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This is the second blog to focus on Miller’s recent basal ganglia findings in Chronic Fatigue Syndrome. First  a  quick review of the first blog.

Review

 “Recent evidence indicates that the basal ganglia and dopamine (DA) may be primary targets of inflammatory cytokines leading to cytokine-induced behavioral changes.” – Miller

dopamine

Reduced dopamine levels showed up big time in Miller’s study. Now we take a look at why they’re low and possibly how to fix them.

Reduced activity in the basal ganglia during a reward game was associated with fatigue in people with Chronic Fatigue Syndrome (ME/CFS).  A similar pattern found in people with hepatitis C who have been given the interferon alpha (IFN-a) cytokine suggests immune activation may be driving basal ganglia problems, since the lack  of reward and the fatigue is present in both groups. Studies suggest that reduced dopamine inputs from the striatum may cause the reduced activation of the basal ganglia. The basal ganglia problems in ME/CFS suggest dopamine may be reduced brain-wide.

Perhaps the most intriguing outcome of the Miller ME/CFS basal ganglia study is the idea dopamine production may be causing the brain to over-respond to inflammatory signals resulting in increased fatigue and other symptoms associated with “sickness behavior”. This suggests that mild elevations in inflammation found in many people with Chronic Fatigue Syndrome could be having exaggerated effects.

Now we turn to possible causes of the reduced dopamine in ME/CFS, and we are given evidence of reduced dopamine in Fibromyalgia (FM) as well.

The Fibromyalgia Connection ?

We may not be just talking about ME/CFS here. Several recent studies suggest an immune component may be present in Fibromyalgia, and FM often begins with a viral trigger. Pridgen, we’ve observed, believes an active herpesvirus infection causes FM.

fibromyalgia

Reduced dopamine may be one finding ME/CFS and FM have in common

Several studies implicate reduced dopamine in Fibromyalgia, including a recent fMRI study which found reduced levels of reward.  The reduced reward was associated with reductions in activity in an area of the brain with high dopamine levels. (One hypothesis proposes brain reward circuit functioning plays an important role in determining pain sensitivity.)

Reduced dopamine functioning could also help to explain the poor responsiveness to opiates often found in FM. Reduced response in the regions of the brain associated with ‘reward’ is common in people who don’t get results from opiates. Opiates do help some FM patients, but in general their effects are blunted in FM.

Another study suggested reduced dopamine metabolism in FM was associated with reduced brain grey matter. A small PET scan study found reduced brain dopamine uptake,  and one study suggests reduced dopamine levels are associated with increased pain sensitivity in FM.

Blocked Dopamine Synthesis – Focus on BH4

 “It is reasonable to assume that slight elevations in Phen or the Phen/Tyr [phenylamine/tyrosine] ratio during chronic immune activation may confer physiological relevance, particularly in terms of predicting increased oxidative stress, behavioral alterations, and decreased dopamine synthesis.” – Miller

It all goes back to inflammation. Inflammatory cytokines and oxidative stress reduce the production of an enzyme co-factor called tetrahydrobiopterin (BH4) that converts phenylalanine to tyrosine, the amino acid precursor to dopamine. The low levels of dopamine found in the brains of ME/CFS patients could all start with inflammation or oxidative stress whacking the BH4 enzyme and thus reducing the amino acid dopamine is made from – tyrosine.

The degree to which tyrosine is available for transformation into dopamine can be measured in several ways in both the blood and cerebral spinal fluid.

blood-test-dopamine

Miller proposed a simple blood test (phenyalamine/tyrosine) could pick out people with reduced brain dopamine synthesis

BH4 is also an essential cofactor for the endothelial NOS (eNOS) enzyme at work in our blood vessels.  During times when we have low BH4 levels, eNOS switches from producing NO to generating oxygen-derived free radicals that increase oxidative stress. BH4 is currently being evaluated in cardiovascular disorders.

Miller’s finding that increased levels of phenylalanine and reduced levels of tyrosine in the blood and the spinal fluid were associated with increased fatigue (but not depression) in hepatitis C patients treated with IFN-a suggested that immune activation and oxidative stress could be knocking down dopamine production in those patients and possibly in ME/CFS patients.

Miller proposed that a reduced phenylalanine/tyrosine ratio in the blood could be a marker of reduced dopamine production in the brain.

Traditional Dopamine Enhancing Drugs Fail

Stimulants such as amphetamines and dopamine reuptake inhibitors which increase dopamine release may be ineffective because innate immune activation is blocking dopamine synthesis.

Increasing dopamine synthesis (not enhancing dopamine release) is a more likely target in disorders like ME/CFS, and it’s to that we turn next.

Increasing Dopamine Synthesis 

Directly Boosting Dopamine Synthesis

Since BH4 appears to get hit hard by oxidative stress and cytokines in these disorders, and BH4 converts phenylalanine to tyrosine – which gets transformed into dopamine – Miller first focuses in increasing BH4 levels.

epigenetics

How interesting to see methylation show up as a possible contributor to reduced dopamine in ME/CFS

Sapropterin (Kuvan), a synthetic form of BH4 approved by the FDA to treat phenylketonuria (PKU) is a possibility. PKU, which refers to high phenylalanine levels in the blood, can be associated with significant brain damage, mental retardation, seizures, and behavioral alterations.

Supplements that impact BH4 synthesis/regeneration such as folic acid, L-methylfolate, and S-adenosyl-methionine (SAMe) are another possibility, and with them we’ve entered into the complex and fascinating world of methylation – which we will leave for another blog.  It’s intriguing, however, to see this subject, which has been of great interest in ME/CFS, suddenly show up as a treatment possibility for dopamine-induced basal ganglia dysfunction, fatigue, and motor slowness in ME/CFS.

Enhancing Dopamine Synthesis By Blocking Oxidative Stress

free-radicals

Reducing oxidative stress might be able to help with dopamine production

The Kynurenine pathway – Miller noted the kynurenine pathway in his section on oxidative stress. Mady Hornig, who in a discussion with me called the kynurenine pathway her ‘favorite pathway’, is deeply interested in this pathway a.  Some evidence suggests abnormalities in this pathway may be implicated in some Fibromyalgia and ME/CFS patients.  A kynurenine gene polymorphism predicts the sudden appearance of depression in hepatitis patients treated with IFN-a.

In any case the high rates of oxidative stress invariably found in ME/CFS studies suggest that reducing oxidative stress could be a viable means of reversing the problems with dopamine synthesis present in some people with ME/CFS.

Enhancing Dopamine Synthesis By Blocking Immune Activation

Etanercept (Enbrel) is a tumor necrosis factor blocker used to treat a variety of inflammatory disorders. It’s possible a number of different drugs could be used to reduce an immune activation that is whacking dopamine production in some people with ME/CFS.

Drugs Effecting Dopamine Receptors

Drugs that can stimulate dopamine receptors (e.g. pramipexole, levodopa) fall into the experimental category but might be helpful as well.

Inflammation,  BH4, Depression (and ME/CFS and FM)

It’s not surprising given the stresses associated with Fibromyalgia and Chronic Fatigue Syndrome that depression is common, but is it all due to psychological stress? Much of Miller’s career has been spent exploring the inflammatory aspects of depression. We’ve seen that a significant proportion of hepatitis C patients treated with the IFN-a immune factor suffer from severe fatigue, and some of those become depressed.  Could a substantial portion of the depression found in ME/CFS be immune-mediated? Let’s take a brief look at inflammation and depression.

depressed-woman

Could some of the depression found in ME/CFS be due to inflammation?

It appears that inflammation either augments or causes depression in about a third of depressed patients. We’ve just seen that low BH4 levels are associated with inflammation-caused reductions in dopamine and, ultimately, fatigue and depression in hepatitis C patients.

That’s an intriguing finding for Miller’s inflammation/depression work given that low serum levels of folate – a factor in BH4 production – have been associated with increased risk of depression and a poor response or even a non-response to antidepressants.

If you’re depressed and not doing well on anti-depressants note that the inflammation-associated depression group tends to respond poorly to antidepressants.

Miller notes that L-methylfolate (marketed as Deplin and Zervalx), folic acid, and folinic acid (Leucovorin) have been shown to enhance antidepressant therapy, and that SAMe, in a placebo-controlled, double-blinded trial increased remission rates and symptoms significantly.

RNase L Returns – After a Decade or So

The fact that not all hepatitis C patients given IFN-a become highly fatigued indicates some other factor in combination with IFN-a is needed to produce the fatigue, motor slowing, and similar symptoms found in that group.  Could that factor also be present in ME/CFS patients?

Miller’s earlier gene expression study suggests it might be. The only difference in the gene expression between the fatigued and non-fatigued patients receiving IFN-a was, remarkably, a gene associated with Ribonuclease L, a.k.a. RNase L.

IFN

Years after study on RNase L stopped in ME/CFS it shows up in IFN-a treated hepatitis patients with fatigue (This is interferon)

This is an IFN-associated enzyme that was implicated in ME/CFS well over a decade ago. RNase L and the IFN pathway was the cat’s meow for a time in ME/CFS, and an entire book by Englebienne and De Meirleir was devoted to the implications of IFN pathway problems in this disorder. Interest faded over time, and it has not been studied in ME/CFS for years.

Now the differences in gene expression of that very enzyme appears to predict who comes down with ME/CFS – at least for a time – in hepatitis C patients who are given IFN-a. When asked, Miller stated that his findings were consistent with what was seen in the RNase L findings of a decade or so ago. They suggested an upregulated IFN system could very well be associated with the basal ganglia problems found in ME/CFS.

That makes the IFN findings in FM all the more interesting. A gene expression study that strongly implicated the interferon pathway in Fibromyalgia suggests, at least to me, that a similar pattern of immune (IFN) activation, dopamine reduction, and increased fatigue and pain could prevail in FM as well. The study found that interferon signaling and interferon regulatory pathway genes were much more highly expressed in FM patients with high levels of pain (Lukahatei, et al.).

A Talk with Andrew Miller

Giving endotoxin to healthy controls reduces basal ganglia functioning.  Giving IFN-a to hepatitis C patients makes many of them fatigued and depressed and causes the same kind of basal ganglia dysfunction that seen in ME/CFS. What would be your guess as to the cause of the basal ganglia problems in ME/CFS?

Increased inflammation as a consequence of chronic viral infection (IFN-alpha is an anti-viral cytokine) and/or chronic stress and/or issues related to diet or obesity, all of which lead to inflammation.

andrew-miller

Andrew Miller has no ongoing ME/CFS studies but believes his basal ganglia work will help a subset of patients

[Miller has pointed out that researchers, including him, fully expected to find inflammatory pathways that were unique to depression, but that hasn’t occurred. The inflammation in a person suffering from chronic stress or from a reactivated virus looks very similar physiologically. The point is, as Miller notes below, the inflammation in a disease as heterogeneous as ME/CFS could come from a wide variety of sources.  The basal ganglia problems in one person with ME/CFS could be due to immune activation

from a chronic viral infection and in another could be associated with stress.

Any of these contribute to a central nervous system that has become unduly responsive to inflammation; i.e., a CNS which starts pumping out factors that cause sickness behavior at the drop of a hat, so to speak.]

Does the fact that inflammation plays a role in a least a subset of people with ME/CFS suggest that inflammation associated depression is more common in ME/CFS with depression and those people might want to check out anti-inflammatories? If that’s true are some anti-inflammatories more likely to work in inflammation associated depression than others? 
I would be careful about the use of the term depression… Although both depression and fatigue are related, there are many patients who are fatigued but not depresssed AND have inflammation. As far as using anti-inflammatories, as a licensed physician, I am not at liberty to recommend unapproved uses of medications.
inflammation

Miller suggested several options for people with high levels of inflammation

That said, I think that if someone is chronically fatigued, they should get their inflammation level checked (CRP) and if it is high (>3 mg/L), they should begin a lifestyle plan of diet and graded exercise as well as possibly meditation to get it down. Anti-inflammatories might also be used, but I am not confident in that statement until I have done more research.

I agree however that I also have known people who have seen improvement in fatigue and depression with anti-inflammatory drugs (we have published this in our infliximab paper).
[ Infliximab is a tumor necrosis factor antagonist. The CDC found increased rates of inflammation in Chronic Fatigue Syndrome  which were associated with an increased risk of depression. ]
With regard to whether he was working on more ME/CFS studies, Miller wrote:

“Not specifically, but we are working hard to understand how we can treat the basal ganglia problem … which will have direct relevance to some CFS patients. CFS is a heterogeneous disorder, so it will help to get a biomarker that we can then apply to the CFS population to determine who might benefit from our therapies. … This will be a win for CFS.”

Miller was careful to point out in the study that, even though the study was positive, not everyone in the study had basal ganglia dysfunction.  Clearly, those patients with basal ganglia dysfunction – and it is likely a substantial number – may very well benefit at some point from Miller’s and other’s long and now quite extensive research into the relationship between basal ganglia dysfunction and inflammation, immune activation, and fatigue.

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Tyrosine Metabolism During Interferon-alpha Administration: Association with Fatigue and CSF Dopamine Concentrations. Jennifer C. Felger 1,2,*, Li Li 3, Paul J. Marvar 1, Bobbi J. Woolwine 1,2, David G. Harrison 4,Charles L. Raison 5, and Andrew H. Miller. Brain Behav Immun. 2013 July ; 31: 153–160. doi:10.1016/j.bbi.2012.10.010

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