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The data suggest that the neurocircuitry of fatigue in CFS patients may share a similar basis in the basal ganglia as is observed in other neurologic disorders and cases of basal ganglia lesions, as well as in the context of immune activation.” Miller et. al.

Andrew Miller has been focused on the effects of immune activation for decades

Andrew Miller has been focused on the effects of immune activation for decades

Andrew Miller M.D. is a psychoneuroimmunologist who is deeply interested in how immune activation affects symptoms and behavior.  A highly  published researcher with over 200 citations, Dr. Miller has produced a rich  body of work.  His research has mostly focused the biological roots of depression and the effects an immune agent called interferon alpha (IFN-a) given to fight hepatitis A patients has on their symptoms and behavior. He has created a rich body of work for us to work from.

He’s not a behaviorist – he doesn’t believe ME/CFS results from poor coping. In fact, when I asked him about ME/CFS at the Ottawa International IACFS/ME conference he stated he believes a pathogenic process probably plays a key role in many people with Chronic Fatigue Syndrome.  Note that in the above quote he referred to ME/CFS as a neurological disorder.

A Different Approach to Neuroinflammation

Miller has been taking a different approach to ME/CFS and inflammation than other researchers.  The extreme fatigue and sometimes depression experienced by many (but not all) hepatitis C patients who have been given interferon alpha – a cytokine – caught his eye years ago.

The IFN-a/hepatitis C/fatigue findings helped lay the foundation for our understanding of the effects of immune factors on fatigue, depression, and other symptoms of ‘sickness behavior’. They supported the idea that ‘sickness behavior’ is largely due to the immune system’s response to the pathogen, not the pathogen itself.  Sickness behavior is the process whereby central nervous system processes induce feelings of fatigue, fever, and other flu-like sensations to stop an infected person from moving and cause them to take to bed, and thereby stop transmitting the pathogen to others in the community.

Motored Down

Miller believes the ‘sickness behavior’ he finds in many hepatitis C patients given IFN-a is similar to what’s happening in Chronic Fatigue Syndrome (ME/CFS). Interferon-alpha plays a major role in combatting intracellular viruses, and as such, is used to knock down hepatitis C infections. Unfortunately, IFN-a therapy often comes at the cost of severe fatigue and even depression in a large subset of patients receiving it. It appears to particularly affect basal ganglia functioning.

motor-cortex

The idea that the motor cortex is being impaired from activating the muscles in ME/CFS is not new – it just hasn’t been raised for a while

Miller and others have been exploring the role the basal ganglia, found in limbic system in the brain, plays in the producing the fatigue and other symptoms found in ME/CFS and other disorders.

Miller starts off the paper in fascinating fashion by talking about the basal ganglia’s effects on ‘motor’ or movement problems. The first  I heard researchers refer to possible ‘motor problems’ in ME/CFS was the last time the basal ganglia was brought up almost fifteen years ago by Chaudhuri and Behan.  In a series of papers, one of which (Fatigue and Neurological Disorders) appeared in The Lancet and another (Fatigue and Basal Ganglia) in the Journal of Neurological Science in 2000, Chaudhuri and Behan proposed basal ganglia problems were at the epicenter of ME/CFS and other fatiguing disorder.

The most recent mention of the motor cortex and ME/CFS came last years as Japanese researchers posited that an over-active fatigue enhancement neural circuit in ME/CFS stops the motor cortex from sending signals to activate the muscles.

Miller points out – as Chaudhuri and Behan did back then – that fatigue is common in neurological disorders such as Parkinson’s disease and multiple sclerosis.   He notes that ‘psychomotor’ slowing – one of the most consistent findings in ME/CFS – is also common in people with basal ganglia dysfunction – and that it’s also highly associated with fatigue severity.

Chaudhuri and Behan went on to document increased choline concentrations in the basal ganglia of ME/CFS patients that suggested inflammation and/or ischemic conditions were present. Since then other studies have found indications of basal ganglia problems in ME/CFS, but this is the first study in over ten years to focus directly on the basal ganglia in ME/CFS.  Miller did this study in collaboration with the CDC.

Unrewarding Reward

PLoS One. 2014 May 23;9(5):e98156. doi: 10.1371/journal.pone.0098156. eCollection 2014.  Decreased basal ganglia activation in subjects with chronic fatigue syndrome: association with symptoms of fatigueMiller AH1, Jones JF2, Drake DF1, Tian H2, Unger ER2, Pagnoni G3.

In this study Miller used functional MRI (fMRI) to measure the basal ganglia’s response to ‘reward’ in ME/CFS patients and healthy controls.  Why focus on reward? Because it turns out that the ‘hedonic reward circuit’ Miller examined in the basal ganglia affects not just how rewarding a task is but also what our mood is, how fatigued we are and, interestingly, how well we move.

The basal ganglia light up like a Christmas tree when we’re winning at something. Hitting the brain with an immune factor, such as IFN-a, however, throws that reward circuit off.  An earlier study of hepatitis C patients receiving IFN-a indicated that reduced reward was highly associated with fatigue.  Studies have shown that reward, fatigue, and psychomotor slowing are all associated with each other.

basal ganglia

Basal ganglia activation is tied to reward, fatigue and motor cortex activity.

This isn’t true only in sick people; a study of healthy controls given a by-product of infection – an endotoxin – found reduced basal ganglia responses to reward as well.  Other studies indicate that exposure to inflammatory factors reduces blood flow and activity in the basal ganglia as well.  It appears that reduced ‘reward’ is another way the brain has of keeping us immobile and   in bed during an infection.

The big difference between the ME/CFS patients and the hepatitis C patients and healthy controls being given endotoxins, of course, is that the ME/CFS patients in this study aren’t being given anything to activate their immune systems. Their immune systems are already activated.  If Miller gets the same results in the ME/CFS patients as in the interferon alpha (IFN-a) hepatitis C patients, he can suggest that the same process – immune activation – perhaps driven by a pathogen, is causing the fatigue, motor slowness, and depression.

The Study

These findings provide further evidence that inflammatory stimuli, including inflammatory cytokines, target basal ganglia and dopamine function to induce behavioral changes associated with inflammation in humans.

 In the study ME/CFS patients and healthy controls engaged in a gambling task which they were allowed to win.  While they were doing that, functional MRIs (fMRIs) were assessing the level of activity in their basal ganglia.

The results of this study were presented at the Ottawa IACFS/ME conference over three years ago, but the study was not published until this year. (This brings to mind, perhaps not fairly, the CDC multi-site results presented at the FDA meeting a year and a half ago which have yet to be published.)

globus pallidus

One section of the basal ganglia – the globus pallidus – was particularly effected

The study found significantly reduced activation throughout the basal ganglia in ME/CFS patients compared to controls. A cross analysis found that mood disorders (anxiety) played no role in the findings; i.e., anxiety did not produce more reduced BG activation.  (This kind of analysis is done frequently. I cannot remember a single ME/CFS study where the presence of a mood disorder impacted a physiological finding.)

Very strong correlations (p<.0001) between reduced activity in a section of the basal ganglia (BG) called the globus pallidus (GP) and mental fatigue as well as significant correlations between the GP and physical fatigue and reduced activity suggested damage to this section of the BG may play a key role in Chronic Fatigue Syndrome.

Discussion

The study suggested that rewards are less rewarding in ME/CFS than they are in healthy controls.  To put it another way, the highs aren’t as high as they used to be. A recent Fibromyalgia study also suggested people with FM experienced less reward than healthy controls in the same positive situations.

A great deal of past research on the basal ganglia by Miller and others allowed him to flesh out the findings dramatically.

The reduced basal ganglia activity found could be affecting or be affected by several other parts of the brain. The basal ganglia, for instance, receives GABA input from the striatum.  GABA, a ‘feel-good’ chemical in the brain, dampens excitation in the central nervous system and is probably the source of feelings of reward and enthusiasm we feel when we’re winning at something like gambling.

The fact that those fatigued hepatitis C patients receiving interferon demonstrate lower activation of the striatum and evince basal ganglia problems similar to ME/CFS patients suggests the reduced basal ganglia activation in ME/CFS could be due to reduced inputs from the striatum – and that implicates dopamine in ME/CFS.

Let’s take a look at dopamine.

Dopamine

“The latter finding supports the hypothesis of a general hypofunctional dopaminergic system in CFS that exposes the right basal ganglia structures to a greater vulnerability.” – Miller et. al.

The reduced input from the striatum is probably indicative, Miller thinks, of an under-functioning dopamine system. The lower activation in the right side (but not the left side) of the basal ganglia in ME/CFS suggests that problems with reduced dopamine functioning are found across the brain in general, not just in the basal ganglia.

dopamine

Reduced dopamine production could be driving the basal ganglia problems

Dopamine, which functions as both a neurotransmitter and a hormone, plays a pivotal role in the regulation of mood, motivation, reward, psychomotor activity, and sleep-wake cycles. A wide variety of disorders including Parkinson’s, ADHD, restless leg syndrome, and schizophrenia are all associated with decreased dopamine levels.

Dopamine is produced in the ventral integument area of the brain. For such a powerful agent, it is released into surprisingly few areas of the brain, including the nucleus accumbens, the prefrontal cortex, and the striatum, a.k.a. the basal ganglia.

Abnormalities in all of these areas have been associated with ME/CFS, and all exert powerful influences on other parts of the brain. Japanese ME/CFS researchers recently proposed that the prefrontal cortex determines whether fatigue-reducing or fatigue-enhancing processes are activated by the brain.

Note that both the nucleus accumbens and prefrontal cortex – both of which are served by the same dopaminergic neurons – have been implicated in the transition from acute to chronic pain.

The striatum, which appears to be strongly associated with the fatigue produced in both ME/CFS and in IFN-administered hepatitis C patients, is heavily involved in motor control, motivation and decision-making.  Dopamine neurons also project into the hypothalamus and pituitary glands, both of which have been implicated in ME/CFS.

High Effort

Dopamine also determines the amount of ‘effort’ it takes to engage in a task or activity.  Low levels of dopamine can result in high levels of effort being needed to engage even in simple tasks.  To put it another way, dopamine promotes action – except when it’s not present, in  which case fatigue and inaction is the rule. The fatigue-dopamine connection can be seen in dopamine-reducing antipsychotic drugs that produce cognitively dulled and fatigued states.

Hypersensitized to Inflammation?

“Thus, the activation of inflammatory pathways by viruses or other pathogens may represent one mechanism of altered basal ganglia function leading to symptoms of fatigue in patients with CFS.”  – Miller et al.

One of Miller’s earlier papers suggested that reduced dopamine uptake may leave the central nervous system particularly vulnerable to the negative effects of inflammatory processes.  This bears repeating. Miller suggests reduced dopamine may be causing your system to get overly disturbed by whatever inflammation that is present. That could result in low levels of inflammation causing high levels of fatigue, motor slowness, cognitive problems, etc.

inflammation

If Miller’s right, small amounts of inflammation could be having exaggerated effects

He’s not the first to suggest this kind of process is occurring.  The Lights believe low signals of muscle damage are having an exaggerated effect, and Younger suggests that the microglia may be over-reacting to leptin in ME/CFS. In these scenario’s it’s the body’s reaction to a substance, not  the substance itself, that is the problem.

Miller’s findings may suggest that reduced dopamine levels could turn a mild inflammatory state into a real problem.  That’s an intriguing idea given the generally low level of   inflammation found in ME/CFS. This is not to say that some ME/CFS patients don’t have very high levels of inflammation, but in general my understanding is that increased but quite moderate levels of inflammation are generally found.  Mild to moderate levels of inflammation are often also found in cardiovascular disorders and in a subset of patients with mood disorders.

Miller’s findings suggest knocking dopamine down could predispose one to having the worst kind of sickness behavior.

It actually can go both ways: an earlier primate study suggested inflammation may be knocking down dopamine which then exacerbates the effects of inflammation.  Dopamine levels tanked in the basal ganglia of primates four weeks after they were given IFN-a. Studies suggest that dopamine-deprived individuals suffer from enormous fatigue, motor slowing, and depression when they’re immune-activated (i.e., given IFN-a). That means they could also be the people that get ME/CFS following an infection.

This presents the possibility that an infection-produced inflammation knocks out dopamine production permanently, leaving behind a hypersensitized reaction to inflammation and resultant chronic fatigue. The Dubbo studies finding that increased cytokine levels early in an infection predispose people to ME/CFS appears to fit this scenario well.

Conclusion

Trying to piece together the positive results from other ME/CFS studies into a coherent whole can seem overwhelming. Miller’s results appear to fit well with other recent findings. The limbic system lies in the lower region of the brain that is showing up frequently in ME/CFS studies. The linkages formed by the basal ganglia to other areas of the brain (prefrontal cortex, hypothalamus, and pituitary gland) also highlight  areas of interest in ME/CFS.

  • Next Up: Part II – Reducing Dopamine, RNase L and the Basal Ganglia and a Talk With  Andrew Miller

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