Anatomy and Physiology of Cerebrospinal Fluid Dynamics

C H A P T E R

5 Anatomy and Physiology of Cerebrospinal Fluid Dynamics Bryn A. Martin*, Soroush Heidari Pahlavian† *

Neurophysiological Imaging and Modeling Laboratory, Department of Biological Engineering, University of Idaho, Moscow, ID, United States †Laboratory of Functional MRI Technology, Stevens Neuroimaging and Informatics Institute, Department of Neurology, University of Southern California, Los Angeles, CA, United States

INTRODUCTION Understanding the anatomy and physiology of cerebrospinal fluid (CSF) dynamics is an essential element for investigating many diseases of the central nervous system (CNS) and potential disease therapeutics. CSF is a clear, colorless fluid with a viscosity similar to that of water at body temperature,1 and constitutes a major part of the extracellular fluid of the CNS. CSF serves many physiological functions, including structural protection, metabolic homeostasis, and immunological support of the CNS. Abnormalities in CSF production, absorption, and/or dynamics are thought to play an important role in several CNS disorders such as Alzheimer disease,2 hydrocephalus,3, 4 normal-pressure hydrocephalus,4 Chiari malformation,5-7 and syringomyelia.8, 9 A number of CSF-based therapeutics are presently under investigation, including intrathecal drug delivery (IDD),10-12 CSF filtration,13, 14 CSF cooling,15, 16 and CSF pulse control.17 This chapter provides a description of CSF function in the CNS and the physiological aspects of its pulsation and circulation throughout the cranial and spinal subarachnoid space (SAS).

SUMMARY OF CEREBROSPINAL FLUID SPACE ANATOMY Cerebrospinal fluid resides in two primary regions that are located within the intracranial space and spine (Fig. 1). Total CSF volume is estimated to range from 250 to 400 mL in healthy adult humans,18-22 with approximately 75% of that volume located intracranially. Intracranial

Nervous System Drug Delivery https://doi.org/10.1016/B978-0-12-813997-4.00005-0

73

# 2019 Elsevier Inc. All rights reserved.

74

5. ANATOMY AND PHYSIOLOGY OF CEREBROSPINAL FLUID DYNAMICS

FIG. 1 Three-dimensional reconstruction of the complete cerebrospinal fluid system based on subject-specific, T2-weighted magnetic resonance imaging of a healthy 23-year-old female patient. Based on Sass LR, Khani M, Natividad GC, Tubbs RS, Baledent O, Martin BA. A 3D subject-specific model of the spinal subarachnoid space with anatomically realistic ventral and dorsal spinal cord nerve rootlets. Fluids Barriers CNS 2017;14(1):36.

CSF spaces can be roughly divided into the cortical SAS, cisterns, and ventricles that contain about 180, 77, and 23 mL of CSF, respectively. The spinal CSF space has a volume of approximately 97 mL.23 The intracranial ventricles consist of the lateral ventricles (8.5 mL each), the third ventricle (2.2 mL), and the fourth ventricle (3.6 mL). These volumes are provided based on a single subject-specific model of the CSF system developed at University of Idaho using high-resolution T2-weighted magnetic resonance imaging (MRI), and can vary by subject and by disease state. It should be noted that the total CSF volume reported above is higher than the volume traditionally cited in medical textbooks18, 24, 25 and review articles (i.e., 150 mL).26, 27 In fact, the reported value of 150 mL total CSF volume has become so standard that an empirical reference is often omitted. Early studies reporting total CSF volume used relatively crude and invasive techniques 28 and have since been determined to be prone to error.29, 30 The difference in total CSF volumes reported likely stems from the vastly different measurement methods. In general, more recent methods have yielded larger CSF volumes when noninvasive, high-resolution MRI techniques are used. More study is needed to understand CSF volume variation in healthy individuals and those diagnosed with CNS disease. Designation of CSF-containing compartments including ventricles, cisterns, and SASs is based on their anatomical position (i.e., intra- vs extraparenchymal) and size (e.g., cisterns are dilated SASs). The intracranial ventricles are enveloped entirely by brain tissue. The SAS, both cranial and spinal, lies between pia and arachnoid mater. Within the spinal SAS, 31 pairs of dorsal and ventral nerve rootlets and denticulate ligaments are present

I. PHYSIOLOGY OF NERVOUS SYSTEM DRUG DELIVERY

SUMMARY OF CEREBROSPINAL FLUID SPACE ANATOMY

75

(Fig. 1). The spinal cord terminates at the conus and divides into many nerve segments called the filum terminale or “horse’s tail.” Several openings connect the ventricular CSF spaces. The intraventricular foramina, also called the foramina of Monro, are openings (left and right) that connect the third ventricle to the lateral ventricles. A relatively long and narrow tube-like canal called the Aqueduct of Sylvius connects the third and fourth ventricles with a minimum diameter of approximately 1-3 mm. In addition to the Aqueduct of Sylvius, the fourth ventricle has three other narrow openings called the median aperture or foramen of Magendie, and the lateral apertures (left and right) or foramen of Luschka. The foramen of Magendie and Luschka are the only direct fluidic connections between the intraventricular CSF spaces and the cortical and spinal SAS. The extracranial CSF spaces form a complex, interconnected region that includes the cortical SAS and a number of CSF cisterns that can be stratified into 7 “paired” (left and right) and 10 “unpaired” cisterns. Briefly, paired cisterns include the cerebellomedullary, Sylvian, trigeminal, cerebellopontine, carotid, crural, and ambient cisterns. Unpaired cisterns include the cisterna magna, cerebellar, superior cerebellar, quadrigeminal, interpeduncular, pericallosal, carotid, chiasmatic, prepontine, and premedullary cistern. Based on the University of Idaho model, the largest single cistern in terms of volume is the cerebellar cistern, which holds approximately 23 mL of CSF, followed by the Sylvian cistern, with a CSF volume of roughly 8.5 mL on each side (left and right). In total, there are 31 distinct CSF regions in terms of SASs, cisterns, and ventricles (Fig. 2 shows connectivity between regions). Note that

FIG. 2

Cerebrospinal fluid (CSF) space connectivity diagram shows fluidic connections between the various ventricles, cisterns, and subarachnoid space. Note: violet- and blue-colored boxes indicate that these regions are the same and are fluidically connected. Also, semicircular canals, utricle, cochlea, and vestibular aqueducts are included for completeness, but are not typically considered integral parts of the CSF system.

I. PHYSIOLOGY OF NERVOUS SYSTEM DRUG DELIVERY

76

5. ANATOMY AND PHYSIOLOGY OF CEREBROSPINAL FLUID DYNAMICS

FIG. 3

(A) Anatomy of the subarachnoid space with detail of the location and structure of the arachnoid trabeculae, blood vessels, pia mater, arachnoid mater, dura mater, and brain tissue. (B) Second-harmonic image generation of ovine cortical subarachnoid space shows the collagen microstructure within the arachnoid trabeculae in terms of sheets, pillars, and blood vessel walls. Samples were stained with 4,6-diamidino-2-phenylindole (DAPI) to visualize cell nuclei. Ovine trabecular fiber diameter ranges from approximately 5 to 30 μm, and shows both straight and crimped morphology.

some texts may divide CSF into greater or fewer regions; this chapter highlights the regions most commonly described in the literature. Cerebrospinal fluid system anatomy has important features that range in size over four orders of magnitude (10 μm-10 cm). Arterial and venous blood vessels traverse the CSF spaces to the brain and spinal cord. In addition, tiny web-like fibers measuring 15 μm in diameter,31 called arachnoid trabeculae, stretch from the arachnoid to the pia mater (Fig. 3). These fibers are distributed nonuniformly throughout the CSF system32, 33 and can have a sheet-like morphology that contains holes.34 Microstructural characterization of the pia arachnoid complex using optical scanning tomography has estimated arachnoid trabeculae volume fraction to be roughly 30% in a pig brain postmortem.32 Many thin arachnoid membranes are also present in the CSF system, such as the dorsal and dorsolateral septum within the spinal SAS,35 which may perturb distribution of tracers and affect CSF flow dynamics.36

BIOLOGICAL SIGNIFICANCE OF CSF The presence of CSF within and around the brain and spinal cord is advantageous to the CNS in several ways. First, CSF provides a mechanical support system for the brain. The average adult brain weighs approximately 1400 g,37 but when the brain is floating in CSF, buoyancy forces reduce its effective weight to roughly 50 g, according to Archimedes’ law. CSF acts as a cushion that protects the brain from hitting the skull when the head moves abruptly or sustains mild trauma. Another protective function of CSF is its role in regulating intracranial pressure (ICP) in response to sudden fluctuations caused by obstructed venous

I. PHYSIOLOGY OF NERVOUS SYSTEM DRUG DELIVERY

CSF CIRCULATION

77

outflow and/or expanding mass lesion. This function is described in the Munro–Kellie doctrine,38 which states that the total volume of the cranial cavity is constant and equals the sum of brain, intracranial blood, and intracranial CSF. In essence, alterations in intracranial brain or blood volume are accommodated by a change in the intracranial CSF volume, thereby maintaining normal ICP. A second important function of CSF is to sustain metabolic homeostasis of the CNS by supplying nutrients to neural and glial cells, removing metabolic by-products generated by the activities of these cells, and transporting neurotransmitters, hormones, and other biologically active substances throughout the CNS.39, 40 According to a classical concept initially articulated by Davson and Segal,41-43 CSF circulation and reabsorption serve as a sink for metabolic wastes that cannot be easily eliminated across the blood–brain barrier (BBB). More recently, the glymphatic system has been termed as a potential pathway for the exchange of CSF and interstitial fluid within the CNS tissue.44-46 This process is thought to facilitate clearance of potentially neurotoxic waste products (e.g., β-amyloid) and its dysfunction was postulated to contribute to the progression of Alzheimer disease.47 However, it is yet unclear how a flow of CSF to the interstitial spaces in the brain, as proposed in the glymphatic concept, could occur.48

CSF CIRCULATION According to a classical hypothesis,41, 49-51 CSF is primarily produced within the brain ventricles by the highly vascular ingrowth of ependymal linings, known as the choroid plexus, and circulates among ventricles, cisterns, and the SAS to be ultimately reabsorbed into the blood at the arachnoid granulations of the superior sagittal sinus and at other locations within the CSF system. According to this hypothesis, CSF is produced by the epithelial cells of the choroid plexus of the brain ventricles and flows from the lateral ventricles through the foramina of Monro to the third ventricle. From there, the CSF flows through the aqueduct of Sylvius into the fourth ventricle. CSF exits the ventricular system through the median aperture and the two lateral apertures of Luschka, and enters the cisterns surrounding the cerebellum in the inferior cranial SAS. The CSF continues to move superiorly and inferiorly to the cranial and spinal SAS, respectively. The main postulates of the traditional hypothesis regarding the choroidal production and circulation of CSF were recently questioned.52 Experimental measurement of aqueductal CSF flow in animals has demonstrated no CSF secretion inside the brain ventricles in physiological conditions.53 Furthermore, recent MRI studies using the time-spatial labeling inversion pulse (Time-SLIP) technique54 disputed the notion that CSF flows from sites of production to sites of absorption, as this imaging modality indicated a bidirectional flow between the lateral and third ventricles and an absence of CSF displacement toward the superior sagittal sinus. The aforementioned findings are in line with the older studies that reported no change in CSF formation rate or chemical composition after choroid plexectomy (i.e., removal) in animals.55-59 According to a new hypothesis, CSF is consistently produced and absorbed throughout the whole CSF system as a consequence of filtration and reabsorption of water through the capillary walls into the surrounding CNS tissues. Its volume is regulated by the hydrostatic and osmotic forces between CSF and neural tissues.52 As such, a significant portion of CSF

I. PHYSIOLOGY OF NERVOUS SYSTEM DRUG DELIVERY

78

5. ANATOMY AND PHYSIOLOGY OF CEREBROSPINAL FLUID DYNAMICS

formation is thought to occur outside the brain ventricles, through filtration of water from blood to interstitial fluid and eventually CSF at the arterial capillaries (high capillary pressure). Based on this model, CNS venous capillaries that are under low hydrostatic pressure are the main spots for CSF reabsorption due to their large surface area. Meanwhile, arachnoid granulations and paraneural sheaths of the cranial and spinal nerves serve as accessory pathways for CSF absorption, which becomes significant when substances are infused into CSF under high experimental pressure.60 Further research is needed to confirm the source(s) of CSF production and absorption.

ORIGINS OF CSF PULSATIONS Cerebrospinal fluid pulsations and their sensitivity to the cardiac cycle and venous pressure have been documented since the earliest monomeric evaluation of CSF61; however, the mechanisms that drive pulsatile CSF flow are still not fully comprehended. The development of phase-contrast MRI techniques over the past several decades has allowed study of the pulsatile nature of CSF flow, which appears to be craniocaudally oriented during cardiac systole and in the reverse direction during diastole.62-65 Some have suggested that CSF pulsations are caused by a change in brain volume (resulting from alterations in intracranial blood perfusion during cardiac and respiratory cycles).66, 67 Brain volume changes due to the phase difference between the inflow of arterial blood and outflow of venous blood from the cranium.68, 69 The total cerebral blood volume is reported to change the same amount as the CSF exchange between the cranial and spinal SAS (0.5–2.0 mL per cardiac cycle).70 Based on the Munro–Kellie hypothesis described earlier in this chapter, the volume change in intracranial blood must be compensated by CSF flow to and from the brain ventricles and cranial SAS. As such, a net increase in cranial blood volume during cardiac systole and the accompanying increase in ICP result in a craniocaudally directed CSF flow. Likewise, a decrease in intracranial blood volume during cardiac diastole leads to CSF flow in the caudocranial direction. CSF system compliance in healthy humans (i.e., cranial and spinal combined) has been estimated to range from roughly 0.5 to 2.0 mL/mmHg.71 Cranial venous return changes in response to respiration are thought to be an additional source underlying CSF pulsation. Williams documented the impact of respiration on CSF dynamics via thoracic pressure changes using invasive manometer recordings.72 Recent noninvasive quantification of CSF flow using Time-SLIP73 and real-time multislice echo planar imaging MRI techniques74-76 have revealed a significant contribution of respiration on CSF pulsations in the ventricular system and SAS. These modalities found the magnitude of CSF movement during deep inhalation and exhalation to be greater than that of cardiac-generated pulsations. Alterations in thoracic pressure are transmitted to the intracranial space through nonvalved venous channels (i.e., the vertebrobasilar system and longitudinal vertebral veins) and thoracic CSF,77 and are believed to affect cranial venous return and ICP.73, 78 The increased cephalad CSF flow observed during deep inhalation could be explained by reduced cranial venous blood volume, which is caused by diminished thoracic pressure during deep inhalation. Similarly, during deep exhalation, an increase in thoracic pressure reduces the venous return from the brain and results in caudally directed CSF flow to compensate for increased intracranial venous blood volume. Other actions such as coughing,79 sneezing, the Valsalva maneuver, or

I. PHYSIOLOGY OF NERVOUS SYSTEM DRUG DELIVERY

NUMERICAL ASSESSMENT OF CSF DYNAMICS

79

application of continuous positive airway pressure80 could cause complicated pressure environments that are also likely to affect CSF pulse magnitude and flow direction. Based on MRI measurements, the initiating point of CSF velocity pulsation has been estimated to be located at the foramen magnum near the base of the brain, and is associated with blood volume fluctuations in the nearby highly vascularized cerebellar tonsils.68 From that location, the CSF pulse spreads outward in both cranial and caudal directions.81, 82 Using high-speed phase-contrast MRI, CSF pulse wave velocity in the human cervical spine has been measured to be 4.6 m/s in the craniocaudal direction during systole.83 Cortical CSF pulse wave velocity has not been measured.

IN VIVO ASSESSMENT OF CSF DYNAMICS CSF dynamics (e.g., velocity, stroke volume, flow rate) have been quantified using MRI. These dynamics have been studied with the hope of elucidating the onset and progression of CNS disorders such as Type 1 Chiari malformation, hydrocephalus, normal-pressure hydrocephalus, and syringomyelia. The earliest MRI visualization of CSF flow was reported by Bradley et al. as a distinct MR artifact, known as flow void, caused by the diminishing signal due to the fluid motion.3 Over the past decades, several studies have used different MRIbased flow-imaging techniques to evaluate the physiology and pathophysiology of CSF dynamics. The most commonly applied technique is cardiac-gated phase-contrast MRI,84 which allows noninvasive measurement of CSF velocity profiles over the cardiac cycle. This technique has improved over the years in terms of spatial and temporal resolution. Current methods include four-dimensional phase-contrast MRI, which allows measurement of CSF velocity field in three directions over an entire volume (Fig. 4).85, 86 In addition, real-time phase-contrast MRI has allowed assessment of CSF dynamics that are not cardiac-related and are caused by respiration and other maneuvers.74, 76, 87 The region of the CSF system with the highest CSF velocities in healthy people and patients is typically the aqueduct of Sylvius, with peak velocity values ranging from roughly 4 to 20 cm/s in the caudal direction during cardiac systole.4, 88 Within the spinal SAS, peak CSF velocities are highest in the cervical spine, with a peak value from 2 to 20 cm/s and stroke volume of about 0.5-2 mL per CSF flow cycle.85, 89 CSF stroke volume during each cardiac cycle has a decreasing trend, moving caudally along the spinal SAS, and is zero at the spinal SAS termination. This decreasing trend is attributed to distributed compliance along the spine, associated with blood vessels within the spine and the distensible dura and surrounding epidural space.90

NUMERICAL ASSESSMENT OF CSF DYNAMICS Several researchers have implemented computational techniques as an engineering approach to help understand the nature of CSF dynamics and CSF alterations in patients with CNS disorders. These methods have helped to noninvasively investigate flow parameters, which can be difficult to measure using phase-contrast MRI or invasive modalities.

I. PHYSIOLOGY OF NERVOUS SYSTEM DRUG DELIVERY

80

5. ANATOMY AND PHYSIOLOGY OF CEREBROSPINAL FLUID DYNAMICS

FIG. 4 Cerebrospinal fluid (CSF) velocity measurement in an in-vitro model of the craniovertebral junction using four-dimensional phase-contrast magnetic resonance imaging (4D Flow MRI). (A) Three-dimensional visualization of in vitro model. (B) CSF velocity profiles visualized by 4D Flow MRI. (C) CSF vortical flow structures around dorsal and ventral spinal cord nerve roots visualized by 4D Flow MRI-based streamlines.

The first numerical simulation of CSF motion in the spinal SAS was carried out by Loth et al.91 who used an idealized annular geometry based on anatomical data from the Visible Human Project. In this study, CSF velocity and pressure fields were obtained by solving the two-dimensional governing equations of fluid dynamics with the assumption of rigid walls. The inertial effects were shown to dominate the flow field under normal physiological flow rates, particularly in the cervical and lower lumbar regions. More recently, Helgeland et al.92 studied CSF flow in the spinal SAS using a direct numerical simulation model based on a subject-specific geometry of a patient diagnosed with a Type 1 Chiari malformation, and observed flow features similar to those observed in a transient flow. This similarity in features suggested the possible existence of transient velocity fluctuation in patients with extreme SAS geometrical abnormalities. It is unclear whether these velocity fluctuations exist in healthy subjects.

I. PHYSIOLOGY OF NERVOUS SYSTEM DRUG DELIVERY

SOLUTE TRANSPORT WITHIN THE CSF

81

Numerical modeling has also been used to investigate physiological CSF hydrodynamics in the ventricles of the brain and cranial SAS. Kurtcuoglu et al.88 investigated CSF motion in the third ventricle and in the aqueduct of Sylvius using a computational fluid dynamics model based on subject-specific geometry, flow rate, and wall motion. Their results demonstrated the existence of fluid jets exiting the aqueduct and recirculation zones superior and inferior to the observed jet. Subsequently, Gupta et al.93, 94 characterized CSF motion in the cranial SAS and superior spinal SAS using subject-specific computational fluid dynamics models. These studies quantified the complex CSF flow patterns, including the large variation in the spatial distribution of velocities, and found the velocity profile of CSF entering the spinal SAS to be blunt or plug-like, which was consistent with in vivo observations.89, 95 In addition to their utility in detailing characteristics of CSF flow, numerical simulations provide a powerful tool for variational analysis to determine the importance of various anatomical features and physiological functions on CSF dynamics. These include spinal cord nerve roots,96 denticulate ligaments,97, 98 frequency and magnitude of CSF pulsations,99 presence of arachnoid trabeculae,98 focal spinal arachnoiditis,100 tonsillar descent in patients with Chiari malformations,6, 101 and properties of the spinal cord and dura.102 In addition to producing new engineering-based parameters, these studies are necessary for evaluating the potential of such parameters for clinical use. Fig. 5 shows an example of numerical simulation of intrathecal CSF dynamics conducted by Khani et al.96

SOLUTE TRANSPORT WITHIN THE CSF A solute injected into the CSF in the spinal SAS mixes with the CSF,103 spreads throughout the CSF system, passes through the pia mater, and is then taken up into the brain parenchyma, perhaps via the paravascular route.104 Unlike solutes injected into the blood, this process bypasses the BBB (and the endothelial tight junctions), which allows for delivery of many molecules to the brain that may not be deliverable through the vascular system.105, 106 These range from small molecules to biologics, including protein and cell-based and gene therapies involving tropic factors to stimulate dying neurons.107, 108 Moreover, direct delivery of therapeutic agents that bypass the BBB may allow lower doses, decreasing the risk of potential toxic effects, compared to therapeutic agents that are systemically administered.109, 110 Several therapies have shown promise in animal studies111; others have been shown to be safe in human clinical trials.112 In addition, CSF-based delivery is a relatively simple surgical intervention with a potentially lower risk to the patient than other surgical interventions, such as convection-enhanced drug delivery, and can be safer than other therapeutic options such as deep brain stimulation. CSF solute transport has been investigated in several studies. Early clinical studies in humans showed that intrathecal and intracerebroventricular administration of small, lipidsoluble molecules did not result in efficient CNS tissue penetration.113, 114 However, recent studies have demonstrated strong evidence that IDD might be ideal for the delivery of therapeutic proteins with large biomolecules.115 Numerous animal studies have shown that leveraging the CSF to CNS pathway can result in widespread distribution of therapeutic agents in brain parenchyma.115-119 Pharmacokinetics and bioavailability of therapeutic

I. PHYSIOLOGY OF NERVOUS SYSTEM DRUG DELIVERY

82

5. ANATOMY AND PHYSIOLOGY OF CEREBROSPINAL FLUID DYNAMICS

FIG. 5 Numerical simulation of intrathecal cerebrospinal fluid (CSF) dynamics by Khani et al.96 (A) Reynolds number, computed based on hydraulic diameter along the model. (B) Three-dimensional geometric visualization of intrathecal space with 31 pairs of anatomically realistic dorsal and ventral nerve root pairs. (C) Numerical prediction of CSF velocity profiles around the spinal cord at 90 ms after cardiac systole (note: CSF flow is nonuniform along the spinal SAS). (D) Visualization of velocity streamlines in the cervical spine show vortices that form around spinal cord nerve roots during CSF flow reversal.

enzymes administered intrathecally have also been evaluated in experimental studies through direct measurements and noninvasive imaging techniques.120 Numerical modeling has helped elucidate how a net motion of particle tracers can occur along the spine while the CSF time-averaged flow (cyclic average flow rate at any cross section) can be zero. This net motion of particles has been reported in radionuclide tracer studies by Di Chiro121 and others. In order to investigate this phenomenon, Sanchez et al.122 formulated an anatomically idealized numerical model of the intrathecal space and identified that bulk CSF circulation along the spine, or localized “steady-streaming” CSF motion, I. PHYSIOLOGY OF NERVOUS SYSTEM DRUG DELIVERY

REFERENCES

83

can result due to convective acceleration. Local steady-streaming CSF velocities on one side of the spinal canal were found to reach up to 1 mm/s, depending on eccentricity of the spinal cord. Khani et al.96 also corroborated these findings in a numerical model of the intrathecal space with anatomically realistic spinal cord geometry and nonuniform CSF pulsation. They found similar degrees of steady-streaming CSF velocities, with a complex steady-streaming velocity profile that was affected by the presence of spinal cord nerve roots and spinal curvature. Together, these numerical studies provide a mechanistic explanation for radionuclide tracer studies that indicate net CSF flow direction within the CSF system. Variational analysis of different parameters involved in IDD has been carried out in multiple experimental and numerical studies. Using an in vitro model, Nelissen123 investigated CSF dynamics around a catheter tip, and reported the adjacent flow vortices to be the main drivers of drug movement. The first numerical model of IDD was developed by Myers,124 based on a three-dimensional geometry of the spinal SAS. This study reported that lower values for the ratio of the cross-sectional dimension of the spinal SAS to the diameter of the catheter can result in more uniform drug distribution. More recent simulation studies with varying degrees of anatomical detail and physiological accuracy have evaluated the impact of various parameters on IDD. These parameters include injection rate,10, 125 catheter geometry and position,10 CSF flow stroke volume and frequency,126 anatomical microstructures,127 and drug diffusion properties.11 Numerical models were also implemented to evaluate the drug transport in CNS tissue.128-130 Cerebrospinal fluid dynamics are spatially and temporally complex due to the plethora of underlying physiologic and anatomic factors that govern its motion. Noninvasive MRI has been applied in many studies in an effort to objectively quantify volumes and flow velocities in the CSF system, but much remains to be known and confirmed under both physiological and pathophysiological conditions. Multidisciplinary research aimed to deepen our understanding of CSF, in combination with technological advances, will inevitably help develop new treatment strategies for patients suffering from the many pathologies in which CSF alterations are considered an important factor.

Acknowledgment The authors thank Mohammadreza Khani, Lucas Sass, Nathan Schiele, Sophia Theodossiou, Claire Majors, Gabryel Conley Natividad, Ann Norton, and Suraj Thyagaraj for assistance with images used in figures.

Funding statement This work was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences (NIGMS) of the National Institutes of health (NIH) under Grant #P20GM1033408 and #4U54GM10494404TBD, The National Institute of Mental Health Grant #1R44MH112210-01A1, University of Idaho Vandal Ideas Project, and American Syringomyelia and Chiari Alliance Project.

References 1. Bloomfield IG, Johnston IH, Bilston LE. Effects of proteins, blood cells and glucose on the viscosity of cerebrospinal fluid. Pediatr Neurosurg. 1998;28(5):246-251. 2. Weller RO. Pathology of cerebrospinal fluid and interstitial fluid of the CNS: significance for Alzheimer disease, prion disorders and multiple sclerosis. J Neuropathol Exp Neurol. 1998;57(10):885-894.

I. PHYSIOLOGY OF NERVOUS SYSTEM DRUG DELIVERY

84

5. ANATOMY AND PHYSIOLOGY OF CEREBROSPINAL FLUID DYNAMICS

3. Bradley Jr. WG, Kortman KE, Burgoyne B. Flowing cerebrospinal fluid in normal and hydrocephalic states: appearance on MR images. Radiology. 1986;159(3):611-616. 4. Bradley Jr. WG, Scalzo D, Queralt J, Nitz WN, Atkinson DJ, Wong P. Normal-pressure hydrocephalus: evaluation with cerebrospinal fluid flow measurements at MR imaging. Radiology. 1996;198(2):523-529. 5. Bunck AC, Kroger JR, Juttner A, et al. Magnetic resonance 4D flow characteristics of cerebrospinal fluid at the craniocervical junction and the cervical spinal canal. Eur Radiol. 2011;21(8):1788-1796. 6. Shaffer N, Martin BA, Loth F. Cerebrospinal fluid hydrodynamics in type I Chiari malformation. Neurol Res. 2011;33(3):247-260. 7. Shaffer N, Martin BA, Rocque B, et al. Cerebrospinal fluid flow impedance is elevated in type I Chiari malformation. J Biomech Eng. 2013;136(2) 021012. 8. Clarke EC, Stoodley MA, Bilston LE. Changes in temporal flow characteristics of CSF in Chiari malformation type I with and without syringomyelia: implications for theory of syrinx development clinical article. J Neurosurg. 2013;118(5):1135-1140. 9. Stoodley MA, Gutschmidt B, Jones NR. Cerebrospinal fluid flow in an animal model of noncommunicating syringomyelia. Neurosurgery. 1999;44(5):1065-1075 [discussion 1075-1066]. 10. Haga PT, Pizzichelli G, Mortensen M, et al. A numerical investigation of intrathecal isobaric drug dispersion within the cervical subarachnoid space. PLoS One. 2017;12(3). 11. Pizzichelli G, Kehlet B, Evju O, et al. Numerical study of intrathecal drug delivery to a permeable spinal cord: effect of catheter position and angle. Comput Methods Biomech Biomed Engin. 2017;1-10. 12. Tangen KM, Leval R, Mehta AI, Linninger AA. Computational and in vitro experimental investigation of intrathecal drug distribution: parametric study of the effect of injection volume, cerebrospinal fluid pulsatility, and drug uptake. Anesth Analg. 2017;124(5):1686-1696. 13. Tangen K, Narasimhan NS, Sierzega K, Preden T, Alaraj A, Linninger AA. Clearance of subarachnoid hemorrhage from the cerebrospinal fluid in computational and in vitro models. Ann Biomed Eng. 2016;44(12):3478-3494. 14. Bechter K, Schreiner V, Herzog S, et al. Cerebrospinal fluid filtration as experimental therapy in therapy refractory psychoses in Borna disease virus seropositive patients. Therapeutic effects, findings. Psychiatr Prax. 2003; 30(suppl 2):S216-S220. 15. Meylaerts SA, Kalkman CJ, de Haan P, Porsius M, Jacobs MJ. Epidural versus subdural spinal cord cooling: cerebrospinal fluid temperature and pressure changes. Ann Thorac Surg. 2000;70(1):222-227 [discussion 228]. 16. Goetz T, Romero-Sierra C, Ethier R, Henriksen RN. Modeling of therapeutic dialysis of cerebrospinal fluid by epidural cooling in spinal cord injuries. J Neurotrauma. 1988;5(2):139-150. 17. Luciano MG, Dombrowski SM, Qvarlander S, et al. Novel method for dynamic control of intracranial pressure. J Neurosurg. 2017;126(5):1629-1640. 18. Levi Chazen J, Dyke JP, Holt RW, et al. Automated segmentation of MR imaging to determine normative central nervous system cerebrospinal fluid volumes in healthy volunteers. Clin Imaging. 2017;43:132-135. 19. Hodel J, Lebret A, Petit E, et al. Imaging of the entire cerebrospinal fluid volume with a multistation 3D SPACE MR sequence: feasibility study in patients with hydrocephalus. Eur Radiol. 2013;23(6):1450-1458. 20. Courchesne E, Chisum HJ, Townsend J, et al. Normal brain development and aging: quantitative analysis at in vivo MR imaging in healthy volunteers. Radiology. 2000;216(3):672-682. 21. Coffey CE, Lucke JF, Saxton JA, et al. Sex differences in brain aging: a quantitative magnetic resonance imaging study. Arch Neurol. 1998;55:169. Erratum in: Arch Neurol 1998 May;55(5):627. 22. Pfefferbaum A, Mathalon DH, Sullivan EV, Rawles JM, Zipursky RB, Lim KO. A quantitative magnetic resonance imaging study of changes in brain morphology from infancy to late adulthood. Arch Neurol. 1994; 51(9):874-887. 23. Sass LR, Khani M, Natividad GC, Tubbs RS, Baledent O, Martin BA. A 3D subject-specific model of the spinal subarachnoid space with anatomically realistic ventral and dorsal spinal cord nerve rootlets. Fluids Barriers CNS. 2017;14(1):36. 24. Guyton AC, Hall JE. Textbook of Medical Physiology. 9th ed. Philadelphia, PA: W.B. Saunders; 1996. 25. Davson H, Segal MB. Physiology of the CSF and Blood-Brain Barriers. Boca Raton, FL: CRC Press; 1996. 26. Johanson CE, Duncan III JA, Klinge PM, Brinker T, Stopa EG, Silverberg GD. Multiplicity of cerebrospinal fluid functions: new challenges in health and disease. Cerebrospinal Fluid Res. 2008;5:10. 27. Sakka L, Coll G, Chazal J. Anatomy and physiology of cerebrospinal fluid. Eur Ann Otorhinolaryngol Head Neck Dis. 2011;128(6):309-316.

I. PHYSIOLOGY OF NERVOUS SYSTEM DRUG DELIVERY

REFERENCES

85

28. Last RJ, Tompsett DH. Casts of the cerebral ventricles. Br J Surg. 1953;40(164):525-543. 29. Wyper DJ, Pickard JD, Matheson M. Accuracy of ventricular volume estimation. J Neurol Neurosurg Psychiatry. 1979;42(4):345-350. 30. Grant R, Condon B, Lawrence A, et al. Human cranial CSF volumes measured by MRI: sex and age influences. Magn Reson Imaging. 1987;5(6):465-468. 31. Killer HE, Laeng HR, Flammer J, Groscurth P. Architecture of arachnoid trabeculae, pillars, and septa in the subarachnoid space of the human optic nerve: anatomy and clinical considerations. Br J Ophthalmol. 2003; 87(6):777-781. 32. Scott G, Coats B. Microstructural characterization of the pia-arachnoid complex using optical coherence tomography. IEEE Trans Med Imaging. 2015;34(7):1452-1459. 33. Scott GG, Margulies SS, Coats B. Utilizing multiple scale models to improve predictions of extra-axial hemorrhage in the immature piglet. Biomech Model Mechanobiol. 2016;15(5):1101-1119. 34. Mortazavi MM, Quadri SA, Khan MA, et al. Subarachnoid Trabeculae: a comprehensive review of their embryology, histology, morphology and surgical significance. World Neurosurg. 2017;111:279-290. 35. Nauta HJ, Dolan E, Yasargil MG. Microsurgical anatomy of spinal subarachnoid space. Surg Neurol. 1983; 19(5):431-437. 36. Gottschalk A, Schmitz B, Mauer UM, et al. Dynamic visualization of arachnoid adhesions in a patient with idiopathic syringomyelia using high-resolution cine magnetic resonance imaging at 3 T. J Magn Reson Imaging. 2010;32(1):218-222. 37. Bradbury MWB. The Concept of a Blood-Brain Barrier. Chichester, NY: Wiley; 1979. 38. Mokri B. The Monro–Kellie hypothesis applications in CSF volume depletion. Neurology. 2001;56 (12):1746-1748. 39. Johnston M, Zakharov A, Koh L, Armstrong D. Subarachnoid injection of microfil reveals connections between cerebrospinal fluid and nasal lymphatics in the non-human primate. Neuropathol Appl Neurobiol. 2005; 31(6):632-640. 40. Knigge K, Joseph S, Schock D, et al. Role of the ventricular system in neuroendocrine processes: synthesis and distribution of thyrotropin releasing factor (TRF) in the hypothalamus and third ventricle. Can J Neurol Sci. 1974;1(01):74-84. 41. Davson H, Segal MB. Physiology of the CSF and Blood Brain Bariers. CRC-Press; 1995. 42. Segal M. Extracellular and cerebrospinal fluids. J Inherit Metab Dis. 1993;16(4):617-638. 43. Segal M, Pollay M. The secretion of cerebrospinal fluid. Exp Eye Res. 1977;25:127-148. 44. Iliff JJ, Wang M, Zeppenfeld DM, et al. Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain. J Neurosci. 2013;33(46):18190-18199. 45. Murlidharan G, Crowther A, Reardon RA, Song J, Asokan A. Glymphatic fluid transport controls paravascular clearance of AAV vectors from the brain. JCI Insight. 2016;1(14):e88034. 46. Simon MJ, Iliff JJ. Regulation of cerebrospinal fluid (CSF) flow in neurodegenerative, neurovascular and neuroinflammatory disease. Biochim Biophys Acta. 2016;1862(3):442-451. 47. Iliff JJ, Lee H, Yu M, et al. Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J Clin Invest. 2013;123(3):1299-1309. 48. Abbott NJ, Pizzo ME, Preston JE, Janigro D, Thorne RG. The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system? Acta Neuropathol. 2018;135(3):387-407. 49. Cserr HF. Role of secretion and bulk flow of brain interstitial fluid in brain volume regulation. Ann N Y Acad Sci. 1988;529(1):9-20. 50. Cushing H. Studies on the cerebro-spinal fluid: I. Introduction. J Med Res. 1914;31(1):1. 51. Dandy WE. Experimental hydrocephalus. Ann Surg. 1919;70(2):129. 52. Oresˇkovic D, Klarica M. The formation of cerebrospinal fluid: nearly a hundred years of interpretations and misinterpretations. Brain Res Rev. 2010;64(2):241-262. 53. Oreskovic D, Klarica M, Vukic M. Does the secretion and circulation of the cerebrospinal fluid really exist? Med Hypotheses. 2001;56(5):622-624. 54. Yamada S, Kelly E. Cerebrospinal fluid dynamics and the pathophysiology of hydrocephalus: new concepts. Semin Ultrasound CT MR. 2016;37(2):84-91. 55. Hammock MK, Milhorat TH. Recent studies on the formation of cerebrospinal fluid. Dev Med Child Neurol. 1973;15(s29):27-34.

I. PHYSIOLOGY OF NERVOUS SYSTEM DRUG DELIVERY

86

5. ANATOMY AND PHYSIOLOGY OF CEREBROSPINAL FLUID DYNAMICS

56. Milhorat T, Hammock M, Davis D, Fenstermacher J. Choroid plexus papilloma. Pediatr Neurosurg. 1976; 2(5):273-289. 57. Milhorat TH. Choroid plexus and cerebrospinal fluid production. Science. 1969;166(3912):1514-1516. 58. Milhorat TH. The third circulation revisited. J Neurosurg. 1975;42(6):628-645. 59. Milhorat TH, Hammock MK, Chien T, Davis DA. Normal rate of cerebrospinal fluid formation five years after bilateral choroid plexectomy: case report. J Neurosurg. 1976;44(6):735-739. 60. Bulat M, Klarica M. Recent insights into a new hydrodynamics of the cerebrospinal fluid. Brain Res Rev. 2011; 65(2):99-112. 61. O’Connell JE. The vascular factor in intracranial pressure and the maintenance of the cerebrospinal fluid circulation. Brain. 1943;66(3):204-228. 62. Enzmann D, Pelc N. Normal flow patterns of intracranial and spinal cerebrospinal fluid defined with phasecontrast cine MR imaging. Radiology. 1991;178(2):467-474. 63. Greitz D, Franck A, Nordell B. On the pulsatile nature of intracranial and spinal CSF-circulation demonstrated by MR imaging. Acta Radiol. 1993;34(4):321-328. 64. Nitz W, Bradley Jr W, Watanabe A, et al. Flow dynamics of cerebrospinal fluid: assessment with phase-contrast velocity MR imaging performed with retrospective cardiac gating. Radiology. 1992;183(2):395-405. 65. Scroth G, Klose U. Cerebrospinal fluid flow. I. Physiology of cardiac-related pulsation. Neuroradiology. 1992; 35(1):9. 66. Avezaat C, Van Eijndhoven J, Wyper D. Cerebrospinal fluid pulse pressure and intracranial volume-pressure relationships. J Neurol Neurosurg Psychiatry. 1979;42(8):687-700. 67. Portnoy HD, Chopp M. Cerebrospinal fluid pulse wave form analysis during hypercapnia and hypoxia. Neurosurgery. 1981;9(1):14-27. 68. Henry–Feugeas MC, Idy–Peretti I, Baledent O, et al. Origin of subarachnoid cerebrospinal fluid pulsations: a phase-contrast MR analysis. Magn Reson Imaging. 2000;18(4):387-395. 69. Wa˚hlin A, Ambarki K, Hauksson J, Birgander R, Malm J, Eklund A. Phase contrast MRI quantification of pulsatile volumes of brain arteries, veins, and cerebrospinal fluids compartments: repeatability and physiological interactions. J Magn Reson Imaging. 2012;35(5):1055-1062. 70. Freund M, Adwan M, Kooijman H, et al. Measurement of CSF flow in the spinal canal using MRI with an optimized MRI protocol: experimental and clinical studies. RoFo: Fortschritte auf dem Gebiete der Rontgenstrahlen und der Nuklearmedizin. 2001;173(4):306-314. 71. Marmarou A, Shulman K, LaMorgese J. Compartmental analysis of compliance and outflow resistance of the cerebrospinal fluid system. J Neurosurg. 1975;43(5):523-534. 72. Williams B. Simultaneous cerebral and spinal fluid pressure recordings. I. Technique, physiology, and normal results. Acta Neurochir. 1981;58(3–4):167-185. 73. Yamada S, Miyazaki M, Yamashita Y, et al. Influence of respiration on cerebrospinal fluid movement using magnetic resonance spin labeling. Fluids Barriers CNS. 2013;10(1):36. 74. Yildiz S, Thyagaraj S, Jin N, et al. Quantifying the influence of respiration and cardiac pulsations on cerebrospinal fluid dynamics using real-time phase-contrast MRI. J Magn Reson Imaging. 2017;46(2):431-439. 75. Dreha-Kulaczewski S, Joseph AA, Merboldt KD, Ludwig HC, Gartner J, Frahm J. Inspiration is the major regulator of human CSF flow. J Neurosci. 2015;35(6):2485-2491. 76. Chen L, Beckett A, Verma A, Feinberg DA. Dynamics of respiratory and cardiac CSF motion revealed with realtime simultaneous multi-slice EPI velocity phase contrast imaging. NeuroImage. 2015;122:281-287. 77. Guerci AD, Shi A-Y, Levin H, Tsitlik J, Weisfeldt ML, Chandra N. Transmission of intrathoracic pressure to the intracranial space during cardiopulmonary resuscitation in dogs. Circ Res. 1985;56(1):20-30. 78. Yannopoulos D, McKnite SH, Metzger A, Lurie KG. Intrathoracic pressure regulation for intracranial pressure management in normovolemic and hypovolemic pigs. Crit Care Med. 2006;34(12):S495-S500. 79. Bezuidenhout AF, Khatami D, Heilman CB, et al. Relationship between cough-associated changes in CSF flow and disease severity in chiari I malformation: an exploratory study using real-time MRI. AJNR Am J Neuroradiol. 2018;39(7):1267-1272. 80. Yiallourou TI, Daners MS, Kurtcuoglu V, et al. Continuous positive airway pressure alters cranial blood flow and cerebrospinal fluid dynamics at the craniovertebral junction. Interdiscip Neurosurg Adv Tech Case Manage. 2015; 2(3):152-159.

I. PHYSIOLOGY OF NERVOUS SYSTEM DRUG DELIVERY

REFERENCES

87

81. Yatsushiro S, Sunohara S, Takizawa K, Matsumae M, Kajihara N, Kuroda K. Characterization of cardiac- and respiratory-driven cerebrospinal fluid motions using correlation mapping with asynchronous 2-dimensional phase contrast technique. Conf Proc IEEE Eng Med Biol Soc. 2016;2016:3867-3870. 82. Takizawa K, Matsumae M, Sunohara S, Yatsushiro S, Kuroda K. Characterization of cardiac- and respiratorydriven cerebrospinal fluid motion based on asynchronous phase-contrast magnetic resonance imaging in volunteers. Fluids Barriers CNS. 2017;14(1):25. 83. Kalata W, Martin BA, Oshinski JN, Jerosch-Herold M, Royston TJ, Loth F. MR measurement of cerebrospinal fluid velocity wave speed in the spinal canal. IEEE Trans Biomed Eng. 2009;56(6):1765-1768. 84. Naidich TP, Altman NR, Gonzalez-Arias SM. Phase contrast cine magnetic resonance imaging: normal cerebrospinal fluid oscillation and applications to hydrocephalus. Neurosurg Clin N Am. 1993;4(4):677-705. 85. Bunck AC, Kroeger JR, Juettner A, et al. Magnetic resonance 4D flow analysis of cerebrospinal fluid dynamics in Chiari I malformation with and without syringomyelia. Eur Radiol. 2012;22(9):1860-1870. 86. Heidari Pahlavian S, Bunck AC, Thyagaraj S, et al. Accuracy of 4D flow measurement of cerebrospinal fluid dynamics in the cervical spine: an in vitro verification against numerical simulation. Ann Biomed Eng. 2016; 44(11):3202-3214. 87. Bhadelia RA, Patz S, Heilman C, et al. Cough-associated changes in CSF flow in Chiari I malformation evaluated by real-time MRI. AJNR Am J Neuroradiol. 2016;37(5):825-830. 88. Kurtcuoglu V, Soellinger M, Summers P, et al. Computational investigation of subject-specific cerebrospinal fluid flow in the third ventricle and aqueduct of Sylvius. J Biomech. 2007;40(6):1235-1245. 89. Quigley MF, Iskandar B, Quigley ME, Nicosia M, Haughton V. Cerebrospinal fluid flow in foramen magnum: temporal and spatial patterns at MR imaging in volunteers and in patients with Chiari I malformation. Radiology. 2004;232(1):229-236. 90. Martin BA, Reymond P, Novy J, Baledent O, Stergiopulos N. A coupled hydrodynamic model of the cardiovascular and cerebrospinal fluid system. Am J Physiol Heart Circ Physiol. 2012;302(7):H1492-H1509. 91. Loth F, Yardimci MA, Alperin N. Hydrodynamic modeling of cerebrospinal fluid motion within the spinal cavity. J Biomech Eng. 2001;123(1):71-79. 92. Helgeland A, Mardal KA, Haughton V, Reif BA. Numerical simulations of the pulsating flow of cerebrospinal fluid flow in the cervical spinal canal of a Chiari patient. J Biomech. 2014;47(5):1082-1090. 93. Gupta S, Soellinger M, Boesiger P, Poulikakos D, Kurtcuoglu V. Three-dimensional computational modeling of subject-specific cerebrospinal fluid flow in the subarachnoid space. J Biomech Eng. 2009;131(2). 94. Gupta S, Soellinger M, Grzybowski DM, et al. Cerebrospinal fluid dynamics in the human cranial subarachnoid space: an overlooked mediator of cerebral disease. I. Computational model. J R Soc Interface. 2010; 7(49):1195-1204. 95. Iskandar BJ, Quigley M, Haughton VM. Foramen magnum cerebrospinal fluid flow characteristics in children with Chiari I malformation before and after craniocervical decompression. J Neurosurg. 2004;101(Suppl 2): 169-178. 96. Khani M, Sass L, Xing T, Sharp MK, Baledent O, Martin B. Anthropomorphic model of intrathecal cerebrospinal fluid dynamics within the spinal subarachnoid space: spinal cord nerve roots increase steady-streaming. J Biomech Eng. 2018. 97. Pahlavian SH, Loth F, Luciano M, Oshinski J, Martin BA. Neural tissue motion impacts cerebrospinal fluid dynamics at the cervical medullary junction: a patient-specific moving-boundary computational model. Ann Biomed Eng. 2015;43(12):2911-2923. 98. Stockman HW. Effect of anatomical fine structure on the flow of cerebrospinal fluid in the spinal subarachnoid space. J Biomech Eng. 2006;128(1):106-114. 99. Linge SO, Haughton V, Lovgren AE, Mardal KA, Helgeland A, Langtangen HP. Effect of tonsillar herniation on cyclic CSF flow studied with computational flow analysis. AJNR Am J Neuroradiol. 2011; 32(8):1474-1481. 100. Bertram C, Bilston L, Stoodley M. Tensile radial stress in the spinal cord related to arachnoiditis or tethering: a numerical model. Med Biol Eng Comput. 2008;46(7):701-707. 101. Martin BA, Kalata W, Shaffer N, Fischer P, Luciano M, Loth F. Hydrodynamic and longitudinal impedance analysis of cerebrospinal fluid dynamics at the craniovertebral junction in type I Chiari malformation. PLoS One. 2013;8(10).

I. PHYSIOLOGY OF NERVOUS SYSTEM DRUG DELIVERY

88

5. ANATOMY AND PHYSIOLOGY OF CEREBROSPINAL FLUID DYNAMICS

102. Cirovic S. A coaxial tube model of the cerebrospinal fluid pulse propagation in the spinal column. J Biomech Eng. 2009;131(2). 103. Papisov MI, Belov VV, Gannon KS. Physiology of the intrathecal bolus: the leptomeningeal route for macromolecule and particle delivery to CNS. Mol Pharm. 2013;10(5):1522-1532. 104. Iliff JJ, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med. 2012;4(147):147ra111. 105. Lu CT, Zhao YZ, Wong HL, Cai J, Peng L, Tian XQ. Current approaches to enhance CNS delivery of drugs across the brain barriers. Int J Nanomedicine. 2014;9:2241-2256. 106. Patel T, Zhou JB, Piepmeier JM, Saltzman WM. Polymeric nanoparticles for drug delivery to the central nervous system. Adv Drug Deliv Rev. 2012;64(7):701-705. 107. Deepa P, Shahani N, Alladi PA, et al. Down regulation of trophic factors in neonatal rat spinal cord after administration of cerebrospinal fluid from sporadic amyotrophic lateral sclerosis patients. J Neural Transm (Vienna). 2011;118(4):531-538. 108. Watanabe Y, Kazuki Y, Kazuki K, et al. Use of a human artificial chromosome for delivering trophic factors in a rodent model of amyotrophic lateral sclerosis. Mol Ther Nucleic Acids. 2015;4. 109. Bottros MM, Christo PJ. Current perspectives on intrathecal drug delivery. J Pain Res. 2014;7:615-626. 110. Bhatia G, Lau ME, Koury KM, Gulur P. Intrathecal drug delivery (ITDD) systems for cancer pain. F1000Res. 2013;2:96. 111. Chen L, Jiang M, Pei L. Comparison of three methods of drug delivery in the rat lumbar spinal subarachnoid space. Anat Rec (Hoboken). 2012;295(7):1212-1220. 112. Miller TM, Pestronk A, David W. An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol. 2013;12:435. Erratum in: Lancet Neurol: 2013;12(5):423. 113. Greene HL, Hug G, Schubert WK. Metachromatic leukodystrophy: treatment with arylsulfatase-a. Arch Neurol. 1969;20(2):147-153. 114. Ghersi-Egea JF, Gorevic PD, Ghiso J, Frangione B, Patlak CS, Fenstermacher JD. Fate of cerebrospinal fluid-borne amyloid β-peptide: rapid clearance into blood and appreciable accumulation by cerebral arteries. J Neurochem. 1996;67(2):880-883. 115. Calias P, Banks WA, Begley D, Scarpa M, Dickson P. Intrathecal delivery of protein therapeutics to the brain: a critical reassessment. Pharmacol Ther. 2014;144(2):114-122. 116. Kakkis E, McEntee M, Vogler C, et al. Intrathecal enzyme replacement therapy reduces lysosomal storage in the brain and meninges of the canine model of MPS I. Mol Genet Metab. 2004;83(1–2):163-174. 117. Calias P, Papisov M, Pan J, et al. CNS penetration of intrathecal-lumbar idursulfase in the monkey, dog and mouse: implications for neurological outcomes of lysosomal storage disorder. PLoS One. 2012;7(1). 118. Dickson P, McEntee M, Vogler C, et al. Intrathecal enzyme replacement therapy: successful treatment of brain disease via the cerebrospinal fluid. Mol Genet Metab. 2007;91(1):61-68. 119. Hemsley KM, Norman EJ, Crawley AC, et al. Effect of cisternal sulfamidase delivery in MPS IIIA huntaway dogs—a proof of principle study. Mol Genet Metab. 2009;98(4):383-392. 120. Xie H, Chung JK, Mascelli MA, McCauley TG. Pharmacokinetics and bioavailability of a therapeutic enzyme (idursulfase) in cynomolgus monkeys after intrathecal and intravenous administration. PLoS One. 2015;10(4). 121. Dichiro G. Movement of the cerebrospinal fluid in human beings. Nature. 1964;204:290-291. 122. Sanchez AL, Martinez-Bazan C, Gutierrez-Montes C, et al. On the bulk motion of the cerebrospinal fluid in the spinal canal. J Fluid Mech. 2018;841:203-227. 123. Nelissen RM. Fluid Mechanics of Intrathecal Drug Delivery; 2008. 158 pp. 124. Myers MR. A numerical investigation into factors affecting anesthetic distribution during spinal anesthesia. J Biomech. 1996;29(2):139-149. 125. Kuttler A, Dimke T, Kern S, Helmlinger G, Stanski D, Finelli LA. Understanding pharmacokinetics using realistic computational models of fluid dynamics: biosimulation of drug distribution within the CSF space for intrathecal drugs. J Pharmacokinet Pharmacodyn. 2010;37(6):629-644. 126. Hsu Y, Hettiarachchi HD, Zhu DC, Linninger AA. The frequency and magnitude of cerebrospinal fluid pulsations influence intrathecal drug distribution: key factors for interpatient variability. Anesth Analg. 2012; 115(2):386-394.

I. PHYSIOLOGY OF NERVOUS SYSTEM DRUG DELIVERY

REFERENCES

89

127. Tangen KM, Hsu Y, Zhu DC, Linninger AA. CNS wide simulation of flow resistance and drug transport due to spinal microanatomy. J Biomech. 2015;48(10):2144-2154. 128. Linninger AA, Somayaji MR, Mekarski M, Zhang L. Prediction of convection-enhanced drug delivery to the human brain. J Theor Biol. 2008;250(1):125-138. 129. Sarntinoranont M, Banerjee RK, Lonser RR, Morrison PF. A computational model of direct interstitial infusion of macromolecules into the spinal cord. Ann Biomed Eng. 2003;31(4):448-461. 130. Støverud KH, Darcis M, Helmig R, Hassanizadeh SM. Modeling concentration distribution and deformation during convection-enhanced drug delivery into brain tissue. Transp Porous Media. 2012;92(1):119-143.

I. PHYSIOLOGY OF NERVOUS SYSTEM DRUG DELIVERY