Renewed attention has come to the cerebrospinal fluid (CSF) system due to its importance for central nervous system (CNS) homeostasis. The CSF system constitutes a crucial role in the CNS as it provides mechanical protection, ensures homeostasis, and facilitates communication between the CNS and peripheral nervous system, lymphatic system, vascular system, and immune system (Damkier et al., 2013; Aspelund et al., 2015; Louveau et al., 2015; Adigun and Al-Dhahir, 2021). Yet, some aspects of the CSF system remain to be fully clarified, notably along the spinal cord. Of utmost importance is bridging the knowledge gap between the brain and the spinal cord regarding the controversies of a glymphatic system and a lymphatic network, and further to understanding how these complex relationships in the CSF system contribute to health and disease. This review aims to describe the theories underlying the CSF system in relation to neurological diseases in the brain and spinal cord. This will provide the basis for highlighting the knowledge gaps that should be addressed through further research.

The CSF is a clear, colorless fluid that occupies the ventricular system, the cerebral and spinal subarachnoid spaces, and the perivascular spaces in the CNS. The fluid is a mixture of water, proteins at low concentrations, ions, neurotransmitters, and glucose that is renewed three to four times per day (Damkier et al., 2013; Hladky and Barrand, 2014; Spector et al., 2015). Several theories have been proposed to explain how CSF is produced. The classic theory states that the choroid plexi are the primary sources of CSF production. The choroid plexi develop from the ependyma protruding from the pia mater into the lateral, third, and fourth ventricles (Damkier et al., 2013; Hladky and Barrand, 2014). The plexi consist of a single layer of epithelial cells residing on a basement membrane, connective tissue, and fenestrated capillaries (Figure 1A). The epithelial cells are connected by tight junctions making the epithelial layer relatively tight, whereas the underlying fenestrated capillaries are relatively leaky. This enables the passage of compounds from the blood to the epithelial cells. The production of CSF depends on the transcellular movement of Na⁺ primarily driven by the Na⁺/K⁺-ATPase expressed at the luminal membrane facing the CSF. The movement of Na⁺ is accompanied by Cl⁻ and HCO₃⁻ as well as water that follows the solute gradient. The water transport is distributed from the blood system to the ventricular system through aquaporin-1 (AQP1) water channels (Nielsen et al., 1993; Jensen et al., 2015). CSF is therefore not simply an ultrafiltrate of the blood, but a product of a tightly regulated ion transport that generates osmotic gradients and water transport. The production of CSF by the choroid plexi is believed to be relatively constant; however, the CSF secretion varies over the duration of a day with an average production of 650 ml and maximal production after midnight (Nilsson et al., 1992). The classic theory of CSF production has been challenged by findings in AQP1 knockout mice, demonstrating that water permeability across the choroid plexi is reduced by 85%, while the CSF secretion is only reduced by 35% (Oshio et al., 2005), suggesting other means of water transport across the epithelia. It is generally believed that the choroid plexi are the main sites of CSF production with contribution from extrachoroidal sites (Orešković and Klarica, 2010; Khasawneh et al., 2018); however, it has been proposed that the extrachoroidal sites are the main sites of CSF production with contribution from the choroid plexi (Orešković et al., 2017; Klarica et al., 2019).

As for CSF production, several theories of CSF absorption have emerged. The classic theory of CSF absorption states that absorption takes place from the subarachnoid spaces into the venous blood system through dural venous sinuses via cranial arachnoid granulations and into the lymph system via the nasal cribriform plate and the perineural sheaths (Klarica et al., 2019). Additional absorption is suggested to occur through cranial meningeal lymphatics embedded in the dura mater alongside arterial and venous vessels (Figures 1B,C; Aspelund et al., 2015; Jensen et al., 2015; Louveau et al., 2015; Tamura et al., 2020). Additional absorption has also been suggested to occur through spinal arachnoid granulations and spinal meningeal lymphatics (Chen et al., 2015b; Benveinste et al., 2017). Others have proposed that absorption through dural venous sinuses and/or lymphatics is of minor importance compared to absorption through blood microvessels (Klarica et al., 2019).

Considering the classic theory, the variation in CSF production must be matched by a similar variation in CSF absorption; otherwise, CSF accumulation would arise.

The CSF flow dynamics within the ventricular system and the subarachnoid spaces is thought to consist of two main types of movements: convective flow and pulsatile flow (Yildiz et al., 2017). Convective flow is a unidirectional motion from the choroid plexi in the lateral ventricles through the foramen of Monro into the third ventricle, passing through the cerebral aqueduct into the fourth ventricle. From the fourth ventricle, CSF exits the ventricular system through the three apertures where it enters the cerebral subarachnoid space, the spinal subarachnoid space, and the central canal of the spinal cord.

The driving force of convective flow is thought to be the result of hydrostatic pressure gradients between the choroid plexi (high pressure) and arachnoid granulations (low pressure). The movement of CSF from the spinal subarachnoid space to the perivascular spaces and the lymph system is poorly described, although similar routes have been suggested (Chen et al., 2015b; Benveinste et al., 2017). The unidirectional movement has, however, been questioned by studies showing constant CSF movement, but without net unidirectional CSF displacement, suggesting a pulsatile flow (Orešković and Klarica, 2010; Klarica et al., 2019). Contrary to the unidirectional movement of the convective flow, the pulsatile flow is a bidirectional movement in upward (cranial) and downward direction (caudal) along the spinal cord, and in varying directions in the brain. Prior theories assumed the origin of the pulsatile CSF motion was the choroid plexi (Takizawa et al., 2018); however, to date, two main theories exist: the cardiac-driven theory and the respiratory-driven theory (Figure 2). The cardiac-driven theory states that changes in the blood volume are transmitted directly and indirectly to the CSF, i.e., a direct transmission of blood vessel pulsations to the CSF and an indirect transmission of blood vessel pulsations through other tissues to the CSF (Haughton and Mardal, 2014; Daouk et al., 2017). The respiratory-driven theory states that changes in the intrathoracic pressure are transmitted via the venous system to the CSF (Daouk et al., 2017; Aktas et al., 2019; Lloyd et al., 2020). Natural respiration may not contribute to the respiratory-driving force with the same magnitude as forced respiration. It is generally believed that inspiration elicits a cranial movement of CSF, while expiration elicits a caudal movement (Yamada et al., 2013; Chen et al., 2015a; Dreha-Kulaczewski et al., 2017; Aktas et al., 2019). However, both cranial and caudal CSF movements have been observed during inspiration as a result of epidural venous blood return to the thoracic spine from the cervical and lumbar spine (Lloyd et al., 2020). The relationship between the cardiac- and respiratory-driving forces is debated as the driving forces influence arterial and venous blood flow differently, thereby contributing to CSF movement to a different extent; however, the cardiac-driven force is thought to be responsible for the basic pulsatile CSF flow, while the respiratory-driven force is responsible for the large pulsatile CSF flow (Takizawa et al., 2017). The variability in the relative influence of the cardiac and respiratory forces has been attributed to variations in musculature and respiratory capacity (Yildiz et al., 2017), and the anatomical differences between the cranial and spinal cavity (Yildiz et al., 2017; Aktas et al., 2019; Lloyd et al., 2020). Yet, the exact relationship between the cardiac- and respiratory-driving forces remains to be fully clarified.

An essential function of the CSF system is the maintenance of CNS homeostasis. As the CNS consists of highly active metabolic regions, waste products need to be cleared. The most recently proposed mechanism for waste clearance is the highly debated glymphatic system. The available literature primarily focuses on the mechanisms within the brain; thus, the mechanisms within the spinal cord remain largely elusive. The glymphatic system is a fluid conduit defined as an astrocyte-mediated fluid exchange of CSF and ISF in the brain (Iliff et al., 2012; Jensen et al., 2015; Rasmussen et al., 2018). Within the glymphatic system, CSF is thought to be driven from the subarachnoid space into the periarterial spaces surrounding penetrating arteries (Jensen et al., 2015), and along the periarterial spaces with a net convective flow following the direction of the blood flow (Mestre et al., 2018; Thomas, 2019; Kedarasetti et al., 2020). From the periarterial spaces, CSF enters the brain parenchyma. The water channels aquaporin-4 (AQP4) are expressed in the vascular endfeet of astrocytes (Trillo-Contreras et al., 2019) and have been implicated in the perivascular influx of water. AQP4 is a water channel with selective characteristics (Amasheh et al., 1995). The role of AQP4 is the most controversial part of the glymphatic system as convective transport through AQP4 is questionable from a physiological point of view. There is, however, consensus that CSF has a convective flow along the perivascular spaces of the larger blood vessels (i.e., arteries and arterioles) and diffusion across the smaller blood vessels (i.e., capillaries) situated at the neurovascular unit including AQP4. As discussed by others (Abbott et al., 2018), it is likely that a convective force increases the availability of CSF at the basal lamina in the capillaries, thereby adding to the diffusion. Within the brain parenchyma, CSF disperses and mixes with ISF. The compositions of CSF and ISF are comparable, but the major difference between the two compartments is that ISF is surrounded by an extracellular matrix, thereby enabling alteration in the fluid composition of for instance ions (Syková, 2008). Due to compositional differences in CSF and ISF, it is generally accepted that the two entities can be recognized as two compartments that communicate. The mixture of CSF, ISF, and waste products enters the perivenous space by mechanisms that are poorly understood (Iliff et al., 2012). From the perivenous space, the mixture leaves the brain by returning to the vein itself across the vessel wall or by returning to the CSF in the subarachnoid space (Figure 1D). From here, the CSF mixed with ISF components may leave the subarachnoid space via the meningeal lymphatic vessels, nerve sheaths, and nasal cribriform plate into the deep cervical lymph nodes (Iliff et al., 2012; Mestre et al., 2020).

The existence of a lymphatic network within the meninges of the brain was first described by the Italian anatomist Paolo Mascagni in 1787; a description that recently has been translated and published (Sandrone et al., 2019). With the rediscovery of the lymphatic network, findings demonstrate that the meningeal lymphatic vessels are embedded within the dura mater alongside arteries, veins, and cranial nerves (Aspelund et al., 2015; Jensen et al., 2015; Tamura et al., 2020). Here they create a network that facilitates waste clearance away from the brain and a direct link between the CNS and the peripheral immune system (Oliver et al., 2020). The entry of solutes and immune cells from the CSF to the meningeal lymphatics is proposed to occur through specific entry points along the vessels (Louveau et al., 2018).

Although considerable anatomical differences exist between the brain and the spinal cord, it seems reasonable to assume that the spinal cord has a waste clearance system and a lymphatic system resembling the systems proposed for the brain. In support of this assumption studies have demonstrated the existence of spinal perivascular spaces in rats (Lam et al., 2017; Liu et al., 2018), the existence of meningeal lymphatic vessels along the spinal cord in mice (Jacob et al., 2019), and expression of AQP1 and AQP4 water channels in the rodent spinal cord (Oklinski et al., 2014, 2016; Wei et al., 2017). As these findings are based upon animal studies, there is a need for human studies. These findings may have a vast impact on the emergence and progress of several CNS diseases, thus emphasizing the need for further research.

Knowledge of the CSF system has significant implications for understanding diseases in the brain and the spinal cord. It is, however, of great importance to acknowledge that any alteration in the CSF system may be influenced by other factors, e.g., aging, hypertension, atherosclerosis, and sleep deprivation (Benveinste et al., 2017), and that any alteration in the CSF system may influence other parts of the CSF system. A greater understanding of the relationship between the CSF system and CNS diseases may provide a better understanding of these diseases’ emergence and progress, and thereby reveal potential targets for treatment and intervention. A few examples of these relationships are given below.

Despite significant advances in our understanding of the CSF system, many processes remain to be elucidated. Notably, as the majority of studies focuson the brain, there is a significant knowledge gap regarding the spinal cord. Both the anatomical and physiological differences between the brain and spinal cord hamper the translation of findings found in the brain to the spinal cord, thus more research into the mechanisms in the spinal cord is warranted.

All authors contributed to conception and design of the work. TW and HD wrote sections of the manuscript. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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