Veins and Lymphatics 2019; volume 8:8470 Neurofluids: A holistic ing of the fluid dynamics, rather than focus- approach to their physiology, ing on a single compartment when analyzing Correspondence: Nivedita Agarwal, Hospital neurological diseases. This approach may S. Maria del Carmine, Corso Verona 4, 38068 interactive dynamics and contribute to advance our comprehension of Rovereto (TN), Italy. clinical implications for some common neurological disorders, Tel.: +39.0464.404066 E-mail: [email protected] neurological diseases paving the way to newer treatment options. Key words: Monro-Kellie; phase-contrast magnetic resonance imaging; neurofluids; Nivedita Agarwal,1,2 3 4 chronic cerebrospinal venous insufficiency; Christian Contarino, Eleuterio F. Toro Introduction glymphatic system; meningeal lymphatics: 1Section of Radiology, Hospital Santa IPAD. Maria del Carmine, Rovereto (TN), Neurological disorders constitute a Contributions: NA, designed the paper to link Italy; 2Center for Mind/Brain Sciences major public health challenge and are asso- ciated with life-long disability.1 Much mechanical aspects of neurofluid interaction CIMeC, University of Trento, Italy; progress has been made in understanding and neurological diseases as well as wrote the 3Computational Life Inc., Delaware, manuscript; CC, contributed to the revision of the etiopathogenesis of many of these, how- USA; 4Laboratory of Applied the paper and designed figures; EFT, con- ever, there are still several gaps in our tributed to the design of fluid mechanics Mathematics, University of Trento, Italy knowledge of many others, some of which framework of paper and holistic view of neu- are still considered idiopathic (a disease of rofluids as well as the writing of parts of the unknown etiology). paper. Abstract The Monro-Kellie hypothesis formulat- ed by the Scottish anatomist Alexander Conflict of interest: the authors declare no conflict of interest. There is increasing interest in under- Monro (secundus) and his former student standing the physiology of the extracellular George Kellie in 1783 remains a cardinal Received for publication: 7 August 20019. fluid compartments in the central nervous principle in understanding the physiology Revision received: 31 August 2019. 2 only system and their dynamic interaction. Such of the central nervous system (CNS). This Accepted for publication: 31 August 2019. interest has been in part prompted by a vig- hypothesis, as originally stated, maintains orous resurgence of the role of the venous that: i) brain contents are enclosed in a non- This work is licensed under a Creative system, the recent discoveries of the expandable bony skull; ii) the volume of Commons Attribution 4.0 License (by-nc 4.0). meningeal lymphatics, the brain waste skull contents is constant at all times;use iii) the ©Copyright: the Author(s), 2019 removal mechanisms and their potential brain parenchyma (BP) is largely incom- Licensee PAGEPress, Italy link to neurological diseases, such as idio- pressible; and iv) venous outflow must Veins and Lymphatics 2019; 8:8470 pathic intracranial hypertension, Ménière’s match the arterial blood inflow within the doi:10.4081/vl.2019.8470 disease, migraine, small vessel disease, and cardiac cycle.3 However, over the years, most neurodegenerative diseases. parts of the Monro-Kellie doctrine have The rigid cranial cavity houses several been challenged largely because it ignored space-competing material compartments: the presence of cerebrospinal fluid (CSF). logical diseases that may derive from specif- the brain parenchyma (BP) and four extra- We now know that in addition to venous ic alterations have been schematically illus- cellular fluids, namely arterial, venous, outflow, caudal displacement of CSF con- trated in Figure 1. This will form the basis of cerebrospinal fluid (CSF) and interstitial tributes to counterbalance arterial blood our understanding of the proposed brain fluid (ISF). During cardiac pulsations, the input within the rigid bony skull during waste clearance mechanisms and how a harmonious, temporal and spatial dynamic each cardiac cycle and these movements holistic approach could help provide answers interaction of all these fluid compartments occur in a precise temporal order.4 These to still unsolved questions. and the BP assures a constant intracranial newer concepts help us better understand volume at all times, consistent with the the dynamic interconnection between the Monro-Kellie hypothesis. TheNon-commercial dynamic various compartments and how anomalies interaction involves high-pressure input of in one can affect the dynamics of others.5 Cerebral arterial system arterial blood during systole and efflux of The cranium houses several space-compet- CSF into the spinal subarachnoid space ing material compartments: BP and four Paired internal carotid and vertebral (SSAS) followed by venous blood exiting extracellular fluids, namely arterial, venous, arteries assure a steady blood supply to the directly into the vertebral and internal jugu- interstitial fluid (ISF) and CSF. In light of cerebral hemispheres that anastomose at the lar veins towards the heart and intraventric- recent renewed interest in fluids such as level of the circle of Willis (Figure 2A). The ular CSF displacing caudally towards the ISF, the discovery of the meningeal lym- cardiac input to the brain is approximately SSAS. Arterial pulsatile energy is transmit- phatics6 and proposed mechanisms for brain 15-20% of the total cardiac output. For a ted to the BP that contributes to the smooth waste clearance mechanisms,7-9 it has healthy adult weighing 70 kgs, the cardiac movement of fluids in and out of the brain. become necessary not only to revisit the output is estimated at approximately 5 Perturbing any of these fluid compartments original Monro-Kellie doctrine but also to L/min and brain arterial input is about 750 will alter the entire brain dynamics, poten- comprehend the intricate interplay of the mL/min to 1000 mL/min. Each of these tially increase intracranial pressure, affect different CNS compartments. arteries will divide progressively into small- perfusion and hamper clearance capacity of We will do this by reviewing the relevant er branches (pial or leptomeningeal arteries) metabolic waste. anatomy and physiology of the BP and single as they reach the cortical surface in the cere- This review of all major extracellular CNS extracellular fluid compartments (we bral subarachnoid space (CSAS).10 fluid compartments within the brain, advo- will call them neurofluids). Key elements of The cortical surface is lined by glia lim- cates a holistic approach to our understand- such interactions and major possible neuro- itans, a structure that is made up of astrocyt- [Veins and Lymphatics 2019; 8:8470] [page 49] Review ic end-feet and tight junctions. The pia Equation 3, shows how a change in ves- where ICP is intracranial pressure, JVP is mater overlies the glia limitans and fuses sel radius will determine a flow change jugular venous pressure and MAP is mean with the basement membrane (BM) of the exponentially to the power of four making it arterial pressure. The normal range of MAP pial arteries forming the outer wall of a fun- a powerful mechanism to instantly regulate is 70-100 mmHg. Brain capillaries are lined nel-shaped CSF-filled space.11 Cortical pia Q, or cerebral blood flow (CBF). with a single layer of continuous non-fenes- mater is also reflected over these lep- CPP is defined as: trated endothelial cells that are held togeth- tomeningeal arteries.12,13 The adventitial er with tight junctions and constitute the layer of leptomeningeal arteries is sur- CPP=MAP-max{ICP,JVP} (4) blood-brain barrier (BBB).21 Several specif- rounded by perivascular spaces (PVS), or compartments which are fluid-filled but also contain connective tissue and cells (Figure 1).12,14 PVS are an important exchange route for CSF and ISF for sub- stances including CSF-infused tracers to reach brain parenchyma alongside vessels.15 The arteriolar walls are lined with lay- ers of smooth muscle cells (SMCs) that form the tunica media and have contractile properties that ensure a constant cere- brovascular tone.16 These are innervated by the autonomous nervous system or extrinsic innervation. Sympathetic innervation will cause vasoconstriction in response to an increase in arterial pressure, and reduce blood flow, whereas parasympathetic inner- vation will cause vasodilation of arterioles only in a situation of low arterial pressure and increase blood flow.17 Capillaries are inner- vated by nerves arising within the brain. These are subcortical nuclei in the brain- use stem such as nucleus coeruleus, raphe nuclei and other nuclei in the basal fore- brain.18 This intrinsic innervation is more pronounced at the astrocyte-neuronal junc- tion.17 The contractile activities of SMCs and pericytes in the arterioles and capillar- Figure 1. Schematic drawing on a coronal section of the brain illustrating the interaction ies are major actors that modulate lumen between neurofluid compartments and brain parenchyma and possible neurological dis- diameter thereby determining the entity of eases due to their derangement: 1) Arterial system: branches of carotid arteries (CA) and cerebrovascular resistance (CVR) to flow vertebral arteries (not shown) reach the CSAS, the walls of which contain sympathetic and assures constant cerebral perfusion innervation for smooth muscle cells (ext.nerves) 2) CSF pathway: a) CSF is produced via choroid plexi (CP)