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Everyone comes to a disease with their own preconceptions. That fact never seemed more true than in this Canadian fibromyalgia brain study.  The researchers asked a good question,  got a good answer and then made an interesting interpretation.

Although the interpretation may leave something to be desired the finding was fascinating and potentially important for FM patients and possibly people with ME/CFS as well.

The Study

Clin J Pain. 2015 Sep 3. [Epub ahead of print] Basal Ganglia Perfusion in Fibromyalgia is Related to Pain Disability and Disease Impact – An Arterial Spin Labeling Study. Shokouhi M1, Davis KD, Moulin DE, Morley-Forster P, Nielson WR, Bureau Y, St Lawrence K.

The Canadian researchers wanted to know if reduced brain blood flows in FM were associated with a range of symptoms. Those symptoms included pain (visual analogue score (VAS), pain disability (Pain Disability Index – PDI), overall impact (Fibromyalgia Impact Questionnaire – FIQ), catastrophic thinking (Pain Catastrophizing Scale (PCS) and anxiety and depression (Hospital Anxiety and Depression Scale – HADS).

basal ganglia

A similar basal ganglia dysfunction appears to occur in FM and ME/CFS. Attempts to explain it differ dramatically.

The study found that reduced blood flows to one part of the brain – the basal ganglia – were highly correlated with measures of disability due to pain and the overall impact of FM (FIQ). (Note that the indices of catastrophic thinking and mood were not relevant.)

Situated in the center of the brain the basal ganglia is associated with a variety of brain structures – the brainstem, thalamus and cerebral cortex –  that are of great interest in both FM and ME/CFS. The basal ganglia is a center of dopamine production and is involved in such diverse functions as producing “reward” and regulating motor activity.

How to Turn a Physiological Result into a Psychological One

How were the low blood levels in the basal ganglia causing the increased disability due to pain and overall impact in FM?  The authors first conclusion was that they weren’t. In fact it was the other way around. They suggested that the low blood levels in the basal ganglia reflected “maladaptive behaviors and hypervigilance”.

That was an interesting conclusion given that neither of their primary measures of maladaptive behaviors (catastrophizing or anxiety/depression) were found to be relevant in this study. How did they get beyond that problem?

stress management

The authors proposed that maladaptive behaviors were behind the low blood flows to the basal ganglia in FM.

A multiple regression analysis that found the FIQ scores were more highly correlated with anxiety and pain catastrophizing than with disability caused by pain allowed them to interpret the FIQ scores in a psychological manner. They also found a “trend” – a non-significant result – correlating the catastrophizing and anxiety scores with low blood flows in the basal ganglia.

The authors, thankfully, noted that an alternative to the maladaptive behavior explanation existed. The reduced basal ganglia activity could actually be the result of  basal ganglia problems. They noted that one study suggested reduced dopamine activity in the basal ganglia was, in fact, present in FM.

They also noted that given the basal ganglia’s role in regulating movement that reduced basal ganglia activation could make it more difficult for FM patients to move and be active. They proposed that the dopamine/basal ganglia link should be investigated further.

In the conclusion section, however, the authors simply attributed the low basal ganglia blood flows they found to “fear of movement” and behavioral issues. They highlighted a fear of movement hypothesis which proposes that the degree of disability present depends on whether a patient decides to confront their symptoms or avoid them. Their sole treatment suggestion was cognitive behavioral therapy. The conclusion to their abstract simply stated

“These CBF findings may reflect differences in behavioral and psychological responses between patients.”

The idea that some sort of disease process may be impairing dopamine activity had disappeared.

How to Turn it Back Into a Physiological Result

But was it really gone? It’s true that catastrophizing and anxiety can increase pain levels but are they the sole determinant of pain in FM?  The authors provided no evidence that either can impact basal ganglia functioning. Other, very different explanations for the basal ganglia dysfunction found do exist – and in a closely related disease.

Andrew Miller’s studies have found reduced basal ganglia activity in both chronic fatigue syndrome (ME/CFS) and people with hepatitis receiving interferon injections. These studies suggest that inflammatory cytokines, not maladaptive behaviors are the culprit.

immune activation

Another explanation links immune activation to basal ganglia and dopamine problems

Miller’s studies indicate that interferon therapy causes dramatic drops in basal ganglia functioning and dramatic increases in the fatigue, pain and other symptoms  associated with “sickness behavior”.  The similar basal ganglia/ dopamine findings found in ME/CFS and fatigued interferon treated hepatitis patients strongly suggests the symptoms and basal ganglia problems in ME/CFS are associated with immune activation.

This suggests the basal ganglia problems showing up in the FM study could be the result of inflammatory processes – not maladaptive behaviors.

To put it another way the trend towards maladaptive behaviors the Canadian researchers found could be the natural result of inflammatory processes; i.e. sickness behavior – in FM patients. It’s  notable that the effects of dopamine reduction – reduced activity, reward, pleasure, and increased fatigue – fit sickness behavior to a T.

The Neuroinflammation- Microglia – Dopamine and Pain Connection?

A recent study neatly tied neuroinflammation – a subject of great interest in ME/CFS – to microglial activation and finally to dopamine reductions.

This study, which was described as “paradigm-shifting” found that neuroinflammation

  1. increased the growth rates of microglia cells which then
  2. inhibited the release of dopamine.

The clincher came when a drug that knocked down microglial activity – increased dopamine levels as well.  The neuroinflammation – microglia – dopamine connection appears to be well-established in animal models.

The drug used was minocycline – find out more about it here: Drug Repurposing I: Antibiotics to Reduce Microglial Activation in ME/CFS and Fibromyalgia?

The Opioid Dopamine Connection

“For over 20 years, scientists have been trying to unlock the mechanisms at work that connect opioid use, pain relief, depression and addiction. Our findings represent a paradigm shift which has broad implications that are not restricted to the problem of pain and may translate to other disorders.” Catherine Cahill

Interestingly, a similar process may be occurring in people with chronic pain who unsuccessfully use opioid drugs.  It turns out that opioid drugs stimulate the release of dopamine in rodents in acute pain, but  fail to do that in rodents in chronic pain. For some reason the opioid – dopamine connection gets turned off in chronic pain states.

The finding suggests that the activation of dopamine –  a feel good chemical – plays a major role in the effectiveness (or ineffectiveness) of opioid drugs.

Next Steps

What’s needed now is to establish that neuroinflammation is present in both ME/CFS and FM. If that’s accomplished then the dopamine link to neuroinflammation induced fatigue and pain has already been mapped out.

Are some pieces coming together? One scenario could help explain how the Lipkin/Hornig/ CFI findings of up and then down activation of the immune system works in ME/CFS.

missing puzzle piece - fibromyalgia and ME/CFS

Are some pieces coming together?

First, an infection triggered immune upregulation sends the microglial cells humming – causing reduced dopamine release in the basal ganglia. Over time the untreated infection causes immune cell exhaustion at least in some patients. The resulting immune depletion should give the patients some relief, but Miller’s hypothesis suggests the reduced dopamine levels leave the central nervous system ultra-responsive to lower levels of inflammation. Even if the inflammation has died down the system is still reacting to it – and the disease lives on.

 

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