motor activity (movement), and sleep-wake cycles. Low levels of dopamine can result in high levels of effort being needed for even simple tasks.

Miller proposed that low dopamine levels may also have an insidious effect that leaves the central nervous system vulnerable or sensitive to inflammation; i.e. that suggests low levels of inflammation – perhaps the kind found in ME/CFS and FM – could cause high levels of fatigue, motor slowness, cognitive problems, etc. Studies suggest that when given IFN-a for hepatitis C, it’s the dopamine-deprived individuals suffer who suffer from enormous fatigue, motor slowing, and depression. Dopamine deprivation, then, could possibly set the stage for an ME/CFS-like reaction to an infection.

Since Miller’s 2014 paper, the connection between damage to the basal ganglia and ME/CFS-like symptoms has only strengthened in hepatitis C, ME/CFS and allied diseases.

Just a year ago, a study linked fatigue and perceived stress with inflammation and altered connectivity between the basal ganglia and the insula in hepatitis patients treated with IFN-a. Another 2019 study linked fatigue in these patients to microstructural changes in the striatum – another part of the basal ganglia.

Thapaliya’s 2020 study found microstructural changes in the basal ganglia in ME/CFS. Low putamen activity was associated with fatigue (and low reward) in Japanese children with ME/CFS. A huge (880 person) Japanese study found that increased fatigue and reduced “reward” was associated with three different structures in the basal ganglia.

Wylie’s 2019 study implicated the basal ganglia in fatigue in Gulf War Illness (GWI). While a 2018 review of fatigue and the nervous system couldn’t come up with a definitive region of the brain, the basal ganglia and the limbic system were two of the four brain areas highlighted. Plus, reduced basal ganglia functioning was associated with increased physical fatigue in older adults.

Other researchers are hovering around this area. Japanese researchers have proposed that an inhibited circuit involving the prefrontal cortex, the basal ganglia and other structures stops signals going to the motor cortex to increase muscle performance.

Fatigue Explained? Japanese Assert Brain Damage Causes Fatigue in Chronic Fatigue Syndrome

Barnden’s fascinating study suggested that microglial activation in the midbrain and prefrontal cortex teams up to produce the autonomic nervous system and sleep problems in ME/CFS.

The ‘Insulted Midbrain’ in Chronic Fatigue Syndrome

Dopamine, the Basal Ganglia and Fibromyalgia 

Several studies implicate reduced dopamine in fibromyalgia as well, and one fMRI study also found the same reduced levels of reward found in ME/CFS and IFN-a patients. Connections to pain have cropped up. One hypothesis proposed that reduced brain reward circuit functioning plays an important role in determining our levels of pain sensitivity.

Other studies found reduced dopamine metabolism in FM, reduced brain dopamine uptake, and one study suggested that reduced dopamine levels are associated with increased pain sensitivity in FM.

Treatments?

Dopamine, the Basal Ganglia and Chronic Fatigue Syndrome #II – Treatments

Conclusion

Another unifying hypothesis – this time for fatigue and possibly even for neurological disorders – microglial activation and neuroinflammation

Fatigue is one of the most common and disabling symptoms of MS, yet it is not, oddly enough, related to the lesions which cause the movement and other problems in the disease. Some studies have found brain abnormalities that are associated with fatigue in MS, but it’s never been clear what’s causing them. A small exploratory MS study may have provided an answer – microglial activation and neuroinflammation.

As in ME/CFS and FM, widespread areas of neuroinflammation in the brain were found in MS. It was the key finding of the study, however, that aroused the most interest. The part of the brain most associated with the fatigue in MS was the substantia nigra of the basal ganglia. Damage to the basal ganglia has long been proposed to play a crucial role in the fatigue in ME/CFS and other diseases, and the authors readily cited past findings in ME/CFS.

They didn’t cite, though, the 2014 Miller paper which found that increased mental and physical fatigue and reduced activity was correlated with reduced basal ganglia activation in ME/CFS. Since Miller’s study, several others have implicated the basal ganglia findings in ME/CFS and FM.  Other researchers are focused in on the prefrontal cortex/basal ganglia/hypothalamus connection. There’s more “there there” in this area all the time.

Miller also highlighted dopamine – a hormone/neurotransmitter – which plays a critical role in reward, motor activity (movement), sleep and wakefulness, mood and possibly pain. Low dopamine levels can make even small activities fatiguing.

Miller’s studies suggest that low dopamine levels may sensitize the basal ganglia to inflammation – causing fatigue, flu-like symptoms, etc. even when inflammation levels are low. Several studies suggest that low dopamine levels may also be contributing to the pain and other symptoms found in fibromyalgia.

These studies suggest that microglial activation could be contributing to reduced basal ganglia activation and fatigue not just in ME/CFS and FM, but in MS and other diseases.

Some researchers – including these MS researchers – believe that microglial activation lights the fire that produces central nervous system diseases like MS, as well as other diseases like Parkinson’s disease, ME/CFS, FM and GWI. The type of disease that is produced depends on the where and how of the neuroinflammation and the environment; i.e. the biological construct of the individual involved.

Has a fatigue nucleus that operates in many different diseases been found? Finding out that the fatigue in MS, ME/CFS, FM and other central nervous system diseases are caused by similar processes would be a huge boon. Finding out that neuroinflammation is at the heart of all of them could be an even bigger boon. That might suggest that anything that tamps down neuroinflammation in one disease might help in another – and lots of efforts are being made in other diseases to find ways to reduce neuroinflammation.

Given that it was good to see the authors emphasize that future research studies search for “common…mechanisms of fatigue” in neurological disorders such as MS, ME/CFS and Parkinson’s disease.

“Future research studies are needed to compare the fatigue-related microglial changes in MS with other diseases such as CFS and Parkinson disease and identify common and disease-specific mechanisms of fatigue in neurologic disorders.” The authors.

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