American researchers have shown a previously overlooked structure could provide novel insights into the mechanisms underlying chronic pain.
“Of course it is happening inside your head, Harry, but why on earth should that mean that it is not real?” – Albus Dumbledore
In recent times the skull bone marrow (SBM) has been gathering attention as a source of immune cells in both healthy and disease states.
The 18kDa translocator protein (TSPO), a marker of immune cell density both within and beyond the central nervous system, has been seen to appear in myeloid cells within the SBM has consequently been used as a marker of brain inflammation.
“Although the SBM is emerging as a site for neuroimmune dysregulation in various disorders, its involvement in chronic pain remains largely unknown,” a team of American researchers wrote in Science Translational Medicine.
“Given the emerging recognition of the SBM as a potentially critical hub for neuroimmune signalling, clarifying its involvement in chronic pain could pave the way for the investigation of previously unidentified mechanisms underlying persistent pain, with implications for the development of diagnostic and therapeutic tools.”
Researchers pooled data from two clinical trials to identify 88 individuals with chronic low back pain (52 females, average age 47.3 years), 37 with knee osteoarthritis (16, 66.6 years), and 22 pain-free individuals (11, 55.7 years) for the purposes of this observational imaging study.
All participants were aged ≥18 years and underwent a combined PET and MRI scan of their brain. Individuals with cLBP and KOA were treated as one “pain group” for the primary analyses and compared to the pain-free controls.
Age and sex were included as covariates throughout the analyses after the researchers identified that the SBM TSPO PET signal decreased with age, and that females had a stronger TSPO PET signal in certain SBM regions compared to males.
The spatial pattern of TPSO PET signal was similar between the pain and pain-free individuals, with both groups showing increased intensity in several areas including the lateral part of the frontal bone and the dorsomedial portion of the parietal and occipital bones.
However, the individuals with cLBP and KOA had a stronger PET signal in the bilateral frontal and parietal regions than the pain-free participants.
“Additional sensitivity analysis indicated that our findings were not explained by confounding factors,” the researchers wrote, pointing out that both the neurocranial bone volume and the total intracranial volume were consistent across the two groups.
Self-reported pain intensity and pain interference were associated with the SBM TSPO PET signal among the individuals with chronic pain, with the association being more prominent for pain intensity than pain interference.
Higher pain intensity was associated with increased TSPO PET signal in the frontal portions of the skull as well as the left frontal, parietal, temporal, and occipital peaks. In contrast, greater pain interference was associated with increased signal in the caudal part of the parieto-occipital proportion of the skull.
But the researchers didn’t stop there.
“To further corroborate the SBM origin of our findings, we investigated TSPO expression in human skull bone samples from two 62-year-old male donors,” they wrote. “One without a history of pain… and one with a history of severe diabetic peripheral neuropathy and headaches.”
Samples from the lateral portion of the left occipital bone were taken from both donors and subjected to immunohistochemical analysis.
The researchers found that the sample from the donor with pain had a greater number of cells in the bone marrow than the donor without pain (3826 versus 1616) – and that the pain donor had a higher proportion of TSPO-positive cells (82% versus 55%).
The researchers felt this finding suggested an upregulation of TSPO expression in SBM in individuals with chronic pain.
Related
“Although these data were obtained from a donor with pain but without a known history of the specific conditions investigated in this study, they provide preliminary, corroborative support for our imaging findings in cLBP and KOA, as well as for our previous observations in migraine with visual aura and further suggest that elevations in TSPO PET signal may be accompanied by increased cell density,” they wrote.
The researchers concluded that at least some of the observed SBM alterations may be consistent across different chronic musculoskeletal pain conditions.
“Future work including additional pain conditions will be needed to further corroborate this hypothesis and, vice versa, to test for the existence of regions exhibiting condition-specific patterns,” they said.
The researchers suggested that skull-to-brain neuroimmune crosstalk could serve as a potential mechanism to explain their findings.
“Recent evidence suggests that CNS-derived cures and antigens can be transported by the cerebrospinal fluid from the brain to the SBM hematopoietic niche via recently discovered vascular channels, where they signal and initiate myeloid egress and trafficking from the marrow to the meninges and brain, to mediate a neuroinflammatory response,” they said.
“Because increases in TSPO PET signal are thought to reflect greater immune cell density, the elevated SBM PET signal observed in the pain group may indicate engagement of these mechanisms.”
Leukocytes, or more specifically, neutrophils, were flagged as a potential cell population behind the increased TSPO signal within the SBM of people with chronic pain, with the researchers citing a mouse study where TSPO RNA expression was higher in the SBM of mice with a brain injury than in uninjured mice – especially in the neutrophil population.
The researchers highlighted that the upstream mechanisms responsible for the SBM differences in people with chronic pain are also currently unknown but again outlined a possible role of neutrophils in the process.
“We speculate that inflammatory signals originating in the brain may propagate to the SBM through the skull-meninges channels, thereby activating resident skull marrow immune cells and promoting the mobilisation of myeloid cells, including neutrophils,” they said.
“This neuroimmune signalling may, in turn, be sustained by persistent nociceptive input from peripheral pathology (e.g., in the joints or spine).”
An important limitation of the current study was that TSPO expression is not specific to a particular type of cell. Myeloid cells, endothelial cells, pericytes, and lymphocytes are among the kinds of cell populations that express TSPO.
