Fibromyalgia Syndrome as a CNS Disorder
Fibromyalgia Syndrome has traditionally been classified as either a musculoskeletal disease or a psychological disorder. Accumulating evidence now suggests that fibromyalgia may be associated with CNS dysfunction. 
Here, we have collected some of the research from 2007 and 2008 that supports this view.
Accelerated brain gray matter loss in Fibromyalgia Syndrome patients 
In this study, anatomical changes in the brain associated with Fibromyalgia Syndrome were investigated. Using voxel-based morphometric analysis of magnetic resonance brain images, the brains of 10 female Fibromyalgia Syndrome patients and 10 healthy controls were examined.
It was found that Fibromyalgia Syndrome patients had significantly less total gray matter volume and showed a 3.3 times greater age-associated decrease in gray matter than healthy controls. The longer the individuals had had Fibromyalgia Syndrome, the greater the gray matter loss, with each year of Fibromyalgia Syndrome being equivalent to 9.5 times the loss in normal aging. In addition, Fibromyalgia Syndrome patients demonstrated significantly less gray matter density than healthy controls in several brain regions, including the cingulate, insular and medial frontal cortices, and parahippocampal gyri.
The neuroanatomical changes seen in Fibromyalgia Syndrome patients contribute additional evidence of CNS involvement in Fibromyalgia Syndrome. In particular, Fibromyalgia Syndrome appears to be associated with an acceleration of age-related changes in the very substance of the brain. Moreover, the regions in which objective changes are demonstrated may be functionally linked to core features of the disorder including affective disturbances and chronic widespread pain.
Reduced presynaptic dopamine activity in Fibromyalgia Syndrome 
For this pilot study, presynaptic dopaminergic function was investigated in 6 female Fibromyalgia Syndrome patients in comparison to 8 age- and gender-matched controls as assessed by positron emission tomography with 6-[(18)F]fluoro-L-DOPA as a tracer.
Semiquantitative analysis revealed reductions in 6-[(18)F]fluoro-L-DOPA uptake in several brain regions, indicating a disruption of presynaptic dopamine activity wherein dopamine plays a putative role in natural analgesia.
Although the small sample size made these findings preliminary, they showed that Fibromyalgia Syndrome might be characterized by a disruption of dopaminergic neurotransmission.
Abnormal dopamine response to pain 
Fibromyalgia Syndrome patients and matched healthy control subjects were subjected to deep muscle pain produced by injection of hypertonic saline into the anterior tibialis muscle. In order to determine the endogenous release of dopamine in response to painful stimulation, positron emission tomography was used to examine binding of [(11)C]-raclopride (D2/D3 ligand) in the brain during injection of painful hypertonic saline and nonpainful normal saline.
Fibromyalgia Syndrome patients experienced the hypertonic saline as more painful than healthy control subjects. Control subjects released dopamine in the basal ganglia during the painful stimulation, whereas Fibromyalgia Syndrome patients did not. In control subjects, the amount of dopamine release correlated with the amount of perceived pain but in Fibromyalgia Syndrome patients no such correlation was observed.
These findings provided the first direct evidence that Fibromyalgia Syndrome patients have an abnormal dopamine response to pain.
The disrupted dopaminergic reactivity in Fibromyalgia Syndrome patients could be a critical factor underlying the widespread pain and discomfort in Fibromyalgia Syndrome and suggests that the therapeutic effects of dopaminergic treatments for this intractable disorder should be explored.
Proton MR spectroscopy in the evaluation of cerebral metabolism in patients with Fibromyalgia Syndrome 
For this study, 21 patients with Fibromyalgia Syndrome and 27 healthy controls underwent conventional structural MR imaging and additional 2D-chemical shift imaging (CSI) MR-spectroscopy sequences.
For the 2D-CSI spectroscopy, larger volumes of interest (VOIs) were centered at the level of the basal ganglia and the supraventricular white matter. Within these larger areas, 16 smaller voxels were placed in a number of regions previously implicated in pain processing. N-acetylaspartate (NAA)/creatine(Cr), choline (Cho)/Cr and NAA/Cho ratios were calculated for each voxel. Subjects underwent clinical and experimental pain assessment.
Mean metabolite ratios and ratio variability for each region were analyzed by using repeated-measures analysis of variance (ANOVA). Correlations between clinical symptoms and metabolite ratios were assessed.
Cho/Cr variability in the right dorsolateral prefrontal cortex was significantly different in the 2 groups; a significant correlation between Cho/Cr in this location and clinical pain was present in the Fibromyalgia Syndrome group. Evoked pain threshold correlated significantly with NAA/Cho ratios in the left insula and left basal ganglia.
The data suggests that there are baseline differences in the variability of brain metabolite relative concentrations between patients with Fibromyalgia Syndrome and healthy controls, especially in the right dorsolateral prefrontal cortex. Furthermore, there are significant correlations between metabolite ratios and clinical and experimental pain parameters in patients with Fibromyalgia Syndrome.
Hippocampus dysfunction may explain symptoms of Fibromyalgia Syndrome 
The case-control study was performed in 15 female patients, who met American College of Rheumatology criteria for classification of Fibromyalgia Syndrome, and 10 healthy age-matched female controls. Patients and controls were receiving no medications known to affect cognitive functioning or central nervous system metabolites before their participation in the study.
In all patients and controls, proton magnetic resonance spectroscopy (1H-MRS) was used to assess N-acetylaspartate (NAA), choline (Cho), creatine (Cr), and their ratios from both hippocampi. Levels of metabolites and their ratios were determined and the findings compared between the groups. All patients and controls underwent psychological assessment to assess cognitive function, depression, and structured sleep interview with sleep diary; Fibromyalgia Impact Questionnaire (FIQ), number of tender points, and visual analog scale (VAS) for pain were assessed in all patients.
NAA levels of right and left hippocampi differed significantly between patients and controls. Cho levels in the right hippocampus were higher in the patient group than in controls, while no differences were found with respect to Cr levels in both hippocampi. NAA/Cho and NAA/Cr ratios differed significantly between patients and controls, while the Cho/Cr ratio showed no differences.
Significant correlations were found between language score and right Cho and right Cr levels, while no significant correlations were found between metabolites and their ratios with FIQ, VAS for pain, or number of tender points.
The hippocampus was dysfunctional in patients with Fibromyalgia Syndrome, as shown by lower NAA levels compared to controls, representing neuronal or axonal metabolic dysfunction. As the hippocampus plays crucial roles in maintenance of cognitive functions, sleep regulation, and pain perception, it was suggested that metabolic dysfunction of hippocampus may be implicated in the appearance of these symptoms in Fibromyalgia Syndrome.
Hippocampal Metabolite Abnormalities in Fibromyalgia Syndrome 
In this study, researchers interrogated the bilateral hippocampus of 16 premenopausal female Fibromyalgia Syndrome patients with no psychiatric comorbidity in comparison to 8 age- and gender-matched healthy control subjects using single voxel proton magnetic resonance spectroscopy.
The results demonstrate a significant reduction in the ratio of N-acetylaspartate to creatine (NAA/Cr) in Fibromyalgia Syndrome patients versus matched control subjects specifically in the right temporal lobe from a voxel centered on the right hippocampus. Moreover, correlation analysis demonstrated a significant negative correlation between patient scores on the Fibromyalgia Impact Questionnaire and NAA/Cr ratio within the right hippocampus.
The results indicate that Fibromyalgia Syndrome is associated with brain metabolite abnormalities within the right hippocampus that correlate with patient symptoms. A significant negative correlation between patient subjective experience of symptoms and a reduced NAA/Cr ratio suggests a role for hippocampal pathology in Fibromyalgia Syndrome.
- Kuchinad A, Schweinhardt P, Seminowicz DA, Wood PB, Chizh BA, Bushnell MC. Accelerated brain gray matter loss in fibromyalgia patients: premature aging of the brain? J Neurosci. 2007 Apr 11;27(15):4004-7.
- Wood PB, Patterson JC 2nd, Sunderland JJ, Tainter KH, Glabus MF, Lilien DL. Reduced presynaptic dopamine activity in fibromyalgia syndrome demonstrated with positron emission tomography: a pilot study. J Pain. 2007 Jan;8(1):51-8. Epub 2006 Oct 4.
- Wood PB, Schweinhardt P, Jaeger E, Dagher A, Hakyemez H, Rabiner EA, Bushnell MC, Chizh BA. Fibromyalgia patients show an abnormal dopamine response to pain. Eur J Neurosci. 2007 Jun;25(12):3576-82.
- Petrou M, Harris RE, Foerster BR, McLean SA, Sen A, Clauw DJ, Sundgren PC. Proton MR spectroscopy in the evaluation of cerebral metabolism in patients with fibromyalgia: comparison with healthy controls and correlation with symptom severity. AJNR Am J Neuroradiol. 2008 May;29(5):913-8. Epub 2008 Mar 13.
- Emad Y, Ragab Y, Zeinhom F, El-Khouly G, Abou-Zeid A, Rasker JJ. Hippocampus dysfunction may explain symptoms of fibromyalgia syndrome. A study with single-voxel magnetic resonance spectroscopy. J Rheumatol. 2008 Jul;35(7):1371-7. Epub 2008 May 15.
- Wood PB, Ledbetter CR, Glabus Deceased MF, Broadwell LK, Patterson JC 2nd. Hippocampal Metabolite Abnormalities in Fibromyalgia: Correlation With Clinical Features. J Pain. 2008 Sep 2. [Epub ahead of print]