83 research outputs found
Determination of spinal tracer dispersion after intrathecal injection in a deformable CNS model
Background: Traditionally, there is a widely held belief that drug dispersion after intrathecal (IT) delivery is confined locally near the injection site. We posit that high-volume infusions can overcome this perceived limitation of IT administration.Methods: To test our hypothesis, subject-specific deformable phantom models of the human central nervous system were manufactured so that tracer infusion could be realistically replicated in vitro over the entire physiological range of pulsating cerebrospinal fluid (CSF) amplitudes and frequencies. The distribution of IT injected tracers was studied systematically with high-speed optical methods to determine its dependence on injection parameters (infusion volume, flow rate, and catheter configurations) and natural CSF oscillations in a deformable model of the central nervous system (CNS).Results: Optical imaging analysis of high-volume infusion experiments showed that tracers spread quickly throughout the spinal subarachnoid space, reaching the cervical region in less than 10 min. The experimentally observed biodispersion is much slower than suggested by the Taylor–Aris dispersion theory. Our experiments indicate that micro-mixing patterns induced by oscillatory CSF flow around microanatomical features such as nerve roots significantly accelerate solute transport. Strong micro-mixing effects due to anatomical features in the spinal subarachnoid space were found to be active in intrathecal drug administration but were not considered in prior dispersion theories. Their omission explains why prior models developed in the engineering community are poor predictors for IT delivery.Conclusion: Our experiments support the feasibility of targeting large sections of the neuroaxis or brain utilizing high-volume IT injection protocols. The experimental tracer dispersion profiles acquired with an anatomically accurate, deformable, and closed in vitro human CNS analog informed a new predictive model of tracer dispersion as a function of physiological CSF pulsations and adjustable infusion parameters. The ability to predict spatiotemporal dispersion patterns is an essential prerequisite for exploring new indications of IT drug delivery that targets specific regions in the CNS or the brain
A computational model of cerebrospinal fluid production and reabsorption driven by Starling forces
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
Phase contrast reflectance confocal brain imaging at 1650 nm
ABSTRACT: Significance The imaging depth of microscopy techniques is limited by the ability of light to penetrate biological tissue. Recent research has addressed this limitation by combining a reflectance confocal microscope with the NIR-II (or shortwave infrared) spectrum. This approach offers significant imaging depth, is straightforward in design, and remains cost-effective. However, the imaging system, which relies on intrinsic signals, could benefit from adjustments in its optical design and post-processing methods to differentiate cortical cells, such as neurons and small blood vessels. Aim We implemented a phase contrast detection scheme to a reflectance confocal microscope using NIR-II spectral range as illumination. Approach We analyzed the features retrieved in the images while testing the imaging depth. Moreover, we introduce an acquisition method for distinguishing dynamic signals from the background, allowing the creation of vascular maps similar to those produced by optical coherence tomography. Results The phase contrast implementation is successful to retrieve deep images in the cortex up to 800μm using a cranial window. Vascular maps were retrieved at similar cortical depth and the possibility of combining multiple images can provide a vessel network. Conclusions Phase contrast reflectance confocal microscopy can improve the outlining of cortical cell bodies. With the presented framework, angiograms can be retrieved from the dynamic signal in the biological tissue. Our work presents an optical implementation and analysis techniques from a former microscope design
Starling forces drive intracranial water exchange during normal and pathological states
Aim To quantify the exchange of water between cerebral
compartments, specifically blood, tissue, perivascular
pathways, and cerebrospinal fluid-filled spaces, on the basis
of experimental data and to propose a dynamic global
model of water flux through the entire brain to elucidate
functionally relevant fluid exchange phenomena.
Methods The mechanistic computer model to predict
brain water shifts is discretized by cerebral compartments
into nodes. Water and species flux is calculated between
these nodes across a network of arcs driven by Hagen-Poiseuille
flow (blood), Darcy flow (interstitial fluid transport),
and Starling’s Law (transmembrane fluid exchange). Compartment
compliance is accounted for using a pressurevolume
relationship to enforce the Monro-Kellie doctrine.
This nonlinear system of differential equations is solved implicitly
using MATLAB software.
Results The model predictions of intraventricular osmotic
injection caused a pressure rise from 10 to 22 mmHg, followed
by a taper to 14 mmHg over 100 minutes. The computational
results are compared to experimental data with
R2 = 0.929. Moreover, simulated osmotic therapy of systemic
(blood) injection reduced intracranial pressure from 25
to 10 mmHg. The modeled volume and intracranial pressure
changes following cerebral edema agree with experimental
trends observed in animal models with R2 = 0.997.
Conclusion The model successfully predicted time course
and the efficacy of osmotic therapy for clearing cerebral
edema. Furthermore, the mathematical model implicated
the perivascular pathways as a possible conduit for water
and solute exchange. This was a first step to quantify fluid
exchange throughout the brain
A mechanistic pharmacokinetic model for intrathecal administration of antisense oligonucleotides
Intrathecal administration is an important mode for delivering biological agents targeting central nervous system (CNS) diseases. However, current clinical practices lack a sound theorical basis for a quantitative understanding of the variables and conditions that govern the delivery efficiency and specific tissue targeting especially in the brain. This work presents a distributed mechanistic pharmacokinetic model (DMPK) for predictive analysis of intrathecal drug delivery to CNS. The proposed DMPK model captures the spatiotemporal dispersion of antisense oligonucleotides (ASO) along the neuraxis over clinically relevant time scales of days and weeks as a function of infusion, physiological and molecular properties. We demonstrate its prediction capability using biodistribution data of antisense oligonucleotide (ASO) administration in non-human primates. The results are in close agreement with the observed ASO pharmacokinetics in all key compartments of the central nervous system. The model enables determination of optimal injection parameters such as intrathecal infusion volume and duration for maximum ASO delivery to the brain. Our quantitative model-guided analysis is suitable for identifying optimal parameter settings to target specific brain regions with therapeutic drugs such as ASOs
Impact of stalling events on microcirculatory hemodynamics in the aged brain
ABSTRACT: Objective The role of cerebral microvasculature in cognitive dysfunction can be investigated by identifying the impact of blood flow on cortical tissue oxygenation. In this paper, the impact of capillary stalls on microcirculatory characteristics such as flow and hematocrit (Ht) in the cortical angioarchitecture is studied. Methods Using a deterministic mathematical model to simulate blood flow in a realistic mouse cortex, hemodynamics parameters, including pressure, flow, vessel diameter-adjustable hematocrit, and transit time are calculated as a function of stalling events. Results Using a non-linear plasma skimming model, it is observed that Ht increases in the penetrating arteries from the pial vessels as a function of cortical depth. The incidence of stalling on Ht distribution along the blood network vessels shows reduction of RBCs around the tissue near occlusion sites and decreased Ht concentration downstream from the blockage points. Moreover, upstream of the occlusion, there is a noticeable increase of the Ht, leading to larger flow resistance due to higher blood viscosity. We predicted marked changes in transit time behavior due to stalls which match trends observed in mice in vivo. Conclusions These changes to blood cell quantity and quality may be implicated in the development of Alzheimer's disease and contribute to the course of the illness
Modelling Blood Flow and Metabolism in the Preclinical Neonatal Brain during and Following Hypoxic-Ischaemia
Hypoxia-ischaemia (HI) is a major cause of neonatal brain injury, often leading to long-term damage or death. In order to improve understanding and test new treatments, piglets are used as preclinical models for human neonates. We have extended an earlier computational model of piglet cerebral physiology for application to multimodal experimental data recorded during episodes of induced HI. The data include monitoring with near-infrared spectroscopy (NIRS) and magnetic resonance spectroscopy (MRS), and the model simulates the circulatory and metabolic processes that give rise to the measured signals. Model extensions include simulation of the carotid arterial occlusion used to induce HI, inclusion of cytoplasmic pH, and loss of metabolic function due to cell death. Model behaviour is compared to data from two piglets, one of which recovered following HI while the other did not. Behaviourally-important model parameters are identified via sensitivity analysis, and these are optimised to simulate the experimental data. For the non-recovering piglet, we investigate several state changes that might explain why some MRS and NIRS signals do not return to their baseline values following the HI insult. We discover that the model can explain this failure better when we include, among other factors such as mitochondrial uncoupling and poor cerebral blood flow restoration, the death of around 40% of the brain tissue. Copyright
Multiplicity of cerebrospinal fluid functions: New challenges in health and disease
This review integrates eight aspects of cerebrospinal fluid (CSF) circulatory dynamics: formation rate, pressure, flow, volume, turnover rate, composition, recycling and reabsorption. Novel ways to modulate CSF formation emanate from recent analyses of choroid plexus transcription factors (E2F5), ion transporters (NaHCO3 cotransport), transport enzymes (isoforms of carbonic anhydrase), aquaporin 1 regulation, and plasticity of receptors for fluid-regulating neuropeptides. A greater appreciation of CSF pressure (CSFP) is being generated by fresh insights on peptidergic regulatory servomechanisms, the role of dysfunctional ependyma and circumventricular organs in causing congenital hydrocephalus, and the clinical use of algorithms to delineate CSFP waveforms for diagnostic and prognostic utility. Increasing attention focuses on CSF flow: how it impacts cerebral metabolism and hemodynamics, neural stem cell progression in the subventricular zone, and catabolite/peptide clearance from the CNS. The pathophysiological significance of changes in CSF volume is assessed from the respective viewpoints of hemodynamics (choroid plexus blood flow and pulsatility), hydrodynamics (choroidal hypo- and hypersecretion) and neuroendocrine factors (i.e., coordinated regulation by atrial natriuretic peptide, arginine vasopressin and basic fibroblast growth factor). In aging, normal pressure hydrocephalus and Alzheimer's disease, the expanding CSF space reduces the CSF turnover rate, thus compromising the CSF sink action to clear harmful metabolites (e.g., amyloid) from the CNS. Dwindling CSF dynamics greatly harms the interstitial environment of neurons. Accordingly the altered CSF composition in neurodegenerative diseases and senescence, because of adverse effects on neural processes and cognition, needs more effective clinical management. CSF recycling between subarachnoid space, brain and ventricles promotes interstitial fluid (ISF) convection with both trophic and excretory benefits. Finally, CSF reabsorption via multiple pathways (olfactory and spinal arachnoidal bulk flow) is likely complemented by fluid clearance across capillary walls (aquaporin 4) and arachnoid villi when CSFP and fluid retention are markedly elevated. A model is presented that links CSF and ISF homeostasis to coordinated fluxes of water and solutes at both the blood-CSF and blood-brain transport interfaces
A model for simulation and patient-specific visualization of the tissue volume of influence during brain microdialysis
- …