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This paper presents a mathematical model of the global, arterio-venous circulation in the entire human body, coupled to a refined description of the cerebrospinal fluid (CSF) dynamics in the craniospinal cavity. The present model represents a substantially revised version of the original Müller-Toro mathematical model. It includes one-dimensional (1D), non-linear systems of partial differential equations for 323 major blood vessels and 85 zero-dimensional, differential-algebraic systems for the remaining components. Highlights include the myogenic mechanism of cerebral blood regulation; refined vasculature for the inner ear, the brainstem and the cerebellum; and viscoelastic, rather than purely elastic, models for all blood vessels, arterial and venous. The derived 1D parabolic systems of partial differential equations for all major vessels are approximated by hyperbolic systems with stiff source terms following a relaxation approach. A major novelty of this paper is the coupling of the circulation, as described, to a refined description of the CSF dynamics in the craniospinal cavity, following Linninger et al. The numerical solution methodology employed to approximate the hyperbolic non-linear systems of partial differential equations with stiff source terms is based on the Arbitrary DERivative Riemann problem finite volume framework, supplemented with a well-balanced formulation, and a local time stepping procedure. The full model is validated through comparison of computational results against published data and bespoke MRI measurements. Then we present two medical applications: (i) transverse sinus stenoses and their relation to Idiopathic Intracranial Hypertension; and (ii) extra-cranial venous strictures and their impact in the inner ear circulation, and its implications for Ménière's disease.

BACKGROUND: Among diffusely infiltrative gliomas in adults, 20%–30% contain a point mutation in isocitrate dehydrogenase 1 (IDH1(mut)), which increases production of D-2-hydroxyglutarate (D2HG). This is so efficient that D2HG often reaches 30 mM within IDH1(mut) gliomas. Yet, while up to 100 µM D2HG can be detected in the circulating cerebrospinal fluid of IDH1(mut) glioma patients, the exposure of nonneoplastic cells within and surrounding an IDH1(mut) glioma to D2HG is unknown and difficult to measure directly. METHODS: Conditioned medium from patient-derived wild type IDH1 (IDH1(wt)) and IDH1(mut) glioma cells was analyzed for D2HG by liquid chromatography–mass spectrometry (LC-MS). Mathematical models of D2HG release and diffusion around an IDH1(mut) glioma were independently generated based on fluid dynamics within the brain and on previously reported intratumoral and cerebrospinal D2HG concentrations. RESULTS: LC-MS analysis indicates that patient-derived IDH1(mut) glioma cells release 3.7–97.0 pg D2HG per cell per week. Extrapolating this to an average-sized tumor (30 mL glioma volume and 1 × 10(8) cells/mL tumor), the rate of D2HG release by an IDH1(mut) glioma (S(A)) is estimated at 3.2–83.0 × 10(−12) mol/mL/sec. Mathematical models estimate an S(A) of 2.9–12.9 × 10(−12) mol/mL/sec, within the range of the in vitro LC-MS data. In even the most conservative of these models, the extracellular concentration of D2HG exceeds 3 mM within a 2 cm radius from the center of an IDH1(mut) glioma. CONCLUSIONS: The microenvironment of an IDH1(mut) glioma is likely being exposed to high concentrations of D2HG, in the low millimolar range. This has implications for understanding how D2HG affects nonneoplastic cells in an IDH1(mut) glioma.

Intrathecal drug delivery is an attractive option to circumvent the blood-brain barrier for pain management through its increased efficacy of pain relief, reduction in adverse side effects, and cost-effectiveness. Unfortunately, there are limited guidelines for physicians to choose infusion or drug pump settings to administer therapeutic doses to specific regions of the spine or the brain. Although empiric trialing of intrathecal drugs is critical to determine the sustained side effects, currently there is no inexpensive in vitro method to guide the selection of spinal drug delivery parameters. The goal of this study is to demonstrate current computational capabilities to predict drug biodistribution while varying 3 parameters: (1) infusion settings, (2) drug chemistry, and (3) subject-specific anatomy and cerebrospinal fluid dynamics. We will discuss strategies to systematically optimize these 3 parameters to administer drug molecules to targeted tissue locations in the central nervous system.We acquired anatomical data from magnetic resonance imaging (MRI) and velocity measurements in the spinal cerebrospinal fluid with CINE-MRI for 2 subjects. A bench-top surrogate of the subject-specific central nervous system was constructed to match measured anatomical dimensions and volumes. We generated a computational mesh for the bench-top model. Idealized simulations of tracer distribution were compared with bench-top measurements for validation. Using reconstructions from MRI data, we also introduced a subject-specific computer model for predicting drug spread for the human volunteer.MRI velocity measurements at 3 spinal regions of interest reasonably matched the simulated flow fields in a subject-specific computer mesh. Comparison between the idealized spine computations and bench-top tracer distribution experiments demonstrate agreement of our drug transport predictions to this physical model. Simulated multibolus drug infusion theoretically localizes drug to the cervical and thoracic region. Continuous drug pump and single bolus injection were successful to target the lumbar spine in the simulations. The parenchyma might be targeted suitably by multiple boluses followed by a flush infusion. We present potential guidelines that take into account drug specific kinetics for tissue uptake, which influence the speed of drug dispersion in the model and potentially influence tissue targeting.We present potential guidelines considering drug-specific kinetics of tissue uptake, which determine the speed of drug dispersion and influence tissue targeting. However, there are limitations to this analysis in that the parameters were obtained from an idealized healthy patient in a supine position. The proposed methodology could assist physicians to select clinical infusion parameters for their patients and provide guidance to optimize treatment algorithms. In silico optimization of intrathecal drug delivery therapies presents the first steps toward a possible care paradigm in the future that is specific to personalized patient anatomy and diseases.

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Cerebrospinal fluid (CSF) is not stagnant but displays fascinating oscillatory flow patterns inside the ventricular system and reversing fluid exchange between the cranial vault and spinal compartment. This review provides an overview of the current knowledge of pulsatile CSF motion. Observations contradicting classical views about its bulk production and clearance are highlighted. A clinical account of diseases of abnormal CSF flow dynamics, including hydrocephalus, syringomyelia, Chiari malformation type 1, and pseudotumor cerebri, is also given. We survey medical imaging modalities used to observe intracranial dynamics in vivo. Additionally, we assess the state of the art in predictive models of CSF dynamics. The discussion addresses open questions regarding CSF dynamics as they relate to the understanding and management of diseases.

Extracranial cerebrospinal fluid (CSF) shunt obstruction is one of the most important problems in hydrocephalus patient management. Despite ongoing research into better shunt design, robust and reliable detection of shunt malfunction remains elusive. The authors present a novel method of correlating degree of tissue ingrowth into ventricular CSF drainage catheters with internal electrical impedance. The impedance based sensor is able to continuously monitor shunt patency using intraluminal electrodes. Prototype obstruction sensors were fabricated for in-vitro analysis of cellular ingrowth into a shunt under static and dynamic flow conditions. Primary astrocyte cell lines and C6 glioma cells were allowed to proliferate up to 7 days within a shunt catheter and the impedance waveform was observed. During cell ingrowth a significant change in the peak-to-peak voltage signal as well as the root-mean-square voltage level was observed, allowing the impedance sensor to potentially anticipate shunt malfunction long before it affects fluid drainage. Finite element modeling was employed to demonstrate that the electrical signal used to monitor tissue ingrowth is contained inside the catheter lumen and does not endanger tissue surrounding the shunt. These results may herald the development of “next generation” shunt technology that allows prediction of malfunction before it affects patient outcome.

Intrathecal delivery of opiates directly into the cerebrospinal fluid (CSF) is the oldest technique for the delivery of anesthetics to the central nervous system (CNS). Despite the long empirical experience with spinal anesthetics, the relationships between CSF dynamics and biodistribution of intrathecally delivered drugs are complex and the mechanisms that lead to this complex distribution are poorly understood. First-principle models of fluid mechanics have been created to elucidate complex flow patterns in subject-specific computations. It has also been shown that complex CSF flow patterns are responsible for the vigorous mixing effects that govern the biodistribution of intrathecally delivered drugs. This chapter aims to link CSF flow patterns to expected drug dispersion. However, predicting the biodistribution of drugs is not an easy task. Due to the difficulty of access to the CNS, computational analysis capable of interpreting spatial and temporally distributed imaging data plays a vital role in elucidating pharmacokinetics and pharmacodynamics of intrathecal drug delivery. We review progress in our lab as well as the open literature to give a snapshot of this very active field. The chapter aims to understand better the relationship between infusion parameters and achievable drug distribution. In the near future we expect that the integration of imaging data with first-principle computational models such as those described here will enable us to design more effective drug administration strategies so that specific cells and tissue in any point of the CNS can be more effectively targeted than is the case with existing methods. We close by pointing out research directions that will pave the way for these imminent developments.

Experimental evidence has cast doubt on the classical model of river-like cerebrospinal fluid (CSF) flow from the choroid plexus to the arachnoid granulations. We propose a novel model of water transport through the parenchyma from the microcirculation as driven by Starling forces. This model investigates the effect of osmotic pressure on water transport between the cerebral vasculature, the extracellular space (ECS), the perivascular space (PVS), and the CSF. A rigorous literature search was conducted focusing on experiments which alter the osmolarity of blood or ventricles and measure the rate of CSF production. Investigations into the effect of osmotic pressure on the volume of ventricles and the flux of ions in the blood, choroid plexus epithelium, and CSF are reviewed. Increasing the osmolarity of the serum via a bolus injection completely inhibits nascent fluid flow production in the ventricles. A continuous injection of a hyperosmolar solution into the ventricles can increase the volume of the ventricle by up to 125%. CSF production is altered by 0.231 μL per mOsm in the ventricle and by 0.835 μL per mOsm in the serum. Water flux from the ECS to the CSF is identified as a key feature of intracranial dynamics. A complete mathematical model with all equations and scenarios is fully described, as well as a guide to constructing a computational model of intracranial water balance dynamics. The model proposed in this article predicts the effects the osmolarity of ECS, blood, and CSF on water flux in the brain, establishing a link between osmotic imbalances and pathological conditions such as hydrocephalus and edema.

Intrathecal (IT) drug delivery is a preferred treatment for chronic pain, brain cancers and spasticity. However, the application of IT drug delivery treatment is still limited by the large patient-to-patient variations and numerous kinds of rare genetic diseases. A fast, relatively cheap and subject-specific in-vitro method to study the drug bio-dispersion mechanism and optimize the intrathecal drug therapies for individual patients is in great need. In this study, we will investigate the model design and additive manufacturing process for producing a subject-specific spine model, which will simulate the interaction of the real human spine with cerebrospinal fluid (CSF). Research issues including watertight 3D printable model construction and 3D printing of anatomical accurate, physiological functional spine models are discussed in this paper. A pipeline of additive manufacturing in-vitro subject-specific models for study of cerebrospinal fluid and drug transport in spine is presented.

Object Experimental data about the evolution of intracranial volume and pressure in cases of hydrocephalus are limited due to the lack of available monitoring techniques. In this study, the authors validate intracranial CSF volume measurements within the lateral ventricle, while simultaneously using impedance sensors and pressure transducers in hydrocephalic animals. Methods A volume sensor was fabricated and connected to a catheter that was used as a shunt to withdraw CSF. In vitro bench-top calibration experiments were created to provide data for the animal experiments and to validate the sensors. To validate the measurement technique in a physiological system, hydrocephalus was induced in weanling rats by kaolin injection into the cisterna magna. At 28 days after induction, the sensor was implanted into the lateral ventricles. After sealing the skull using dental cement, an acute CSF drainage/infusion protocol consisting of 4 sequential phases was performed with a pump. Implant location was confirmed via radiography using intraventricular iohexol contrast administration. Results Controlled CSF shunting in vivo with hydrocephalic rats resulted in precise and accurate sensor measurements (r = 0.98). Shunting resulted in a 17.3% maximum measurement error between measured volume and actual volume as assessed by a Bland-Altman plot. A secondary outcome confirmed that both ventricular volume and intracranial pressure decreased during CSF shunting and increased during infusion. Ventricular enlargement consistent with successful hydrocephalus induction was confirmed using imaging, as well as postmortem. These results indicate that volume monitoring is feasible for clinical cases of hydrocephalus. Conclusions This work marks a departure from traditional shunting systems currently used to treat hydrocephalus. The overall clinical application is to provide alternative monitoring and treatment options for patients. Future work includes development and testing of a chronic (long-term) volume monitoring system.

Object The dynamics of fluid flow in normal pressure hydrocephalus (NPH) are poorly understood. Normally, CSF flows out of the brain through the ventricles. However, ventricular enlargement during NPH may be caused by CSF backflow into the brain through the ventricles. A previous study showed this reversal of flow; in the present study, the authors provide additional clinical data obtained in patients with NPH and supplement these data with computer simulations to better understand the CSF flow and ventricular wall displacement and emphasize its clinical implications. Methods Three NPH patients and 1 patient with aqueductal stenosis underwent cine phase-contrast MR imaging (cine MR imaging) for measurement of CSF flow and ventricle wall movement during the cardiac cycle. These data were compared to data previously obtained in 8 healthy volunteers. The CSF flow measurements were obtained at the outlet of the aqueduct of Sylvius. Calculation of the ventricular wall movement was determined from the complete set of cine MR images obtained axially at the middle of the lateral ventricle. The data were obtained before and after CSF removal with a ventriculoperitoneal shunt with an adjustable valve. To supplement the clinical data, a computational model was used to predict the transmural pressure and flow. Results In healthy volunteers, net CSF aqueductal flow was 1.2 ml/minute in the craniocaudal direction. In patients with NPH, the net CSF flow was in the opposite direction—the caudocranial direction—before shunt placement. After shunting, the magnitude of the abnormal fluid flow decreased or reversed, with the flow resembling the normal flow patterns observed in healthy volunteers. Conclusions The authors' MR imaging–based measurements of the CSF flow direction and lateral ventricle volume size change and the results of computer modeling of fluid dynamics lead them to conclude that the directional pattern and magnitude of CSF flow in patients with NPH may be an indication of the disease state. This has practical implications for shunt design and understanding the mechanisms that produce hydrocephalus.

Knowledge of intracranial ventricular volume is important for the treatment of hydrocephalus, a disease in which cerebrospinal fluid (CSF) accumulates in the brain. Current monitoring options involve MRI or pressure monitors (InSite, Medtronic). However, there are no existing methods for continuous cerebral ventricle volume measurements. In order to test a novel impedance sensor for direct ventricular volume measurements, we present a model that emulates the expansion of the lateral ventricles seen in hydrocephalus. To quantify the ventricular volume, sensor prototypes were fabricated and tested with this experimental model. Fluid was injected and withdrawn cyclically in a controlled manner and volume measurements were tracked over 8 h. Pressure measurements were also comparable to conditions seen clinically. The results from the bench-top model served to calibrate the sensor for preliminary animal experiments. A hydrocephalic rat model was used to validate a scaled-down, microfabricated prototype sensor. CSF was removed from the enlarged ventricles and a dynamic volume decrease was properly recorded. This method of testing new designs on brain phantoms prior to animal experimentation accelerates medical device design by determining sensor specifications and optimization in a rational process.

Spinal microstructures are known to substantially affect cerebrospinal fluid patterns, yet their actual impact on flow resistance has not been quantified. Because the length scale of microanatomical aspects is below medical image resolution, their effect on flow is difficult to observe experimentally. Using a computational fluid mechanics approach, we were able to quantify the contribution of micro-anatomical aspects on cerebrospinal fluid (CSF) flow patterns and flow resistance within the entire central nervous system (CNS). Cranial and spinal CSF filled compartments were reconstructed from human imaging data; microscopic trabeculae below the image detection threshold were added artificially. Nerve roots and trabeculae were found to induce regions of microcirculation, whose location, size and vorticity along the spine were characterized. Our CFD simulations based on volumetric flow rates acquired with Cine Phase Contrast MRI in a normal human subject suggest a 2-2.5 fold increase in pressure drop mainly due to arachnoid trabeculae. The timing and phase lag of the CSF pressure and velocity waves along the spinal canal were also computed, and a complete spatio-temporal map encoding CSF volumetric flow rates and pressure was created. Micro-anatomy induced fluid patterns were found responsible for the rapid caudo-cranial spread of an intrathecally administered drug. The speed of rostral drug dispersion is drastically accelerated through pulsatile flow around microanatomy induced vortices. Exploring massive parallelization on a supercomputer, the feasibility of computational drug transport studies was demonstrated. CNS-wide simulations of intrathecal drugs administration can become a practical tool for in silico design, interspecies scaling and optimization of experimental drug trials.

Intrathecal (IT) drug delivery is a standard technique which involves direct injection of drugs into the cerebrospinal fluid (CSF)-filled space within the spinal canal to treat many diseases of the central nervous system. Currently, in order to reach the therapeutic drug concentration at certain locations within the spinal canal, high drug doses are used. With no method to deliver the large drug doses locally, current IT drug delivery treatments are hindered with wide drug distributions throughout the central nervous system (CNS) which cause harmful side effects. In order to overcome the current limitations of IT drug delivery, we have developed the novel method of intrathecal magnetic drug targeting (IT-MDT). Gold-coated magnetite nanoparticles are infused into a physiologically and anatomically relevant in vitro human spine model and then targeted to a specific site using external magnetic fields, resulting in a substantial increase in therapeutic nanoparticle localization at the site of interest. Experiments aiming to determine the effect of key parameters such as magnet strength, duration of magnetic field exposure, location of magnetic field, and ferrous implants on the collection efficiency of our superparamagnetic nanoparticles in the targeting region were performed. Our experiments indicate that intrathecal magnetic drug targeting and implant-assisted IT-MDT are promising techniques for concentrating and localizing drug-functionalized nanoparticles at required target sites within the spinal canal for potential treatment of diseases affecting the central nervous system.

Aquaporin-4 (AQP4) channels play an important role in brain water homeostasis. Water transport across plasma membranes has a critical role in brain water exchange of the normal and the diseased brain. AQP4 channels are implicated in the pathophysiology of hydrocephalus, a disease of water imbalance that leads to CSF accumulation in the ventricular system. Many molecular aspects of fluid exchange during hydrocephalus have yet to be firmly elucidated, but review of the literature suggests that modulation of AQP4 channel activity is a potentially attractive future pharmaceutical therapy. Drug therapy targeting AQP channels may enable control over water exchange to remove excess CSF through a molecular intervention instead of by mechanical shunting. This article is a review of a vast body of literature on the current understanding of AQP4 channels in relation to hydrocephalus, details regarding molecular aspects of AQP4 channels, possible drug development strategies, and limitations. Advances in medical imaging and computational modeling of CSF dynamics in the setting of hydrocephalus are summarized. Algorithmic developments in computational modeling continue to deepen the understanding of the hydrocephalus disease process and display promising potential benefit as a tool for physicians to evaluate patients with hydrocephalus.

Object Experimental data about the evolution of intracranial volume and pressure in cases of hydrocephalus are limited due to the lack of available monitoring techniques. In this study, the authors validate intracranial CSF volume measurements within the lateral ventricle, while simultaneously using impedance sensors and pressure transducers in hydrocephalic animals. Methods A volume sensor was fabricated and connected to a catheter that was used as a shunt to withdraw CSF. In vitro bench-top calibration experiments were created to provide data for the animal experiments and to validate the sensors. To validate the measurement technique in a physiological system, hydrocephalus was induced in weanling rats by kaolin injection into the cisterna magna. At 28 days after induction, the sensor was implanted into the lateral ventricles. After sealing the skull using dental cement, an acute CSF drainage/infusion protocol consisting of 4 sequential phases was performed with a pump. Implant location was confirmed via radiography using intraventricular iohexol contrast administration. Results Controlled CSF shunting in vivo with hydrocephalic rats resulted in precise and accurate sensor measurements (r = 0.98). Shunting resulted in a 17.3% maximum measurement error between measured volume and actual volume as assessed by a Bland-Altman plot. A secondary outcome confirmed that both ventricular volume and intracranial pressure decreased during CSF shunting and increased during infusion. Ventricular enlargement consistent with successful hydrocephalus induction was confirmed using imaging, as well as postmortem. These results indicate that volume monitoring is feasible for clinical cases of hydrocephalus. Conclusions This work marks a departure from traditional shunting systems currently used to treat hydrocephalus. The overall clinical application is to provide alternative monitoring and treatment options for patients. Future work includes development and testing of a chronic (long-term) volume monitoring system.

Background Intrathecal drug delivery is an efficient method to administer therapeutic molecules to the central nervous system. However, even with identical drug dosage and administration mode, the extent of drug distribution in vivo is highly variable and difficult to control. Different cerebrospinal fluid (CSF) pulsatility from patient to patient may lead to different drug distribution. Medical image-based computational fluid dynamics (miCFD) is used to construct a patient-specific model to quantify drug transport as a function of a spectrum of physiological CSF pulsations. Methods Magnetic resonance imaging (MRI) and CINE MRI were performed to capture the patient's central nervous system anatomy and CSF pulsatile flow velocities. An miCFD model was reconstructed from these MRIs and the patient's CSF flow velocities were computed. The effect of CSF pulsatility (frequency and stroke volume) was investigated for a bolus injection of a model drug at the L2 vertebral level. Drug distribution profiles along the entire spine were computed for different heart rates: 43, 60, and 120 bpm, and varied CSF stroke volumes: 1, 2, and 3 mL. To assess toxicity risk for patients with different physiological variables, therapeutic and toxic concentration thresholds for a common anesthetic were derived from experimental studies. Toxicity risk analysis was performed for an injection of a spinal anesthetic for patients with different heart rates and CSF stroke volumes. Results Both heart rate and CSF stroke volume of the patient strongly influence drug distribution administered intrathecally. Doubling the heart rate (from 60 to 120 bpm) caused a 26.4% decrease in peak concentration in CSF after injection. Doubling the CSF stroke volume diminished the peak concentration after injection by 38.1%. Computations show that potentially toxic peak concentrations due to injection can be avoided by changing the infusion rate. Using slower infusion rates could avoid high peak concentrations in CSF while maintaining drug concentrations above the therapeutic threshold. Conclusions Our computations identify key variables for patient to patient variability in drug distribution in the spine observed clinically. The speed of drug transport is strongly affected by the frequency and magnitude of CSF pulsations. Toxicity risks associated with an injection can be reduced for a particular patient by adjusting the infusion variables with our rigorous miCFD model.

The dynamics of fluid flow in normal pressure hydrocephalus (NPH) are poorly understood. Normally, CSF flows out of the brain through the ventricles. However, ventricular enlargement during NPH may be caused by CSF backflow into the brain through the ventricles. A previous study showed this reversal of flow; in the present study, the authors provide additional clinical data obtained in patients with NPH and supplement these data with computer simulations to better understand the CSF flow and ventricular wall displacement and emphasize its clinical implications.Three NPH patients and 1 patient with aqueductal stenosis underwent cine phase-contrast MR imaging (cine MR imaging) for measurement of CSF flow and ventricle wall movement during the cardiac cycle. These data were compared to data previously obtained in 8 healthy volunteers. The CSF flow measurements were obtained at the outlet of the aqueduct of Sylvius. Calculation of the ventricular wall movement was determined from the complete set of cine MR images obtained axially at the middle of the lateral ventricle. The data were obtained before and after CSF removal with a ventriculoperitoneal shunt with an adjustable valve. To supplement the clinical data, a computational model was used to predict the transmural pressure and flow.In healthy volunteers, net CSF aqueductal flow was 1.2 ml/minute in the craniocaudal direction. In patients with NPH, the net CSF flow was in the opposite direction--the caudocranial direction--before shunt placement. After shunting, the magnitude of the abnormal fluid flow decreased or reversed, with the flow resembling the normal flow patterns observed in healthy volunteers.The authors' MR imaging-based measurements of the CSF flow direction and lateral ventricle volume size change and the results of computer modeling of fluid dynamics lead them to conclude that the directional pattern and magnitude of CSF flow in patients with NPH may be an indication of the disease state. This has practical implications for shunt design and understanding the mechanisms that produce hydrocephalus.

The dynamics of cerebral blood flow and its role in maintaining homeostasis of the central nervous system (CNS) is of high clinical relevance. A mechanistic understanding of intracranial dynamics may lead to greater insight of cerebrovascular disorders and how cerebral blood flow is controlled. Computational models of the cerebral vasculature can assist neurosurgeons in diagnosis and risk assessment of surgical intervention for specific patients. To this end, computer models of cerebral vasculature which capture hemodynamic properties of the human vasculature are constructed using modern medical imaging combined with automatic vessel generation techniques. The artificially generated cerebral networks enable realistic simulation of blood flow and pressure distribution throughout the entire brain. These studies permit a quantitative analysis of cerebral hemodynamics and may lead to fundamental understanding of complex dynamics and control mechanisms like autoregulation and functional hyperemia.

Intrathecal drug delivery bypasses the blood brain barrier by infusing therapeutic agents into the cerebrospinal fluid. Clinical studies have observed rapid distribution of intrathecally infused drugs. We hypothesize that naturally occurring cerebrospinal fluid pulsations inside the spinal canal accelerate drug transport. An experimental model of the human spinal canal was built for infusion tests of a radionucleotide in stagnant and pulsatile flow fields. The distribution of infused Technitium-99 m in the spinal canal model was quantified and validated with computational study. The results show that the oscillatory flow of the cerebrospinal fluid accelerates species dispersion in the spinal canal model by a factor of two to four. To demonstrate a clinically relevant application, physiological cerebrospinal fluid pulsations were reproduced in an anatomically consistent computational model and the dispersion of baclofen, an anti-spasticity drug, inside the central nervous system was predicted. The successful characterization of accelerated drug transport due to cerebrospinal fluid pulsations aids in the rational design of intrathecal drug infusion therapies.

A three-dimensional model of the human cerebrospinal fluid (CSF) spaces is presented. Patient-specific brain geometries were reconstructed from magnetic resonance images. The model was validated by comparing the predicted flow rates with Cine phase-contrast MRI measurements. The model predicts the complex CSF flow patterns and pressures in the ventricular system and subarachnoid space of a normal subject. The predicted maximum rostral to caudal CSF flow in the pontine cistern precedes the maximum rostral to caudal flow in the ventricles by about 10% of the cardiac cycle. This prediction is in excellent agreement with the subject-specific flow data. The computational results quantify normal intracranial dynamics and provide a basis for analyzing diseased intracranial dynamics. Published by Elsevier Ltd. Comput Biol Med

This paper presents a sensor for monitoring and controlling the volume of the cerebrospinal fluid-filled ventricles of the brain. The measurement principle of the sensor exploits electrical conductivity differences between the cerebrospinal fluid and the brain tissue. The electrical contrast was validated using dog brain tissue. Experiments with prototype sensors accurately measured the volume content of elastically deformable membranes and gel phantoms with conductivity properties made to match human brain. The sensor was incorporated into a fully automatic feedback control system designed to maintain the ventricular volume at normal levels. The experimental conductivity properties were also used to assess the sensor performance in a simulated case of hydrocephalus. The computer analysis predicted voltage drops over the entire range of ventricular size changes with acceptable positional dependence of the sensor electrodes inside the ventricular space. These promising experimental and computational results of the novel impedance sensor with feedback may serve as the foundation for improved therapeutic options for hydrocephalic patients relying on volume sensing, monitoring or active feedback control.

Using first principles of fluid and solid mechanics a comprehensive model of human intracranial dynamics is proposed. Blood, cerebrospinal fluid (CSF) and brain parenchyma as well as the spinal canal are included. The compartmental model predicts intracranial pressure gradients, blood and CSF flows and displacements in normal and pathological conditions like communicating hydrocephalus. The system of differential equations of first principles conservation balances is discretized and solved numerically. Fluid-solid interactions of the brain parenchyma with cerebral blood and CSF are calculated. The model provides the transitions from normal dynamics to the diseased state during the onset of communicating hydrocephalus. Predicted results were compared with physiological data from Cine phase-contrast magnetic resonance imaging to verify the dynamic model. Bolus injections into the CSF are simulated in the model and found to agree with clinical measurements. Journal of Mathematical Biology

This article reviews our previous work on the dynamics of the intracranial cavity and presents new clinically relevant results about hydrocephalus that can be gained from this approach. Simulations based on fluid dynamics and poroelasticity theory are used to predict CSF flow, pressures and brain tissue movement in normal subjects. Communicating hydrocephalus is created in the model by decreasing CSF absorption. The predictions are shown to reflect dynamics demonstrated by structural MRI and cine-MRI studies of normal subjects and hydrocephalus patients. The simulations are then used to explain unilateral hydrocephalus and how hydrocephalus could occur without CSF pulsations. The simulations also predict the known pressure/volume relationships seen on bolus infusions of CSF, and the small transmural pressure gradients observed in animal experiments and in patients with hydrocephalus. The complications and poor performance of shunts based on pressure-sensitive valves are explained and a system of feedback control is suggested as a solution.

Advances in magnetic resonance (MR) imaging techniques enable the accurate measurements of cerebrospinal fluid (CSF) flow in the human brain. In addition, image reconstruction tools facilitate the collection of patient-specific brain geometry data such as the exact dimensions of the ventricular and subarachnoidal spaces (SAS) as well as the computer-aided reconstruction of the CSF-filled spaces. The solution of the conservation of CSF mass and momentum balances over a finite computational mesh obtained from the MR images predict the patients' CSF flow and pressure field. Advanced image reconstruction tools used in conjunction with first principles of fluid mechanics allow an accurate verification of the CSF flow patters for individual patients. This paper presents a detailed analysis of pulsatile CSF flow and pressure dynamics in a normal and hydrocephalic patient. Experimental CSF flow measurements and computational results of flow and pressure fields in the ventricular system, the SAS and brain parenchyma are presented. The pulsating CSF motion is explored in normal and pathological conditions of communicating hydrocephalus. This paper predicts small transmantle pressure differences between lateral ventricles and SASs (approximately 10 Pa). The transmantle pressure between ventricles and SAS remains small even in the hydrocephalic patient (approximately 30 Pa), but the ICP pulsatility increases by a factor of four. The computational fluid dynamics (CFD) results of the predicted CSF flow velocities are in good agreement with Cine MRI measurements. Differences between the predicted and observed CSF flow velocities in the prepontine area point towards complex brain-CSF interactions. The paper presents the complete computational model to predict the pulsatile CSF flow in the cranial cavity.

Advances in magnetic resonance (MR) imaging techniques enable the accurate measurements of cerebrospinal fluid (CSF) flow in the human brain. In addition, image reconstruction tools facilitate the collection of patient-specific brain geometry data such as the exact dimensions of the ventricular and subarachnoidal spaces (SAS) as well as the computer-aided reconstruction of the CSF-filled spaces. The solution of the conservation of CSF mass and momentum balances over a finite computational mesh obtained from the MR images predict the patients' CSF flow and pressure field. Advanced image reconstruction tools used in conjunction with first principles of fluid mechanics allow an accurate verification of the CSF flow patters for individual patients. This paper presents a detailed analysis of pulsatile CSF flow and pressure dynamics in a normal and hydrocephalic patient. Experimental CSF flow measurements and computational results of flow and pressure fields-in the ventricular system, the SAS and brain parenchyma are presented. The pulsating CSF motion. is explored in normal and pathological conditions of communicating hydrocephalus. This paper predicts small transmantle pressure differences between lateral ventricles and SASs (similar to 10 Pa). The transmantle pressure between ventricles and SAS remains small even in the hydrocephalic patient (similar to 30 Pa), but the ICP pulsatility increases by a factor of four. The computational fluid dynamics (CFD) results of the predicted CSF flow velocities are in good agreement with Cine MRI measurements. Differences between the predicted and observed CSF flow velocities in the prepontine area point towards complex brain-CSF interactions. The paper presents the complete computational model to predict the pulsatile CSF flow in the cranial cavity. Ieee Transactions on Biomedical Engineering