Lumped parameter simulations of cervical lymphatic vessels: dynamics of murine cerebrospinal fluid efflux from the skull.

Abstract

Background: Growing evidence suggests that for rodents, a substantial fraction of cerebrospinal fluid (CSF) drains by crossing the cribriform plate into the nasopharyngeal lymphatics, eventually reaching the cervical lymphatic vessels (CLVs). Disruption of this drainage pathway is associated with various neurological disorders.

Methods: We employ a lumped parameter method to numerically model CSF drainage across the cribriform plate to CLVs. Our model uses intracranial pressure as an inlet pressure and central venous blood pressure as an outlet pressure. The model incorporates initial lymphatic vessels (modeling those in the nasal region) that absorb the CSF and collecting lymphatic vessels (modeling CLVs) to transport the CSF against an adverse pressure gradient. To determine unknown parameters such as wall stiffness and valve properties, we utilize a Monte Carlo approach and validate our simulation against recent in vivo experimental measurements.

Results: Our parameter analysis reveals the physical characteristics of CLVs. Our results suggest that the stiffness of the vessel wall and the closing state of the valve are crucial for maintaining the vessel size and volume flow rate observed in vivo. We find that a decreased contraction amplitude and frequency leads to a reduction in volume flow rate, and we test the effects of varying the different pressures acting on the CLVs. Finally, we provide evidence that branching of initial lymphatic vessels may deviate from Murray's law to reduce sensitivity to elevated intracranial pressure.

Conclusions: This is the first numerical study of CSF drainage through CLVs. Our comprehensive parameter analysis offers guidance for future numerical modeling of CLVs. This study also provides a foundation for understanding physiology of CSF drainage, helping guide future experimental studies aimed at identifying causal mechanisms of reduction in CLV transport and potential therapeutic approaches to enhance flow.