Friday, September 13, 2013

Fibromyalgia: Turned Out to Be All-In-Your-Head After All (Part II )

In part one of Fibromyalgia we discussed the evolution of the understanding of the disease from what was originally thought to be an emotional or psychiatric disorder to various forms of a muscle disease to a peripheral nerve disorder and then full circle to a brain dysfunction. Although diagnostic criteria for fibromyalgia have been available for 2 decades, there remains no definitive diagnostic test and no consensus regarding its etiology.

In Part Two we will consider some of the evidence suggesting fibromyalgia is an affliction of brain dysfunction. Ultimately the goal of part two is to identify and characterize the abnormal functioning of the various brain regions that have been reported in recent neuroscience literature and suggest possible natural approaches to the correction of these dysfunctions. This represents a major leap forward in the treatment of fibromyalgia because it is an attempt to first identify the specific dysfunction and then to restore brain function to normal. Current treatment of fibromyalgia focuses on symptom management not restoration of function.

The hallmark of fibromyalgia is chronic widespread pain perception in the absence of an identifiable cause. Depression and or anxiety, sleep disturbances and emotional problems are often also found in fibromyalgia patients. Therefore there appears to be a number of additional abnormalities above and beyond abnormal pain perception seen in fibromyalgia patients. This suggests widespread involvement in a number of brain regions.

Among the secondary or associated findings commonly seen in chronic pain patients, in general, and fibromyalgia patients, in particular, are signs of cogitative dysfunction, memory problems, and a higher brain process termed executive function (the ability to comprehend, sequence and perform complex tasks).

Fibromyalgia patients frequently have signs of cognitive impairment that sometimes can be demonstrated through clinical testing. A simple bedside test known as the clock test was frequently found to be abnormal in patients diagnosed with fibromyalgia. In this test the patient is asked to first, draw a picture of a clock and then they are asked to draw the hands on the clock to illustrate a specific time. This task assesses a number of higher cortical brain region functions. Various degrees of inability to precisely draw the face of a clock and then set the hands of the clock to a specific time are used to evaluate different lobes of the brain, in particular the frontal lobes. This simple test when given to patients diagnosed with fibromyalgia suggests impaired brain function of the frontal and other brain regions not normally associated with pain processing. So patients with fibromyalgia appear to have alterations in brain function that goes well beyond pain processing. Much more sophisticated research on brain function in fibromyalgia supports this theory. Let us review some recent studies on brain function and fibromyalgia.

There are a number of brain imaging techniques that allow researchers to literally see how the brain reacts metabolically to various types of stimulation. For the most part they are based on MRI testing, but go beyond standard MRI in that they show increased or decreased brain metabolism (and thus implied hyper or hypo function). Because they are a test of brain function they are called functional magnetic resonance imaging, or fMRI for short. For the sake of simplicity, we well say that increased activity seen in these tests (known as brain region activation) is seen when a brain region "lights-up" during the scan. The opposite known as brain deactivation can also be documented in using this technology. These tests become useful in unraveling complex disease processes like fibromyalgia because they can show which brain regions "light-up" which deactivate and how these brain responses compare in patient suffering from fibromyalgia and healthy patients used as controls. Since fibromyalgia is a chronic pain state, it only makes sense that a number of investigators scanned patents with fibromyalgia and used a painful stimulus to observe how the fibromyalgia brain responded to pain. They did the exact same tests on a group of patients without fibromyalgia so they could compare brain responses between patients diagnosed with fibromyalgia and those who did not have fibromyalgia. The results are interesting.

fMRI revealed that fibromyalgia patients had lower activation in the right pre-motor cortex, supplementary motor area, mid-cingulate cortex, putamen and, after controlling for anxiety, in the right insular cortex and right inferior frontal gyrus.

Wow, what does all that mean? Without getting into a lesson in neuroanatomy and neurophysiology, this study found defects in some of the pain processing areas of the brain in fibromyalgia patients, but also found in addition abnormalities in areas associated with muscle movement and also possibly emotional processing. These findings represent abnormal metabolism in the brain of fibromyalgia patients that they did not find in patients who were free from fibromyalgia. The authors of this particular study concluded that in fibromyalgia those parts of the brain which are designed to suppress pain were malfunctioning.

Researchers at the University of Michigan looked at perfusion (basically the blood supply) of different regions of the brain in fibromyalgia patients versus control patients without fibromyalgia.

They found regional brain blood flow of a part of the brain believed to be highly associated with pain processing, the thalamus, was abnormal in fibromyalgia patients compared with the blood flow in this brain structure in non-fibromyalgia patients.

Other researcher from Spain report differences in brain activation patterns between fibromyalgia patients and healthy control patients. Patient with fibromyalgia showed exaggerated repose to pressure. This is similar to the pressure testing used to clinically diagnose patients with fibromyalgia.

fMRI maps following (pressure) stimulation showed a complete pain network response (sensory-motor cortices, operculo-insula, cingulate cortex, and basal ganglia) to measured light pressure in fibromyalgia patients. In contrast the healthy control subject's response to this low intensity pressure involved mainly somatosensory (touch, not pain brain response) cortices. When matched for perceived pain, control subjects showed also comprehensive activation of pain-related regions, but fibromyalgia patients showed significantly larger activation in the anterior insula-basal ganglia complex and the cingulate cortex. (Amplification in pain processing pathways).

Researcher in Italy used a different type of tests known as a Magnetic Resonance Spectroscopy or MRS study to compare fibromyalgia patients with non-fibromyalgia controls. This test the MRS, can measure non-invasively some of the chemical components in different parts of the brain. Using this different technology, they like their colleagues in Michigan found abnormalities in different brain regions when comparing the results scan done on fibromyalgia patients and non-fibromyalgia control patients.

What they found was chemical various in the frontal cortex concluding that the presence of elevated Glu/Cr levels (rations of brain chemicals) in specific regions of the frontal brain region strengthens the opinion that a complex neurophysiologic imbalance of different brain areas involved in pain processing underlies FM.

Other researchers corroborate these findings of altered brain chemistry in specific brain regions of patients suffering from fibromyalgia.

Studies using proton magnetic resonance spectroscopy suggest that glutamate (Glu), a key excitatory neurotransmitter, may be present in higher concentrations within the brains of fibromyalgia patients. This neurotransmitter imbalance is present in multiple brain regions that have been implicated in processing pain information.

Since glutamate is known to excite the nervous system these finding suggest that increased levels of this excitatory chemical in the brain regions associated with pain processing might be responsible for the over reaction to painful stimuli which is the hallmark of fibromyalgia.

A team of researchers at the University of Florida compared the actual volume of brain substances in different patients of the brain in patients suffering from fibromyalgia and health controls. Their findings add to the growing evidence that specific brain regions are abnormal in patients suffering with fibromyalgia.

We found that fibromyalgia patients had significantly less gray matter volumes than healthy control patients in 3 of specific brain regions, including the anterior and mid-cingulate, as well as mid-insular cortices. Using a more stringent analysis than other studies, we provide evidence for decreased gray matter volumes (actual brain nerve cells) in a number of pain-related brain areas in patients suffering with fibromyalgia.

Although the mechanisms for these gray matter changes are presently unclear, they may contribute to some of the core features of this chronic disorder including affective disturbances and chronic widespread pain.

Researchers in London found similar gray matter loss in the brain of fibromyalgia and chronic fatigue patients.

This study aimed to test the hypothesis that structural grey matter brain changes might occur in the chronic intractable pain disorder fibromyalgia. The results of the study revealed significantly lower grey matter density in the patients with fibromyalgia and marked fatigue (chronic fatigue syndrome) in the left supplementary motor area. This brain region plays an important role in cognitive or executive control and in the translation of painful cognition; these functions are impaired in fibromyalgia associated with marked fatigue

German researcher likewise report loss of brain neurons (Gray Matter volume losses) in patient with fibromyalgia:

Studies in fibromyalgia syndrome with functional neuroimaging support the hypothesis of central pain augmentation (amplification). Fibromyalgia patients presented a decrease in gray matter volume in the prefrontal cortex, the amygdala, and the anterior cingulate cortex

Researcher in Denmark took a slightly different approach to investigation of central nervous system function. They looked at a particularly brain function known as "descending pain inhibition" which is a function of the brain responsible for turning off pain perceptions arising from the body. In normal subject without fibromyalgia, sustained muscle contraction activates this descending pain inhibitory circuit. This is why in most patients exercise like physical therapy can be used to treat pain. However in patients with fibromyalgia instead of inhibiting pain, this descending brain pathway actually magnified pain. The researchers concluded that

Descending pain modulation (control) shifts from descending inhibition (pain reduction) towards descending facilitation (pain magnification) following muscle contraction in fibromyalgia.

Other researchers support the theory that descending pain suppressing circuits are abnormal in the fibromyalgia patient.

We focus our discussion on two areas where strong evidence exists for abnormalities in sensory
signaling: the reduction of descending control, including suppression of descending inhibitory pathways and/or enhancement of descending facilitatory pathways, and changes in key neurotransmitters associated with central sensitization.

A team from Sweden further characterized the defective pain modulating circuits in fibromyalgia patients:

Fibromyalgia patients exhibited higher sensitivity to pain provocation than controls as they required less pressure to evoke equal pain magnitudes. Despite lower pressures applied in fibromyalgia patients the fMRI-analysis revealed no difference in activity in brain regions relating to attention and affect or regions with sensory projections from the stimulated body area. However, in the primary link in the descending pain regulating system (the rostral anterior cingulate cortex) the patients failed to respond to pain provocation. The author's conclude that
the observed attenuated response to pain in this brain region is the first demonstration of a specific brain region where the impairment of pain inhibition in FMS patients is expressed.

This may be one explanation why many fibromyalgia patients have trouble tolerating exercise. Normally muscle activity switches on brain based descending pain pathways that reduce pain. In fibromyalgia these appears to be at least ineffective and at worst may actually increase pain perception. Researchers in Germany report similar findings. They created experimental control painful stimuli in both fibromyalgia patients and healthy controls. When they elicited muscle pain they found:

Repetitive (painfully) induced excitation of muscle tissue led to a more prolonged perception of pain and more wide-spread activation in pain-related brain areas in fibromyalgia patients. This altered brain activity was seen especially in the left (Ipsilateral ~ same side) insula brain region, The contrast between the groups (fibromyalgia patients versus healthy control patients) revealed significantly stronger activation for fibromyalgia patients in the left anterior insula. Additonally the researcher found that peak pain ratings were comparable between controls and fibromyalgia patients, but pain duration (sustained pain) was prolonged in fibromyalgia

Researchers at Massachusetts General Hospital found abnormalities in the interaction between various brain structures in patients suffering from fibromyalgia. Using a technique to assess how various brain regions communicate with one another (called functional network connectivity) these investigators found abnormalities that seemed to be specific for patients diagnosed with fibromyalgia. They report:

These findings indicate that resting brain activity within multiple networks is associated with spontaneous clinical pain in patients with fibromyalgia. These findings may also have broader implications for how subjective experiences such as pain arise from a complex interplay among multiple brain networks.

A team of researchers from France report similar findings of altered brain network connectivity that were related to abnormalities in several specific chemical neurotransmitters in specific parts of the brain, in their fibromyalgia patients:

We assessed cortical excitability and intracortical modulation (brain network connectivity) systematically, by transcranial magnetic stimulation (TMS) of the motor cortex, in patients with fibromyalgia. Fibromyalgia is associated with deficits in intracortical modulation involving both GABAergic and glutamatergic mechanisms, possibly related to certain aspects of the pathophysiology of this chronic pain syndrome. Our data adds to the growing body of evidence for objective and quantifiable changes in brain function in fibromyalgia.

So what does all this mean and how can we use it to help those patients afflicted with fibromyalgia syndrome? The most important take home message is that there are specific brain regions that are not working properly in patient suffering with fibromyalgia. We now have a pretty good idea of which brain structure are abnormal. Furthermore we now have a good understanding of many of the chemical abnormalities in these brain regions.

So the next logical step is to discuss targeted therapies that might specifically influence regions of abnormal brain function in patients suffering with fibromyalgia. Restoring pain processing in the brain to more normal function. There are a number of methods and techniques that we can apply.

Next we can consider how to modulate and balance the abnormal chemistry in specific brain regions we discussed in the above article.

Based on some of the same types of studies we discuss in this article, it does appear we have the tools to both re-integrate brain function and balance brain chemistry in patients suffering from fibromyalgia. How do we do it? You'll have to read part three of our series on fibromyalgia. Stay tuned.

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