Preprint Evidence for a role of skull bone marrow in human chronic pain as revealed by TSPO PET imaging, 2025, Mohammadian et al.

[SNT Gatchaman]

Evidence for a role of skull bone marrow in human chronic pain as revealed by TSPO PET imaging

Spoiler: Authors

Mehrbod Mohammadian; Nikos Efthimou; Ludovica Brusaferri; Joya Cooper-Hohn; Minhae Kim; Jennifer P. Murphy; Zeynab Alshelh; Grace Grmek; Jack H. Schnieders; Courtney A. Chane; Thomas G. Carmichael; Danika Yang; Ciprian Catana; Steven M. Stufflebeam; Robert R. Edwards; Vitaly Napadow; Kimberly Sullivan; Matthias Nahrendorf; Jodi M. Gilman; Marco L. Loggia

The skull bone marrow is emerging as a critical hub for neuroimmune signaling in various disorders, with the potential to reshape how we understand brain-immune interactions. However, its role in chronic pain is unknown.

Using integrated positron emission tomography / magnetic resonance imaging, here we show that the levels of 18 kDa translocator (TSPO), a marker of immune cell density, is elevated in the skull bone marrow of patients with chronic pain (N=125; chronic low back pain [cLBP], N=88; knee osteoarthritis [KOA], N=37), compared to healthy controls (N=22). These elevations were very widespread, generally more pronounced for KOA than cLBP, and associated with greater pain intensity, pain interference, depression, and anxiety (all p < 0.001).

Because TSPO is highly expressed in myeloid cells, these results associate skull bone marrow immune dysregulation with chronic pain and its associated psychological and functional impairments. These findings provide a strong rationale for investigating this previously overlooked structure, which remains largely underexplored in the context of pain.

Web | PDF | Preprint: MedRxiv | Open Access

 

[Jonathan Edwards]

I suppose if anyone wants proof that however crazy a hypothesis you will be bound to find some paper that claims to support it, this is a good start.

 

[Utsikt]

So they’ve gone fishing for a correlation between a measurement and pain, and based on finding one, they conclude that it’s evidence for it playing a role in pain?

 

[SNT Gatchaman]

Some summary quotes —

Until recently, the central nervous system (CNS) was thought to be immunologically isolated from the rest of the body, and communication between the CNS and the immune system was thought to occur only under certain pathological conditions, when peripheral/circulating immune cells infiltrate the brain parenchyma after crossing the blood-brain barrier. However, this view has been challenged by the recent discovery of ossified vascular microchannels that traverse the inner skull cortex.

This raises the possibility that neutrophils contribute to the skull TSPO PET signal observed in our studies, potentially reflecting an increased cellular density. Furthermore, our previous work has demonstrated elevated TSPO PET signal in the brains of individuals with various chronic pain conditions, including KOA and cLBP. We speculate that inflammatory signals originating in the brain may propagate through the skullmeninges channels, thereby activating resident skull marrow immune cells and promoting the mobilization of myeloid cells, including neutrophils. This brain inflammation may, in turn, be sustained by persistent nociceptive input from peripheral pathology (e.g., in the joint or spine), consistent with the concept of 'neurogenic neuroinflammation'.

Remarkably, we found a statistically significant and positive correlation between the TSPO PET signal in the skull and the severity of pain and pain-comorbid symptoms, highlighting the potential clinical relevance of our observations.

The distinct spatial distribution of the skull TSPO PET signal observed for different symptoms (i.e., anxiety, depression, and pain intensity/interference) suggests a possible disease- or state-specific topographical signature that warrants further examination.

Notably, a significant negative correlation was observed between skull TSPO signal and age in patients with chronic pain, with a similar trend seen in healthy controls. Similar findings were recently reported in patients with Alzheimer’s disease, further underscoring the generalizability of this observation. This result is somewhat counterintuitive, as aging is generally thought to be accompanied by an increase in inflammation within the brain. However, recent evidence suggests that skull bone marrow undergoes continuous expansion in both volume and vascularization throughout adulthood. Intriguingly, the rate of such decline in skull TSPO signal appeared qualitatively steeper for the chronic pain groups. Nevertheless, future studies with larger samples of healthy controls are needed to formally test this hypothesis.

The present study has several notable strengths, including a large sample size and the inclusion of two separate groups of chronic pain patients. However, there are several limitations. Perhaps most importantly, in this cross-sectional analysis, it is impossible to determine whether the TSPO PET signal is caused by the painful condition or precedes it. Future longitudinal work assessing skull TSPO PET signal before and after the establishment of a chronic pain condition (e.g., due to a surgery with a relatively high likelihood of chronic post-surgical pain, within the context of a preclinical pain model) will be needed to answer the question of causality.

A few of their references —

Skull bone marrow and skull meninges channels: redefining the landscape of central nervous system immune surveillance (2025, Nature Cell Death & Disease)

Skull bone marrow channels as immune gateways to the central nervous system (2023, Nature Neuroscience)

Extra-Axial Inflammatory Signal in Parameninges in Migraine with Visual Aura (2020, Annals of Neurology)

Direct vascular channels connect skull bone marrow and the brain surface enabling myeloid cell migration (2018, Nature Neuroscience)

Adult skull bone marrow is an expanding and resilient haematopoietic reservoir (2024, Nature)