Understanding central nervous system fluid networks: Historical perspectives and a revised model for clinical...

The central nervous system (CNS) lacks traditionally defined lymphatic vasculature. However, CNS tissues and barriers compartmentalize the brain, spinal cord, and adjacent spaces, facilitating the transmittal of fluids, metabolic wastes, immune cells, and vital signals, while more conventional lymphatic pathways in the meninges, cervicofacial and paraspinal regions transmit efflux fluid and molecules to peripheral lymph and lymph nodes. Thus, a unique and highly organized fluid circulation network encompassing intraparenchymal, subarachnoid, dural, and extradural segments functions in unison to maintain CNS homeostasis. Pathways involved in this system have been under investigation for centuries and continue to be the source of considerable interest and debate. Modern imaging and microscopy technologies have led to important breakthroughs pertaining to various elements of CNS fluid circuitry and exchange over the past decade, thus enhancing knowledge on mechanisms of mammalian CNS maintenance and disease. Yet, to better understand precise anatomical routes, the physiology and clinical significance of these CNS pathways, and potential therapeutic targets in humans, fluid conduits, flow-regulating factors, and tissue effects must be analyzed systematically and in a global manner in persons across age, demographical factors, and disease states. Here, we illustrate the system-wide nature of intermixing CNS fluid networks, summarize historical and clinical studies, and discuss anatomical and physiological similarities and differences that are relevant for translation of evidence from mice to humans. We also review Cushing's classical model of cerebrospinal fluid flow and present a new framework of this "third circulation" that emphasizes previously unexplained complexities of CNS fluid circulation in humans. Finally, we review future directions in the field, including emerging theranostic techniques and MRI studies required in humans.