Brain glial activation in fibromyalgia – A multi-site positron emission tomography investigation

Abstract

Fibromyalgia (FM) is a poorly understood chronic condition characterized by widespread musculoskeletal pain, fatigue, and cognitive difficulties. While mounting evidence suggests a role for neuroinflammation, no study has directly provided evidence of brain glial activation in FM. In this study, we conducted a Positron Emission Tomography (PET) study using [C]PBR28, which binds to the translocator protein (TSPO), a protein upregulated in activated microglia and astrocytes. To enhance statistical power and generalizability, we combined datasets collected independently at two separate institutions (Massachusetts General Hospital [MGH] and Karolinska Institutet [KI]). In an attempt to disentangle the contributions of different glial cell types to FM, a smaller sample was scanned at KI with [C]--deprenyl-D PET, thought to primarily reflect astrocytic (but not microglial) signal. Thirty-one FM patients and 27 healthy controls (HC) were examined using [C]PBR28 PET. 11 FM patients and 11 HC were scanned using [C]--deprenyl-D PET. Standardized uptake values normalized by occipital cortex signal (SUVR) and distribution volume (V) were computed from the [C]PBR28 data. [C]--deprenyl-D was quantified using λ k. PET imaging metrics were compared across groups, and when differing across groups, against clinical variables. Compared to HC, FM patients demonstrated widespread cortical elevations, and no decreases, in [C]PBR28 V and SUVR, most pronounced in the medial and lateral walls of the frontal and parietal lobes. No regions showed significant group differences in [C]--deprenyl-D signal, including those demonstrating elevated [C]PBR28 signal in patients (p's ≥ 0.53, uncorrected). The elevations in [C]PBR28 V and SUVR were correlated both spatially (i.e., were observed in overlapping regions) and, in several areas, also in terms of magnitude. In exploratory, uncorrected analyses, higher subjective ratings of fatigue in FM patients were associated with higher [C]PBR28 SUVR in the anterior and posterior middle cingulate cortices (p's < 0.03). SUVR was not significantly associated with any other clinical variable. Our work provides the first in vivo evidence supporting a role for glial activation in FM pathophysiology. Given that the elevations in [C]PBR28 signal were not also accompanied by increased [C]--deprenyl-D signal, our data suggests that microglia, but not astrocytes, may be driving the TSPO elevation in these regions. Although [C]--deprenyl-D signal was not found to be increased in FM patients, larger studies are needed to further assess the role of possible astrocytic contributions in FM. Overall, our data support glial modulation as a potential therapeutic strategy for FM.

Neuraxial Cytokines in Pain States

“…Changes in higher-order functions such as anxiety or depression are critical components of pain phenotypes, especially in the context of a chronic pain state (196,197). Studies in animal models (99,198,199) and in vivo positron emission tomography (PET) associated with magnetic resonance imaging (MRI) in humans (200,201) are consistent with the fact that chronic pain states lead to an alteration of glial function in the brain. Current thinking emphasizes the critical role that cytokines can play in regulating depressive states, through their effects upon key aminergic pharmacological systems regulating depressive states such as increased monoamine transporter activity (202), reduced cofactor availability (203), and reduced expression of glutamate transporters and increased glutamate release from astrocytes (204).…”

No evidence of abnormal metabolic or inflammatory activity in the brains of patients with rheumatoid arthritis: results from a preliminary study using whole-brain magnetic resonance spectroscopic imaging (MRSI)

“…There is currently no available technique to directly measure levels of inflammatory cytokines in the brains of living humans. Non-invasive neuroimaging tools such as MRSI and positron emission tomography (PET) have been utilized to demonstrate elevated neuroinflammatory markers in other diseases involving significant fatigue of a suspected central origin, such as chronic fatigue syndrome and fibromyalgia [14][15][16]. While MRSI is limited to only a few measurable metabolites, several of them have been linked to inflammatory activity in the brain.…”

Unaltered low nerve growth factor and high brain-derived neurotrophic factor levels in plasma from patients with fibromyalgia after a 15-week progressive resistance exercise

“…No definite pathophysiology has been established. Anatomical and functional changes in the brain, neuroinflammation including activation of glia cells, opioidergic dysregulation, nociception-driven amplification of neural signalling (central sensitization), and impaired top-down modulation have been reported, as well as systemic low-grade inflammation and nociceptor and muscle alterations (1)(2)(3)(4)(5)(6). Taken together, these altera-tions may indicate complicated interactions between peripheral nociception and central processes.…”