Neural Substrate

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General comments[edit]

Based on an unpublished review by the author and his associate Mario Garingo, almost every part of the cortex has, in one study or another demonstrated an abnormal cortical signal in fibromyalgia. The search for a useful definitive brain imaging biomarker that is valuable enough to enter mainstream clinical medicine has been elusive.

There are a great number of abnormal types of reaction to stimuli in fibromyalgia such as to pressure pain, or thermal stimulation. It is hard to know what is fundamental and what is just one of a multitude of abnormalities. The situation is all the more confusing when one considers the bewildering number of fibromyalgia co-morbidities each of which could alter the brain in some way or other. New studies are coming along regularly.

Some forms of imaging may be more useful than others for demonstrating the severity of illness to insurance companies.

Studies can be divided into those done to measure the baseline state of the brain and those that measure brain reactions.

Findings of imaging studies[edit]

Cortical perfusion abnormalities in[edit]

A study of 29 women with fibromyalgia using Technetium-99m ethyl cysteinate dimer single photon emission computed tomography found that fibromyalgia patients had hypoperfusion in the left culmen and hyperperfusion in the right precentral gyrus, right posterior cingulate, right superior occipital gyrus, right cuneus, left inferior parietal lobule, right middle temporal gyrus, left postcentral gyrus, and left superior parietal lobule. (Brain perfusion in fibromyalgia patients and its differences between responders and poor responders to gabapentin. Usui C et al., Arthritis Res Ther. 2010;12(2):R64. For the full online version see: http://arthritis-research.com/content/12/2/R64.)


Regional cerebral blood flow.png
Comparison of regional cerebral blood flow (rCBF) between patients with fibromyalgia (FM) and age-matched healthy controls.
Public domain open access article. (For details on this access see: http://www.biomedcentral.com/about/charter


The fibromyalgia patient group exhibited significant hypoperfusion in:

  • the left culmen, and

significant hyperperfusion in:

  • the right precentral gyrus,
  • right posterior cingulate,
  • right superior occipital gyrus,
  • right cuneus,
  • left inferior parietal lobule,
  • right middle temporal gyrus,
  • left postcentral gyrus, and
  • left superior parietal lobule. (Usui et al. Arthritis Research & Therapy 2010 12:R64)

[Author’s comments: It is not easy to interpret these results. Firstly, they are complicated with many areas involved. Each area plays certain rolls in the brain. We may need to distinguish between primary and secondary changes. For example, fibromyalgia patients are notoriously tired due to terrible sleep and chronic sleep deprivation could induce any number of secondary changes in brain function. Furthermore, fibromyalgia is a syndrome with a very wide range of brain related issues. The mere fact that all the patient’s qualified under the ACR criteria does not mean that they are in any sense a heterogeneous group. There are numerous fibromyalgia comorbidities involving the CNS, each one of which may be contributing to the long list of regions of significant hyperperfusion. The finding by the authors of alternations in the default mode network requires further study. In the clinical experience of the author, fibromyalgia patients are often in “danger mode” whereby they are engaged brain processing of a self-protective nature. The default mode network seems to involve monitoring for predators, so perhaps there is a tie.]

A SPECT study of the pontine tegmentum and right thalamus[edit]

A small Single-Photon-Emission Computed Tomography (SPECT) study found decreased blood flow in the pontine tegmentum and right thalamus. (Regional cerebral blood flow in fibromyalgia: single-photon-emission computed tomography evidence of reduction in the pontine tegmentum and thalami. Kwiatek R1, Barnden L, Tedman R, Jarrett R, Chew J, Rowe C, Pile K. Arthritis Rheum. 2000 Dec;43(12):2823-33, available in full online at: https://onlinelibrary.wiley.com/doi/abs/10.1002/1529-0131%28200012%2943%3A12%3C2823%3A%3AAID-ANR24%3E3.0.CO%3B2-E.

Fibromyalgia and chronic fatigue syndrome, Parahippocampal gyrus activities in[edit]

Puri BK et al. used MRI to study chronic fatigue syndrome and found reduced grey matter volume in a number of areas including the posterior division of the left parahippocampal gyrus. Other regions of reduced cortex were: the right and left occipital poles; left lateral occipital cortex, superior division; the left supracalcrine cortex, and the right angular gyrus. White matter volume was reduced in the left occipital lobe. The significance of these findings are still unclear, but they do offer clues to the disease. (Regional grey and white matter volumetric changes in myalgic encephalomyelitis (chronic fatigue syndrome): a voxel-based morphometry 3 T MRI study. Puri BK,.et al.; Br J Radiol. 2012 Jul;85(1015):e270-3) (For further perspective also see the entry posterior parahippocampal cortex, Connections of the.)

Non-noxious SPECT study[edit]

Another SPECT study was done of women with FM who were note exposed to noxious stimuli. (Guedj E1, Taieb D, Cammilleri S, Lussato D, de Laforte C, Niboyet J, Mundler O. Eur J Nucl Med Mol Imaging. 2007 Jan;34(1):130-4. Epub 2006 Aug 25, partially visible online at: https://link.springer.com/article/10.1007%2Fs00259-006-0174-7 and available in full online at: https://www.researchgate.net/publication/6855583_99mTc-ECD_brain_perfusion_SPECT_in_hyperalgesic_fibromyalgia.) The FM patient group had bilateral hyperperfusion of the centro-parietal lobe (BA1, BA2, BA3 and BA5), the superior parietal lobe dominating on the right side (BA7), and the left inferior parietal lobe (BA39 and BA40). The FM patient group also had bilateral hypoperfusion of the medial frontal lobe (BA10), the anterior cingulate (BA32), the posterior cingulate (BA29 and BA30), and cerebellar cortices and the medial temporal structures (amygdala and parahippocampal cortex).

In the study, which was reported in the November issue of The Journal of Nuclear Medicine, 20 women diagnosed with fibromyalgia and 10 healthy women as a control group responded to questionnaires to determine levels of pain, disability, anxiety and depression. SPECT was then performed, and positive and negative correlations were determined.

The researchers confirmed that patients with the syndrome exhibited brain perfusion abnormalities in comparison to the healthy subjects. Further, these abnormalities were found to be directly correlated with the severity of the disease. An increase in perfusion (hyperperfusion) was found in that region of the brain known to discriminate pain intensity, and a decrease (hypoperfusion) was found within those areas thought to be involved in emotional responses to pain.

PET Imaging PET has been used in several FM studies. In the first such study, Yunus and colleagues showed no differences in regional cerebral blood flow between FM and controls.176 More recently, Wood and colleagues used PET to show that attenuated dopaminergic activity may be playing a role in pain transmission in FM167,168 a deficit in part manifest by deficiencies in stress induced analgesia in FM. Harris and colleagues also recently used PET to demonstrate decreased mu opioids receptor availability in FM.

Gracely et al.’s landmark fMRI study of mechanical pain stimulation[edit]

One landmark study by Gracely et al. used fMRI to measure reactions to pressure pain stimuli applied to thumbnails. (Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Gracely RH1, Petzke F, Wolf JM, Clauw DJ. Arthritis Rheum. 2002 May;46(5):1333-43, https://doi.org/10.1002/art.10225, available in full online at: https://onlinelibrary.wiley.com/doi/full/10.1002/art.10225.

They looked at 16 FM patients who were exposed to painful pressures during fMRI scanning. Patients and control both showed activations in the primary and secondary somatosensory cortex, the insula, and the anterior cingulate. “While the regions of activation were similar for the patients and controls, the groups differed with regard to the amount of stimuli needed to activate this pain matrix. “The fibromyalgia patients only needed half of the stimulation for healthy controls to activate a pain matrix. For a figure showing some of their key findings see: https://onlinelibrary.wiley.com/doi/full/10.1002/art.10225.

Dysfunctional pain inhibition in fibromyalgia[edit]

A small fMRI study of females with fibromyalgia by Jensen et al. evaluated cerebral responses “to individually calibrated pain provocations of a pain-free body region (thumbnail).” They applied calibrated “painful pressures representing 50 mm on a visual analogue scale (VAS) ranging from 0 to 100 mm.” Results showed that patients had “higher sensitivity to pain provocation than controls as they required less pressure to evoke equal pain magnitudes (UA = 48, p < .002).” Results also showed that “in the primary link in the descending pain regulating system (the rostral anterior cingulate cortex) the patients failed to respond to pain provocation.” They concluded that fibromyalgia patients had an “attenuated response to pain” in the rostral anterior cingulate cortex and this represented an “impairment of pain inhibition”. (Evidence of dysfunctional pain inhibition in fibromyalgia reflected in rACC during provoked pain. Karin Jensen; Eva Kosek; Frank Petzke; Serena Carville; Peter Fransson; Hanke Marcus; Steven Williams; Ernest Choy; Thorsten Giesecke; Yves Mainguy; Richard Gracely; Martin Ingvar; Pain. 144(1-2):95–100, JULY 2009, DOI: 10.1016/j.pain.2009.03.018.)

Finding of DNIC in fibromyalgia[edit]

DNIC has been “been consistently observed to be attenuated or absent in groups of fibromyalgia patients as compared to healthy controls.” (Page 476, Bonica's Manage-ment of Pain, edited by Scott Fishman, Jane Ballantyne, James P. Rathmell, Lippincott Williams & Wilkins, 2010 https://books.google.ca/books?isbn=0781768276.)

Neurotransmitter abnormalities in fibromyalgia[edit]

“Neurotransmitter studies show that fibromyalgia patients have abnormalities in dopaminergic, opioidergic, and serotoninergic systems.” (Fibromyalgia: a disorder of the brain? Schweinhardt P, Sauro KM, Bushnell MC. Neuroscientist. 2008;14(5):415–421.) Known abnormalities in brain chemistry in FM included altered “levels of N-acetylaspartate, choline or glutamate, among other metabolites, have been observed in the hippocampus, insula, prefrontal and cingular cortex. Neuroradiological findings are nonspecific and similar to those found in other examples of chronic pain.” (Cerebral magnetic resonance changes associated with fibromyalgia syndrome. Murga I1, Guillen V2, Lafuente JV3. Med Clin (Barc). 2017 Jun 7;148(11):511-516. doi: 10.1016/j.medcli.2017.01.034. Epub 2017 Apr 25.)

EEG studies[edit]

Baseline oscillatory abnormalities in[edit]

A study by Lim et al. looked at abnormities in high and low frequency rhythms during the resting MEG of adult women with fibromyalgia patients in relation to their pain.

The experimental conditions were as follows:

No caffeine before the recording “to avoid the caffeine-induced theta power decrease (Landolt et al., 2004).” Subjects instructed to rest but stay alert. During the eyes open segment they had to “keep their gaze fixed on a cross in the center of the front wall. “Subjects were instructed to relax, but to stay alert during the recording.

Results showed that the main findings were “general increases in theta, beta and gamma power along with a slowing of the dominant alpha peak.” (Increased Low- and High-Frequency Oscillatory Activity in the Prefrontal Cortex of Fibromyalgia Patients. Lim M1, Kim JS2, Kim DJ2, Chung CK3. Front Hum Neurosci. 2016; 10: 111, available in full online at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789463/.)

The increased spectral power within the theta-band was mainly “localized to the left dorsolateral prefrontal (DLPFC) and orbitofrontal cortex (OFC).”

They further found that: “Beta and gamma over-activation were localized to insular, primary motor and primary and secondary somatosensory (S2) cortices, as well as the DLPFC and OFC.”

Moreover, they found that “enhanced high-frequency oscillatory activities in the DLPFC and OFC were associated with higher affective pain scores in patients with fibromyalgia.”


Power differences.jpeg
Source imaging of the significant power differences in various frequency bands between fibromyalgia patients and healthy control subjects.
This image is Figure 2 from (Increased Low- and High-Frequency Oscillatory Activity in the Prefrontal Cortex of Fibromyalgia Patients. Lim M1, Kim JS2, Kim DJ2, Chung CK3. Front Hum Neurosci. 2016; 10: 111, available in full online at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789463/.) It is made available through a Creative Commons Attribution License (CC BY). Author’s legend:“DLPFC, dorsolateral prefrontal cortex; OFC, orbitofrontal cortex; AIC, anterior insular cortex; M1, primary motor cortex; S1, primary somatosensory cortex; S2, secondary somatosensory cortex.”


Further information[edit]

Neurobiology Underlying Fibromyalgia Symptoms. Marta Ceko, 1, 2 , M. Catherine Bushnell, 1, 2, 3 , , and Richard H. Gracely 4Pain Res Treat. 2012; 2012: 585419. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)