Researchers have identified a previously unrecognised cerebrospinal fluid drainage route along the human brain’s middle meningeal artery using MRI scans and tissue analysis. The finding suggests that ventral regions of the protective brain membranes play a more active role in clearing brain waste than previously thought, with potential implications for understanding neurological diseases.
Medical University of South Carolina. Image courtesy of Dr Onder Albayram
Medical University of South Carolina. Photo by Julie Taylor
Scientists have mapped what appears to be a distinct cerebrospinal fluid (CSF) clearance pathway in the ventral regions of the human brain, according to research published in iScience on 4 October 2025. The study combines dynamic MRI imaging with detailed tissue analysis to characterise lymphatic-like structures surrounding the middle meningeal artery (MMA), an area that has received limited attention compared to better-studied drainage routes along the brain’s upper surface.
The research team, led by Dr Onder Albayram from the Medical University of South Carolina, used contrast-enhanced MRI to track fluid movement in five healthy adults over six hours. They observed a delayed signal enhancement pattern around the periphery of the MMA that peaked at 90 minutes after contrast injection – substantially later than in other brain regions examined.
Delayed drainage patterns suggest non-vascular clearance
Whilst most anatomical compartments analysed showed rapid signal peaks at 30 minutes, consistent with typical vascular patterns, the MMA-peripheral region demonstrated a distinctly slower enhancement profile. “The MMA-peripheral exhibited significantly higher signal intensity than the MMA-lumen at all time points,” the authors report in their paper, adding that this pattern “closely paralleled the parasagittal dura, a structure known to participate in meningeal lymphatic drainage.”
The team conducted systematic comparisons of signal intensity across five regions: the MMA lumen, MMA periphery, nasal septum, parasagittal dura, and deep cervical lymph nodes. Statistical analysis revealed that the MMA-peripheral showed significantly lower signal intensity than the nasal septum at 30, 90, and 180 minutes, but exhibited no significant differences compared to the parasagittal dura at any timepoint.
“These findings support the hypothesis that the MMA-peripheral exhibits distinct clearance kinetics relative to intravascular and mucosal compartments, but shares signal decay behaviour with other dural regions, such as the parasagittal dura,” the authors state.
Tissue analysis confirms lymphatic vessel presence
To validate their imaging observations, the researchers performed detailed anatomical mapping of dural tissue surrounding both dorsal and ventral segments of the MMA obtained from a neurologically intact cadaver. Using two complementary techniques – immunofluorescence confocal microscopy and Hyperion imaging mass cytometry – they identified robust expression of canonical lymphatic markers in the tissue.
The analysis revealed PROX1-positive, PDPN-positive, and LYVE1-positive lymphatic-like structures aligned along the MMA, particularly enriched in ventral segments near the foramen spinosum. “We identified robust expression of canonical lymphatic markers – PROX1, PDPN, and LYVE1 – within the periosteal dura, particularly in the ventral segment, where signal intensity increased progressively towards the bony interface,” the authors report.
The lymphatic architecture showed distinct organisational patterns across different dural layers. Inner dura displayed anterior-posterior alignment, middle layers followed a superior-inferior axis, and outer dura revealed more complex, multidirectional lymphatic patterns. The researchers also observed lymphatic marker-positive cells within the tunica media of the MMA arterial wall itself, raising questions about potential interactions between vascular and lymphatic systems.
Molecular heterogeneity in lymphatic markers
Interestingly, the tissue analysis revealed divergent expression patterns amongst the lymphatic markers examined. Whilst PROX1 and PDPN showed strong, consistent expression, LYVE1 was notably faint and discontinuous, particularly in ventral regions.
“This divergence likely reflects functional and developmental heterogeneity within human meningeal lymphatic vessels,” the authors explain. “While PROX1 and PDPN are well-established markers of lymphatic endothelial identity, with PDPN also linked to mesenchymallike properties, LYVE1 is more closely associated with classical lymphatic endothelium and is often downregulated in pre-collecting or specialised lymphatic structures.”
This molecular variability underscores the complexity of the meningeal lymphatic system and highlights the importance of using multiple markers for accurate identification of these structures in human tissue.
Bridging animal models and human physiology
The findings represent a significant step towards translating preclinical research on meningeal lymphatics to human anatomy. Animal studies, particularly in rodents, have established the ventral meningeal region – including areas around the MMA and pterygopalatine fossa – as critical sites for CSF and interstitial fluid drainage. However, direct evidence in humans has been limited.
Clinical implications and future directions
The identification of this ventral drainage pathway could have important implications for understanding various neurological conditions. The meningeal lymphatic system is thought to play crucial roles in clearing metabolic waste, maintaining fluid homeostasis, and regulating immune surveillance in the brain. Dysfunction in these pathways has been implicated in ageing, neurodegeneration, and traumatic brain injury.
However, the researchers emphasise several important limitations. The MRI cohort consisted of only five participants imaged at five timepoints over six hours, which constrains both temporal resolution and generalisability. The histological validation was performed on a single postmortem specimen, though the use of two complementary imaging platforms strengthens confidence in the anatomical observations.
The authors are careful to note that their dynamic MRI data provide indirect evidence of fluid transport pathways inferred from signal enhancement kinetics rather than direct tracer tracking or flow measurements. “The delayed enhancement around the MMA-peripheral is consistent with slower clearance dynamics, which may reflect lymphatic involvement; however, alternative explanations, such as interstitial diffusion or perivascular retention, cannot be excluded,” they state.
Regarding the lymphatic marker-positive elements detected within arterial media and periosteal surfaces, the researchers stress that “our data reflect marker localisation alone and do not establish a functional role in perivascular drainage or vessel remodelling. It remains possible that these lymphatic elements contribute to tissue homeostasis or immune surveillance rather than fluid clearance.”
Advancing the anatomical atlas of brain drainage
Despite these caveats, the study provides valuable multimodal evidence for organised lymphatic architecture in the human ventral dura. “To our knowledge, this is a comprehensive study to characterise ventral meningeal lymphatic architecture and CSF-ISF flow patterns in the healthy human brain,” the authors state. “We identify a distinct lymphatic network adjacent to the MMA and propose that this region functions as a previously unrecognised ventral outflow hub in central nervous system fluid clearance.”
The research establishes a methodological foundation for future investigations into meningeal drainage pathways. The authors suggest that larger, demographically diverse cohorts with higher temporal sampling, automated segmentation techniques, and live tracer tracking studies will be needed to definitively establish the functional role of ventral drainage in humans.
As research into brain fluid dynamics continues to evolve, this integrated anatomical framework combining in vivo imaging with high-resolution tissue analysis represents an important step towards understanding how the human brain maintains its complex fluid environment – knowledge that could ultimately inform therapeutic approaches for a range of neurological conditions.
Reference:
Albayram, M., Richmond, S. B., Yagmurlu, K., et. al. (2025). Meningeal lymphatic architecture and drainage dynamics surrounding the human middle meningeal artery. iScience, 28(11), 113693. https://doi.org/10.1016/j.isci.2025.113693
