Fluids and Barriers of the CNS

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ISSN / EISSN : 20458118 / 20458118
Current Publisher: Springer Nature (10.1186)
Total articles ≅ 372
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Esmée Vendel, Vivi Rottschäfer, Elizabeth C. M. De Lange
Fluids and Barriers of the CNS, Volume 16; doi:10.1186/s12987-019-0133-x

Abstract:The blood brain barrier (BBB) is the main barrier that separates the blood from the brain. Because of the BBB, the drug concentration-time profile in the brain may be substantially different from that in the blood. Within the brain, the drug is subject to distributional and elimination processes: diffusion, bulk flow of the brain extracellular fluid (ECF), extra-intracellular exchange, bulk flow of the cerebrospinal fluid (CSF), binding and metabolism. Drug effects are driven by the concentration of a drug at the site of its target and by drug-target interactions. Therefore, a quantitative understanding is needed of the distribution of a drug within the brain in order to predict its effect. Mathematical models can help in the understanding of drug distribution within the brain. The aim of this review is to provide a comprehensive overview of system-specific and drug-specific properties that affect the local distribution of drugs in the brain and of currently existing mathematical models that describe local drug distribution within the brain. Furthermore, we provide an overview on which processes have been addressed in these models and which have not. Altogether, we conclude that there is a need for a more comprehensive and integrated model that fills the current gaps in predicting the local drug distribution within the brain.
M. Keith Sharp, Roxana O. Carare, Bryn A. Martin
Fluids and Barriers of the CNS, Volume 16; doi:10.1186/s12987-019-0132-y

Abstract:As an alternative to advection, solute transport by shear-augmented dispersion within oscillatory cerebrospinal fluid flow was investigated in small channels representing the basement membranes located between cerebral arterial smooth muscle cells, the paraarterial space surrounding the vessel wall and in large channels modeling the spinal subarachnoid space (SSS). Geometries were modeled as two-dimensional. Fully developed flows in the channels were modeled by the Darcy–Brinkman momentum equation and dispersion by the passive transport equation. Scaling of the enhancement of axial dispersion relative to molecular diffusion was developed for regimes of flow including quasi-steady, porous and unsteady, and for regimes of dispersion including diffusive and unsteady. Maximum enhancement occurs when the characteristic time for lateral dispersion is matched to the cycle period. The Darcy–Brinkman model represents the porous media as a continuous flow resistance, and also imposes no-slip boundary conditions at the walls of the channel. Consequently, predicted dispersion is always reduced relative to that of a channel without porous media, except when the flow and dispersion are both unsteady. In the basement membranes, flow and dispersion are both quasi-steady and enhancement of dispersion is small even if lateral dispersion is reduced by the porous media to achieve maximum enhancement. In the paraarterial space, maximum enhancement Rmax = 73,200 has the potential to be significant. In the SSS, the dispersion is unsteady and the flow is in the transition zone between porous and unsteady. Enhancement is 5.8 times that of molecular diffusion, and grows to a maximum of 1.6E+6 when lateral dispersion is increased. The maximum enhancement produces rostral transport time in agreement with experiments.
Anne Benninghaus, Olivier Balédent, Armelle Lokossou, Carlos Castelar, Steffen Leonhardt, Klaus Radermacher
Fluids and Barriers of the CNS, Volume 16; doi:10.1186/s12987-019-0131-z

Abstract:Fluid dynamics of the craniospinal system are complex and still not completely understood. In vivo flow and pressure measurements of the cerebrospinal fluid (CSF) are limited. Whereas in silico modeling can be an adequate pathway for parameter studies, in vitro modeling of the craniospinal system is essential for testing and evaluation of therapeutic measures associated with innovative implants relating to, for example, normal pressure hydrocephalus and other fluid disorders. Previously-reported in vitro models focused on the investigation of only one hypothesis of the fluid dynamics rather than developing a modular set-up to allow changes in focus of the investigation. The aim of this study is to present an enhanced and validated in vitro model of the CSF system which enables the future embedding of implants, the validation of in silico models or phase-contrast magnetic resonance imaging (PC-MRI) measurements and a variety of sensitivity analyses regarding pathological behavior, such as reduced CSF compliances, higher resistances or altered blood dynamics. The in vitro model consists of a ventricular system which is connected via the aqueduct to the cranial and spinal subarachnoid spaces. Two compliance chambers are integrated to cushion the arteriovenous blood flow generated by a cam plate unit enabling the modeling of patient specific flow dynamics. The CSF dynamics are monitored using three cranial pressure sensors and a spinal ultrasound flow meter. Measurements of the in vitro spinal flow were compared to cervical flow data recorded with PC-MRI from nine healthy young volunteers, and pressure measurements were compared to the literature values reported for intracranial pressure (ICP) to validate the newly developed in vitro model. The maximum spinal CSF flow recorded in the in vitro simulation was 133.60 ml/min in the caudal direction and 68.01 ml/min in the cranial direction, whereas the PC-MRI flow data of the subjects showed 122.82 ml/min in the caudal and 77.86 ml/min in the cranial direction. In addition, the mean ICP (in vitro) was 12.68 mmHg and the pressure wave amplitude, 4.86 mmHg, which is in the physiological range. The in vitro pressure values were in the physiological range. The amplitudes of the flow results were in good agreement with PC-MRI data of young and healthy volunteers. However, the maximum cranial flow in the in vitro model occurred earlier than in the PC-MRI data, which might be due to a lack of an in vitro dynamic compliance. Implementing dynamic compliances and related sensitivity analyses are major aspects of our ongoing research.
Steven William Bothwell, Damir Janigro, Adjanie Patabendige
Fluids and Barriers of the CNS, Volume 16; doi:10.1186/s12987-019-0129-6

Abstract:The fine balance between the secretion, composition, volume and turnover of cerebrospinal fluid (CSF) is strictly regulated. However, during certain neurological diseases, this balance can be disrupted. A significant disruption to the normal CSF circulation can be life threatening, leading to increased intracranial pressure (ICP), and is implicated in hydrocephalus, idiopathic intracranial hypertension, brain trauma, brain tumours and stroke. Yet, the exact cellular, molecular and physiological mechanisms that contribute to altered hydrodynamic pathways in these diseases are poorly defined or hotly debated. The traditional views and concepts of CSF secretion, flow and drainage have been challenged, also due to recent findings suggesting more complex mechanisms of brain fluid dynamics than previously proposed. This review evaluates and summarises current hypotheses of CSF dynamics and presents evidence for the role of impaired CSF dynamics in elevated ICP, alongside discussion of the proteins that are potentially involved in altered CSF physiology during neurological disease. Undoubtedly CSF secretion, absorption and drainage are important aspects of brain fluid homeostasis in maintaining a stable ICP. Traditionally, pharmacological interventions or CSF drainage have been used to reduce ICP elevation due to over production of CSF. However, these drugs are used only as a temporary solution due to their undesirable side effects. Emerging evidence suggests that pharmacological targeting of aquaporins, transient receptor potential vanilloid type 4 (TRPV4), and the Na+–K+–2Cl− cotransporter (NKCC1) merit further investigation as potential targets in neurological diseases involving impaired brain fluid dynamics and elevated ICP.
Gökmen Aktas, Jost M. Kollmeier, Arun A. Joseph, Klaus-Dietmar Merboldt, Hans-Christoph Ludwig, Jutta Gärtner, Jens Frahm, Steffi Dreha-Kulaczewski
Fluids and Barriers of the CNS, Volume 16; doi:10.1186/s12987-019-0130-0

Abstract:Respiration-induced pressure changes represent a powerful driving force of CSF dynamics as previously demonstrated using flow-sensitive real-time magnetic resonance imaging (MRI). The purpose of the present study was to elucidate the sensitivity of CSF flow along the spinal canal to forced thoracic versus abdominal respiration. Eighteen subjects without known illness were studied using real-time phase-contrast flow MRI at 3 T in the aqueduct and along the spinal canal at levels C3, Th1, Th8 and L3. Subjects performed a protocol of forced breathing comprising four cycles of 2.5 s inspiration and 2.5 s expiration. The quantitative results for spinal CSF flow rates and volumes confirm previous findings of an upward movement during forced inspiration and reversed downward flow during subsequent exhalation—for both breathing types. However, the effects were more pronounced for abdominal than for thoracic breathing, in particular at spinal levels Th8 and L3. In general, CSF net flow volumes were very similar for both breathing conditions pointing upwards in all locations. Spinal CSF dynamics are sensitive to varying respiratory performances. The different CSF flow volumes in response to deep thoracic versus abdominal breathing reflect instantaneous adjustments of intrathoracic and intraabdominal pressure, respectively. Real-time MRI access to CSF flow in response to defined respiration patterns will be of clinical importance for patients with disturbed CSF circulation like hydrocephalus, pseudotumor cerebri and others. The online version of this article (10.1186/s12987-019-0130-0) contains supplementary material, which is available to authorized users.
Tetsuya Akaishi, Eiko Onishi, Michiaki Abe, Hiroaki Toyama, Kota Ishizawa, Michio Kumagai, Ryosuke Kubo, Ichiro Nakashima, Masashi Aoki, Masanori Yamauchi, et al.
Fluids and Barriers of the CNS, Volume 16; doi:10.1186/s12987-019-0128-7

Abstract:The central nervous system was previously thought to draw oxygen and nutrition from the arteries and discharge carbon dioxide and other metabolic wastes into the venous system. At present, the functional role of cerebrospinal fluid in brain metabolism is not fully known. In this prospective observational study, we performed gas analysis on venous blood and cerebrospinal fluid simultaneously acquired from 16 consecutive preoperative patients without any known neurological disorders. The carbon dioxide partial pressure (pCO2) (p < 0.0001) and lactic acid level (p < 0.001) in the cerebrospinal fluid were significantly higher than those in the peripheral venous blood, suggesting that a considerable proportion of metabolic carbon dioxide and lactic acid is discharged from the central nervous system into the cerebrospinal fluid. The oxygen partial pressure (pO2) was much higher in the cerebrospinal fluid than in the venous blood, corroborating the conventional theory of cerebrospinal fluid circulatory dynamics. The pCO2 of the cerebrospinal fluid showed a strong negative correlation with age (R = − 0.65, p = 0.0065), but the other studied variables did not show significant correlation with age. Carbon dioxide and lactic acid are discharged into the circulating cerebrospinal fluid, as well as into the venules. The level of carbon dioxide in the cerebrospinal fluid significantly decreased with age.
Joel A. Berliner, Thomas Woodcock, Elmira Najafi, Sarah J. Hemley, Magdalena Lam, Shaokoon Cheng, Lynne E. Bilston, Marcus A. Stoodley
Fluids and Barriers of the CNS, Volume 16; doi:10.1186/s12987-019-0127-8

Abstract:Fluid homeostasis in the central nervous system (CNS) is essential for normal neurological function. Cerebrospinal fluid (CSF) in the subarachnoid space and interstitial fluid circulation in the CNS parenchyma clears metabolites and neurotransmitters and removes pathogens and excess proteins. A thorough understanding of the normal physiology is required in order to understand CNS fluid disorders, including post-traumatic syringomyelia. The aim of this project was to compare fluid transport, using quantitative imaging of tracers, in the spinal cord from animals with normal and obstructed spinal subarachnoid spaces. A modified extradural constriction model was used to obstruct CSF flow in the subarachnoid space at the cervicothoracic junction (C7–T1) in Sprague–Dawley rats. Alexa-Fluor 647 Ovalbumin conjugate was injected into the cisterna magna at either 1 or 6 weeks post–surgery. Macroscopic and microscopic fluorescent imaging were performed in animals sacrificed at 10 or 20 min post–injection. Tracer fluorescence intensity was compared at cervical and thoracic spinal cord levels between control and constriction animals at each post-surgery and post-injection time point. The distribution of tracer around arterioles, venules and capillaries was also compared. Macroscopically, the fluorescence intensity of CSF tracer was significantly greater in spinal cords from animals with a constricted subarachnoid space compared to controls, except at 1 week post-surgery and 10 min post-injection. CSF tracer fluorescence intensity from microscopic images was significantly higher in the white matter of constriction animals 1 week post surgery and 10 min post-injection. At 6 weeks post–constriction surgery, fluorescence intensity in both gray and white matter was significantly increased in animals sacrificed 10 min post-injection. At 20 min post-injection this difference was significant only in the white matter and was less prominent. CSF tracer was found predominantly in the perivascular spaces of arterioles and venules, as well as the basement membrane of capillaries, highlighting the importance of perivascular pathways in the transport of fluid and solutes in the spinal cord. The presence of a subarachnoid space obstruction may lead to an increase in fluid flow within the spinal cord tissue, presenting as increased flow in the perivascular spaces of arterioles and venules, and the basement membranes of capillaries. Increased fluid retention in the spinal cord in the presence of an obstructed subarachnoid space may be a critical step in the development of post-traumatic syringomyelia. The online version of this article (10.1186/s12987-019-0127-8) contains supplementary material, which is available to authorized users.
Lori Ray, Jeffrey J. Iliff, Jeffrey J. Heys
Fluids and Barriers of the CNS, Volume 16; doi:10.1186/s12987-019-0126-9

Abstract:Despite advances in in vivo imaging and experimental techniques, the nature of transport mechanisms in the brain remain elusive. Mathematical modelling verified using available experimental data offers a powerful tool for investigating hypotheses regarding extracellular transport of molecules in brain tissue. Here we describe a tool developed to aid in investigation of interstitial transport mechanisms, especially the potential for convection (or bulk flow) and its relevance to interstitial solute transport, for which there is conflicting evidence. In this work, we compare a large body of published experimental data for transport in the brain to simulations of purely diffusive transport and simulations of combined convective and diffusive transport in the brain interstitium, incorporating current theories of perivascular influx and efflux. The simulations show (1) convective flow in the interstitium potentially of a similar magnitude to diffusive transport for molecules of interest and (2) exchange between the interstitium and perivascular space, whereby fluid and solutes may enter or exit the interstitium, are consistent with the experimental data. Simulations provide an upper limit for superficial convective velocity magnitude (approximately \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$v$$\end{document}v = 50 μm min−1), a useful finding for researchers developing techniques to measure interstitial bulk flow. For the large molecules of interest in neuropathology, bulk flow may be an important mechanism of interstitial transport. Further work is warranted to investigate the potential for bulk flow. The online version of this article (10.1186/s12987-019-0126-9) contains supplementary material, which is available to authorized users.
Miles Hudson, Caden Nowak, Richard J. Garling, Carolyn Harris
Published: 12 February 2019
Fluids and Barriers of the CNS, Volume 16; doi:10.1186/s12987-019-0125-x

Abstract:Idiopathic normal pressure hydrocephalus (iNPH) is a subtype of hydrocephalus that occurs more often in the elderly population. It is usually characterized by gait disturbance, dementia and urinary incontinence. Epidemiological studies indicate that 15.7–17.8% of iNPH patients present with type-2 diabetes mellitus (DM). A review of the primary literature shows that these occurrence rates are higher than age- and cohort-matched non-iNPH controls. This suggests that this already vulnerable patient group has an increased risk for presenting with DM compared to their non-iNPH counterparts. Postoperative outcome when treating iNPH patients is inversely related to the number of patient comorbidities and a lower comorbidity status is correlated with better outcomes. This review highlights the need for further research into the relationship between iNPH and DM and speculates on a possible mechanism for an association between the development of ventriculomegaly and the development of DM and iNPH.
Richard F. Keep, Hazel C. Jones, Lester R. Drewes
Published: 5 February 2019
Fluids and Barriers of the CNS, Volume 16; doi:10.1186/s12987-019-0124-y

Abstract:This editorial focuses on the progress made in brain barrier and brain fluid research in 2018. It highlights some recent advances in knowledge and techniques, as well as prevalent themes and controversies. Areas covered include: modeling, the brain endothelium, the neurovascular unit, the blood–CSF barrier and CSF, drug delivery, fluid movement within the brain, the impact of disease states, and heterogeneity.