We know that hepatitis C patients receiving a strong pro-inflammatory drug (IFN-a) that helps them fight off their viral infections and ME/CFS patients have very similar problems with fatigue and identical problems with their basal ganglia.
That suggests that it’s not the presence of an infection which is making them look similar – it’s immune activation. People with hepatitis C who are not taking IFN-a don’t experience severe fatigue and don’t have problems with their basal ganglia. Whatever is going on in ME/CFS the only way to mimic it in hepatitis C patients is to hit them with a very powerful immune booster. (Interferon’s are released by cells to attack viruses.)
That suggests that something more than an infection is going on with people with ME/CFS. Either they have an infection which is prompting an unusually strong immune response (or the equivalent of that) or their immune systems are highly activated.
It’s also true that many hepatitis C patients do experience extreme fatigue, depression, etc. with IFN-a some people sail through the treatment with no problems at all. It’s this dysjunction between a normal and a horrible response that makes this group of patients so interesting. If the researchers can figure out why some people respond so to IFN so poorly they may be able to understand why some people sail through an infection and why others come down with a chronic illness that doesn’t quit; i.e. chronic fatigue syndrome. It’s also telling them a heck of a lot how the immune system causes the symptoms we associate with colds.
This patients then present a possible model for what is going on in ME/CFS.
Biol Psychiatry. 2016 Feb 15; 79(4): 320–328. Acute Changes in Striatal Microstructure Predict the Development of Interferon-Alpha Induced Fatigue Nicholas G. Dowell,* Ella A. Cooper,*† Jeremy Tibble,† Valerie Voon,‡§ Hugo D. Critchley,*¶║ Mara Cercignani,*,** andNeil A. Harrison*¶║⁎
A quantitative magnetization transfer (qMT) imaging was done of 19 hepatitis C patients about to undergo IFN-a treatment and then immediately afterwards and then 4, 8, 12 and 24 weeks later. They also examined their cytokine profiles.
qMT is a new form of MRI which
“exploits the phenomenon of magnetization transfer (MT) between free and macromolecular bound protons, to detect changes in microstructural environment.”
If you can figure that out you know more than me. The key fact, though, appears to be that this new form of MRI, like the new tests for neuroinflammation that are emerging, is able to assess changes at a more detailed level (the “microstructure”) than before. It’s technological developments like these that hopefully will reveal what is going on in chronic fatigue syndrome (ME/CFS) and fibromyalgia.
These UK, Italian and U.S. researchers hypothesized that increased cytokine levels which occurred just after the IFN-a treatment changed the microstructure of a part of the brain called the striatum that feeds dopaminergic and glutamergic inputs to the basal ganglia. Andrew Miller at Emory University believes that the problems found in the basal ganglia in ME/CFS may arise from reduced inputs from the striatum.
These researchers hypothesized that individuals with microstructural changes in their striatum would were be more likely to experience fatigue, depression, etc.
They also determined whether IFN-a impacted the insula, a part of the brain associated with interoceptive issues which has been highlighted in fibromyalgia and other chronic pain diseases as well as ME/CFS.
The study found that IFN-a administration immediately caused high levels of fatigue and then about four weeks later increased levels of depression.
The whole brain MRI analysis highlighted changes occurred within four hours of IFN-a administration in a small, concentrated cluster found in the left striatum. They reported that the development of the severe fatigue was “strikingly correlated” with changes in this part of the brain. No correlations, on the other hand, were found between the changes in the microstructure of the insula and the development of fatigue and mood issues.
The authors reported that this region of the brain has been shown to be “neurochemically and metabolically” sensitive to IFN-a. In fact, the authors stated that this small part of the brain displays “exquisite sensitivity” to this antiviral cytokine. Earlier studies finding increased activity (glucose uptake)and fluorodopa uptake suggested this part of the brain becomes more active when exposed to IFN-a.
The authors believe these changes reflect changes in, get this, lactate – which we’re seeing more of in both ME/CFS and FM – and pH in this region of the brain. Increased lactate or lactic acid levels appear to be present in the brains, muscles and possibly guts of fibromaylgia and ME/CFS patients. Increased lactate levels also predicted which GWS patients were able or unable to exercise. Increased brain lactate levels also appears to be triggering migraines when low oxygen conditions are present. High lactate levels, then, are showing up in several related disorders. That’s good news for those looking for a common thread in these disorders.
It turns out that the basal ganglia are “exquisitely vulnerable” to several factors that could be occurring in ME/CFS/FM – hypoxic (low oxygen level induced injuries), viral invasion and neurodegenerative processes. Given what we know low oxygen conditions could fit very well with what is happening in ME/CFS.
Not all immune events are the same. The authors noted that inflammation induced by bacterial infections or allergic events appears to induce fatigue by acting on a different part of the brain – the insula. (IFN-a administration in this study did alter insular activity, but to a much more modest degree than found in the striatum, and the changes in the insula were not correlated with increased fatigue.)
Is this what is happening in ME/CFS and FM? It’s certainly intriguing to see so many factors (basal ganglia problems, lactate accumulations, low oxygen environments) match up.
The best guess at this point is probably yes and no. If you had a viral onset that torqued up your levels of IFN-a then this model might fit for you. If you had a bacterial infection then a different part of your brain might be affected. Other possibilities surely are present.
The Cytokine Question
In the Dubbo studies Lloyd found that high symptom and cytokine levels early in an infection predisposed some people to come down with an ME/CFS-like illness. This study, however, didn’t find any correlation between cytokine levels in the blood and the appearance of fatigue and mood issues.
Instead the authors suggested something similar to what Younger and Miller have proposed – that it’s the reaction to inflammation in the brain that is key – not the cytokine levels in the blood. Both Andrew Miller and Jarred Younger have hypothesized that the central nervous system may get so sensitized to cytokines in these disorders that even normal levels can set off a fatigue reaction.
As the infection receded Lloyd found that cytokines appeared to play no role in the illness; that whatever happened, happened early on. This study in hepatitis C patients suggested that he was right. It found that small changes to one part of the brain occurring with four hours of the IFN-a administration predicted who would become fatigued and, four months later, depressed or not.
A small Suzanne Vernon/Andrew Lloyd study which, in retrospect, is becoming and more intriguing suggested that interferons may indeed play a role in ME/CFS. It found increased expression of an interferon stimulated gene called ISG20 and several mitochondrial genes after an Epstein-barr virus infection in people with severe fatigue.
ISG20 also showed up in a study examining the effects of IFN-a treatment in people with both HIV and hepatitis C infection. It turned out that half the HIV patients in the study experienced mood changes (depression, anxiety, etc.) after receiving IFN-a. Increased levels of ISG20 gene expression after IFN-a treatment were associated with what the authors called “psychiatric toxicity”; i.e. the induction of mood changes by the immune system.
Since increased ISG20 levels have also been associated with a better response to IFN-a treatment it seems that mood alterations are simply part and parcel of fighting off an infection for many.
Using new technology researchers found that the microstructure of a part of the brain (the striatum) that feeds dopaminergic and other inputs to the basal ganglia is altered by IFN-a treatment for hepatitis C.
Changes in the microstructure of the striatum occurred rapidly and predicted which individuals would experience fatigue and depression. The authors believe that increased levels of lactate – a substance found increased in both ME/CFS and FM – and altered pH may set the stage for these microstructural abnormalities.
Prior studies suggested that similar problems in the striatum and the basal ganglia are present in hepatitis C and ME/CFS patients. The alterations are highly associated with decreased “reward” and increased fatigue and may also effect autonomic nervous system functioning and our ability to move.
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