For a long time, scientists thought that immune cells produced in our bone marrow flocked to the brain when it needed protection from injury or infection.
Then in 2018, scientists discovered the skull contained a secret shortcut.
Researchers found evidence of tiny, hidden channels connecting skull bone marrow to the lining of the brain, suggesting the skull has its own emergency pipelines for immune responses.
In the years since, we've learned more about these mysterious connections between skull bone marrow and the brain, and new findings suggest this center of immune activity may also be involved in disease.
Skull bone marrow also appears to play a significant role in people who experience chronic pain, according to a study published in Science Translational Medicine led by researchers at Harvard Medical School.
In previous work, some of the same team had found signs of elevated levels of a protein called translocator protein (TSPO) in the vicinity of the skull bone marrow in people with migraine and visual aura.
TSPO is abundant in bone marrow immune cells, and the evidence suggested an immune response generated by the skull bone marrow might somehow be implicated in migraine attacks.
"Similar findings in neurodegenerative and psychiatric diseases such as Alzheimer's disease, stroke, depression, and autism suggest that skull marrow activation might not be unique to migraine but may instead represent a more fundamental neuroimmune response shared across diverse neuroinflammatory conditions," the researchers, led by clinical imaging scientist Mehrbod Mohammadian, explain in their paper.
To investigate further, the researchers analyzed PET/ MRI brain scans of 125 adults with chronic pain (88 people with chronic back pain and 37 with knee osteoarthritis) and compared them with brain scans from 22 healthy participants who acted as a control group.
The results showed that participants with chronic pain showed higher levels of TSPO across large portions of the skull compared to the healthy controls, with pronounced increases in the frontal and parietal regions of the skull.
While both groups of participants with chronic pain showed elevated levels of TSPO, participants with knee pain showed the strongest signal.
Higher TSPO signals in the PET data were linked with greater pain intensity and pain interference (with daily life), as reported by the participants in questionnaire responses.
Using different kinds of analyses, the researchers also found varying indicators linking TSPO levels to anxiety, depression, and pain burden.
In a separate investigation to complement the brain scan data, the researchers also examined donated skull tissue from two deceased men, both aged 62, one of whom had a history of chronic pain, while the other reported no such issues.
The bone marrow skull tissue from the man with chronic pain showed more than double the total cell count of the sample from the control donor (3,826 cells compared to 1,616 cells), with a higher proportion of TSPO-positive cells (82 percent compared to 55 percent).
While the researchers say the post-mortem results are only preliminary, taken together with the correlations seen in the brain data, the findings suggest that immune response activity involving skull bone marrow is linked to chronic pain.
"These findings provide a strong rationale for further investigating this previously overlooked structure, which remains largely under-explored in the context of pain," the researchers write, suggesting that therapies targeting or stimulating the skull bone marrow would be worth pursuing to help ease the pain.
As for the cellular activity that can explain what's causing pain here, the researchers say we don't yet understand it, but suggest "mechanisms linked to skull-to-brain neuroimmune cross-talk" are somehow involved.
Related: Scientists Discover a New Organ Hiding in The Skull
The team speculates that immune signals that originate in the brain may propagate to skull bone marrow through the skull-meninges channels, in turn activating skull bone marrow immune cells (myeloid cells) that begin to mobilize, potentially leading to neuroinflammation further downstream.
Because the study was observational, we can't say for sure whether this skull bone marrow activity contributes to chronic pain or if somehow it's the other way around.
There's something going on here, but it will fall to future research to provide more answers.
The findings are reported in Science Translational Medicine.
This article was fact-checked by Clare Watson and edited by Clare Watson. While we pride ourselves on our process, we are only human. If you spot a mistake, please let us know.