- This study examined whether proton magnetic resonance spectroscopy metabolites that have previously been associated with neuroinflammation—choline and myo-inositol—are altered in patients with fibromyalgia and linked with specific glial cells—astrocytes
- Levels of choline, but not myo-inositol, were significantly higher in the anterior insula (aIns) in 43 female patients with fibromyalgia compared to 16 healthy adults, and greater choline levels were linked to worse pain interference scores
- On resting-state functional MRI, reduced connectivity between the aIns and putamen was associated with both elevations in aIns choline and pain interference scores—i.e., the functional burden of fibromyalgia
- Nonhuman primate data suggest that choline levels assessed by proton magnetic resonance spectroscopy track with cellular markers of neuroinflammation that are likely to be associated with astrogliosis
- Noninvasive measures of neuroinflammation in humans could substantially aid in the diagnosis of pain processes and other disease states, as well as the development of new therapies
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Neuroinflammation mediated by activation of microglia or astrocytes is pronounced in patients with chronic pain, according to several neuroimaging studies. MRI techniques such as proton magnetic resonance spectroscopy (1H-MRS) may be promising for noninvasive evaluation of neuroinflammation.
1H-MRS evaluates purported neuroinflammation by quantifying levels of metabolites such as myo-inositol, which has a role in regulating glial cell volume, and choline, which has a greater concentration in glial cells than neurons and has been linked with glial cell membrane turnover.
Researchers Changjin Jung, PhD, and Vitaly Napadow, PhD, of the Martinos Center for Biomedical Imaging at Massachusetts General Hospital, in collaboration with colleagues at the University of Michigan, have published evidence that choline is elevated in patients with fibromyalgia and may be linked with astrogliosis. Their report appears in Pain.
Metabolite Levels in Patients
The researchers first studied 43 women who had been diagnosed with fibromyalgia for at least one year prior to MRI. They and 16 healthy adults completed the short form of the Brief Pain Inventory (separate pain severity and pain interference subscales) and the Fibromyalgia Impact Questionnaire (FIQ). By studying this cohort, they found:
- Choline levels in the anterior insula (aIns) were significantly higher in fibromyalgia patients than in controls
- Among patients, aIns choline levels significantly correlated with pain interference scores
- In contrast, aIns myo-inositol levels did not differ between patients and controls or correlate with aIns choline levels
Resting-state functional MRI showed that within the patient group, greater pain interference was associated with weaker connectivity between the aIns and putamen. Connectivity between the aIns and putamen was also inversely associated with aIns choline levels and FIQ scores.
Nonhuman Primate Model
To explore how choline or myo-inositol might relate to specific cellular neuroinflammatory processes, the researchers linked these 1H-MRS metabolites with molecular markers of astrogliosis and microglial activation in rhesus monkeys. They used data from a previously reported model in PLOS One of neuroinflammation caused by the simian immunodeficiency virus.
The primates were injected with the virus and remained untreated or were treated with minocycline, a drug known to reduce neuroinflammation. Brain data were collected four, six or eight weeks after viral injection. 1H-MRS was performed pre-infection and biweekly following viral transfer.
1H-MRS choline levels were directly linked with levels of:
- Glial fibrillary acidic protein, the principal intermediate filament in mature astrocytes, commonly used as a marker of astrogliosis
- Monocyte chemoattractant protein 1, a chemokine that helps recruit monocytes from the blood into the brain and is involved in activating inflammatory and neural cells
The primates demonstrated no linkage between choline levels and ionized calcium-binding adaptor protein 1, which is essential to microglial activation. Myo-inositol levels did not correlate with any of the three inflammatory markers.
These results are important because they suggest neuroinflammation in humans can be assessed noninvasively using 1H-MRS and linked it with specific alterations of functional brain connectivity, assessed by resting-state fMRI. As these imaging measures were linked with clinical outcomes, the researchers believe such measures may substantially aid pain diagnosis and in the development of new therapies, and may also be associated with many other disease states.
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