From ventricles to lymphatics: A systems-level framework for brain fluid transport

Abstract

Abstract

Understanding of cerebrospinal fluid (CSF) dynamics has undergone a major transformation, shifting from the traditional concept of unidirectional CSF circulation toward a broader framework that incorporates distributed glymphatic and lymphatic clearance systems. This review integrates classical CSF physiology with recent discoveries in glymphatic transport, meningeal lymphatics, and interstitial fluid exchange to provide a unified perspective on brain fluid homeostasis. Evidence from anatomical, physiological, computational, and clinical studies demonstrates that intracranial fluid transport operates through a hierarchical, highly coordinated network extending from microscopic astrocytic interfaces and perivascular pathways to large-scale venous and lymphatic drainage routes. The analysis highlights that diffusion and advection are not opposing mechanisms but complementary, state-dependent processes influenced by vascular pulsatility, sleep–wake cycles, respiratory dynamics, and tissue architecture. Emerging data further indicate that dysfunction within these clearance pathways may contribute to impaired metabolic waste removal, neuroinflammation, hydrocephalus, and neurodegenerative disorders. Rather than functioning as a simple circulation pathway, brain fluid movement should therefore be conceptualized as a modular hydrodynamic system integrating cellular, vascular, and lymphatic components. This updated framework may support the development of more targeted diagnostic and therapeutic strategies for neurological diseases associated with impaired fluid transport and clearance.