Department of Engineering Science Institute of Biomedical Engineering Fluidics and Biocomplexity Group St. Cross College
Water Transport in Brain:
Cerebrospinal Fluid, Capillaries and Glial Cells
Presenter: Dean Chou
Cerebrospinal Fluid (CSF)
Buoyancy
Reduce the net weight from 1400 g to 25 g
Protection
Prevent contact between delicate neural structures and the surrounding bones
Protect from injuries, EX: Jolt, hit
Transport
Nutrients, Chemical messengers, and Metabolic waste products
Epidural Subdural haemorrhage (M. McKinley, V. D. O’Loughlin, Human Anatomy 7th)
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Cerebrospinal Fluid (CSF)
(Sulaiman & Faez, 2010)
The choroid plexus
produces CSF at a rate of around 500 ml/day
The total volume of CSF at any given moment is around 150 ml
Entire volume of CSF is replaced approximately every 8 hours
CSF circulation path
Cerebrospinal Fluid (CSF) - Circulation
Choroid Plexus (CP)
(M. McKinley and V. D. O’Loughlin, Human Anatomy 3rd)
There are four choroid plexi in each ventricles.
The CP acts as a blood-CSF barrier (filtration system).
The CP plays an important role to maintain the delicate
extracellular environment
Capillaries
Around 5-10 μm in diameter
Smallest blood vessels in brain
Connect arterioles and venulae
Site of mass transfer between blood and surrounding tissue, such as oxygen, carbon dioxide, water, ions and so on
The regulation of behaviour via water channel, AQP4, is one of important issues that we are considering in this research
Costantino Iadecola & Maiken Nedergaard Nature Neuroscience 10, 1369 - 1376 (2007)
Glial Cells (Neuroglia)
(M. McKinley and V. D. O’Loughlin, Human Anatomy 3rd)
Central Nervous System (CNS)
• Astrocytes
• Maintain Blood-Brain Barrier
• Provide structural framework
• Regulate ions and nutrients
• Absorb and recycle neurotransmitters
• Oligodendrocytes
• Mylinate CNS axons
• Provide structural framework
• Microglia Cells
• Remove cell debris, waste products, pathogens by phagocytosis
• Ependymal Cells
• Assist for producing and circulating CSF
Peripheral Nervous System (PNS)
• Satellite Cells
• Schwann Cells
Aquaporins (AQPs)
Discovery aquaporin – Peter Agre
the biochemical properties of the Rh proteins from the erythrocyte membrane
Reveal the homology with MIP by cloning the full-length cDNA sequence
The structure of aquaporin
(Suzuki H, Nishikawa K, Hiroaki Y, Fujiyoshi Y., 2008) (TCB Group, UIUC) (PubMed:18678926, 2008)
(http://www.hopkinsmedicine.org/press/2003/october/031008a.htm)
Aquaporins (AQPs)
Effects of AQPs
Expression of water permeability of AQP 1 in Xenopus laevis oocytes
The upper oocytes were injected with mRNA encoding AQP in each photo transfer from an isotonic salt solution to a hypotonic salt solution
The lower oocytes in each photo are normally not permeable to water (without AQP 1 expression)
From 2.5 min to 3.5 min, the lower oocytes continue to keep their
original shape because of impermeability. However, the upper oocytes continue to swell due to osmotic water flux-in. This phenomenon
implies that AQP is a water channel protein (WCP)
(H. Lodish, Molecualr Cell Biology 7th, 2012)
Aquaporins (AQPs)
Phylogenetic tree of Aquaporins
Mammalian Aquaporins
AQP0
AQP1
AQP2
AQP4
AQP5
AQP6
Mammalian Aquaglyceroporins
AQP3
AQP7
AQP8
AQP9
AQP10
Mammalian Superaquaporins
AQP11
AQP12
Other Aquaporins
SoPIP2;1 Plant aquaporin
GIpF Bacterial Aquaglyceroporin
AQPZ Bacterial Aquaporin
AQPM Archaebacterial
aquaporin
Aquaporins (AQPs)
AQPs in CNS
Astrocytes AQP1, AQP3,
AQP4, AQP5, AQP9
Oligodendrocytes AQP8
Microglia cells AQP9
Ependymal cells AQP1, AQP4, AQP9
Neurons AQP1, AQP5,
AQP8 Owler, B, Pitham, T, Dongwei, W. (2010). Aquaporins:
relevance to cerebrospinal fluid physiology and therapeutic potential in hydrocephalus. Cerebrospinal Fluid Research . 7 (15), 1-12
Multiscale Platform
The inherent multiscalarity of the cerebral water flow environment
ventricles aqueductsand
A:cm-mm
subarachnoid the space
B:mm-μm
Glial cells capillariesand
C:μm-nm
Channels and tight junctions
D:nm-below
A B
C D
Multiple-Network Poroelastic Theory (MPET) Model
The concept of MPET comes from geotechnical engineering in order to describe fluid transport phenomena in soil and rock
It is assembled by deformable elastic matrix and multiple fluid networks of pores and fissures
This porous media model vary with porosity and permeability
Equations are built by treating the different fluid networks as
separate compartments which are in communication each other
Biological MPET Model
The concept of MPET model can capture the dynamics of all fluids transfer in the brain
Extend to include independent networks for cerebral blood and CSF
Distinguish four network compartments
1. Arterial blood
2. Arteriole/Capillary blood
3. Cerebrospinal fluid
4. Venous blood
Tully, B. and Y. Ventikos, Cerebral water transport using multiple- network poroelastic theory: application to normal pressure hydrocephalus.Journal of Fluid Mechanics, 2011
Biological MPET Model
Two governing equations of motion for a unit volume
a. Solid-fluid equation of motion
b. Fluid equilibrium and conservation ( each network A= 1,…,a)
Setting A=4 from previous slide and assuming a linear stress- strain relationship, we have following u-p formulations
2 2
1
0
A
M b a a
f
a
f x p
t
22 1,
1 0
A
a a a b a a
b a f
a
b b a
p x x
S f p
Q t t t
Biological MPET Model
Linear stress strain equation (Hooke’s law) inverted for stress and then stress is represented as a function of displacement and where the permeability is isotropic
2
1 2
M G
G
x x M f
f b x
apa e pe cpc vpv 0
1 0
a
a a a b a a
c a e a v a f
a
p S S S p
t t
Q
x
f x
1 0
e
e e e b e e
a e c e v e f
e
p S S S p
t t
Q
x
f x
1 0
c
c c c b c c
a c e c v c f
c
p S S S p
t t
Q
x
f x
1 0
v
v v v b v v
a v e v c v f
v
p S S S p
t t
Q
x
f x
Arterial Blood (a) Arteriole/Ca pillary Blood (c)
Venous Blood (v)
CSF (e)
ke kv
kc ka
Qout
Qin Sac
Scv
Sce
Sev
Biological MPET Model
The one-dimensional spherically symmetric system equations:
2
2 2
2 2 1 2
2 1
a e c v
a e c v b
f r
x x p p p p
x f x
r r r r G r r r r
2 2
2
1 2 2 2
0
a b
a a
f r
a a b a a
c a e a v a f r
a
f x
p x p p
x S S S f x
Q t t r r r r r r r
2 2
2
1 2 2 2
0
e b
e e
f r
e e b e e
a e c e v e f r
e
f x
p x p p
x S S S f x
Q t t r r r r r r r
2 2
2
1 2 2 2
0
c b
c c
f r
c c b c c
a a e c v c f r
c
f x
p x p p
x S S S f x
Q t t r r r r r r r
2 2
2
1 2 2 2
0
v b
v v
f r
v v b v v
a v e v c v f r
v
f x
p x p p
x S S S f x
Q t t r r r r r r r
Arterial Blood (a) Arteriole/Ca pillary Blood (c)
Venous Blood (v)
CSF (e)
ke kv
kc ka
Qout
Qin Sac
Scv
Sce
Sev
Biological MPET Model Assumptions
Tully, B. and Y. Ventikos, Cerebral water transport using multiple- network poroelastic theory: application to normal pressure hydrocephalus.Journal of Fluid Mechanics, 2011
Spherically symmetric geometry
No external forces on the system
Gravity is neglected
Use a stationary reference frame
Long time scale for development of hydrocephalus so the system is
assumed as quasi-steady
Transfer of fluid between networks does not break laws of continuity for the system, hence directional
transport is important ( >0 is a loss from the system)
S
Aquaporins Effect
www.pycnogenall.com/?p=178
Darcy Flow
The Starling’s Law of filtration equation
Permeability coefficient (Isotropic)
v p
J L S p
1 e ref
e
AQP f
e ref
p p p A
Interstitial fluid (ISF)
Q
A p
Aquaporins Effect
www.pycnogenall.com/?p=178
Darcy Flow
The Starling’s Law of filtration equation
Permeability coefficient (Isotropic)
v p
J L S p
1 e ref
e
AQP f
e ref
p p p A
AQP (WCP)
Q
A p
Aquaporins Effect
www.pycnogenall.com/?p=178
Darcy Flow
The Starling’s Law of filtration equation
Permeability coefficient (Isotropic)
v p
J L S p
1 e ref
e
AQP f
e ref
p p p A
H2O
Q
A p
Aquaporins Effect
www.pycnogenall.com/?p=178
Darcy Flow
The Starling’s Law of filtration equation
Permeability coefficient (Isotropic)
v p
J L S p
1 e ref
e
AQP f
e ref
p p p A
Q
A p
MPET Model – Currently Progress
After the assumptions discussed, the MPET governing equations can be cast as following:
2
2 2
2 2 1 2
2 1
a e c v
a e c v b
f r
x x p p p p
x f x
r r r r G r r r r
2 2
2 0
a a
a
a c
p p
r r r S
2 2
2 0
e e
e
c e e v
p p
S S
r r r
2 2
2 0
c c
c
a c c e c v
p p
S S S
r r r
2 2
2 0
v v
v
e v c v
p p
S S
r r r
v p
J L S p
1 e ref
e
AQP f
e ref
p p p A
MPET Model Processes
Biological MPET Model –
What we would like to do?
Assist to explore numerous cerebral pathologies
brain oedema
brain trauma
brain tumors
stroke,
Hydrocephalus
Migraines
other neurological pathologies, such as multiple sclerosis (MS) and neuromyelitis optica (NMO)
Aims to make a tangible contribution to the understanding of
cerebral or neurological pathologies, but also to pharmaceuticals
development.
Hydrocephalus (HCP)
HCP can be described as the abnormal accumulation of CSF with in the brain.
Types of HCP:
a. Obstructive HCP
b. Communicating HCP
c. Normal Pressure Hydrocephalus (NPH)
Symptoms in adults:
a. Headache
b. Vomiting
c. Altered level of consciousness
d. Visual obscurations
e. Cognitive impairment, poor concentration, gait disturbance
Hydrocephalus (HCP)
Treatment Location of Fluid Drain Ventriculo-peritoneal shunt (VP shunt) Peritoneal cavity
Ventriculo-atrial shunt (VA shunt) Right atrium of the heart Ventriculo-pleural shunt (VPL shunt) Pleural cavity
Endoscopic third ventriculostomy (ETV) Choroid plexus cauterization (CPC)
The floor of the 3rdventricle Choroid plexus cauterization
Current Results
Comparing the effect of AQP presence on the ventricular displacement in a case involving an open cerebral aqueduct
Comparing different amplification factors for the ventricular displacement in
transient development
Current Results
Comparing the effect of AQP presence on the ventricular pressure in a case involving an open/severe cerebral aqueduct
Comparing the effect of AQP presence on the ventricular displacement in a case involving an open/severe cerebral aqueduct
Current Results
Velocity distribution in open cerebral aqueduct with AQP effect
Velocity distribution in open cerebral aqueduct without AQP effect
Current Results : Choroid Plexus + ETV
• The severe case causes a ventricular displacement of just over 3.3 mm, mild (0.55mm), open case (0.5 mm)
• ETV significantly reduces
displacement of mild stenosis to the open level
0.04 0.06 0.08 0.1
0 1 2 3 4x 10-3
Skull radius [m]
Ventricular displacement [m]
Open Severe Mild Mild ETV Severe ETV
0.04 0.06 0.08 0.1
950 1000 1050 1100
Skull radius [m]
CSF Pressure [Pa]
Open Severe Mild Mild+ETV Severe+ETV
• CSF pressure is lowest in severely stenosed case (966 Pa)
• Open and mild cases exhibit similar pressure distributions (1070-1072 Pa). All converge to 1089 Pa at skull
• ETV reduces the pressure in both mild and severe cases
Current Results
(Left) Sagittal view of a z-slic of the unobstructed ventricular system
(Centre) Rotated view of lines tangent to the instantaneous velocity vector in the AS and 4th ventricle (open case)
(Right) Sagittal view of lines tangent to the instantaneous velocity vector in the 3rd ventricle and both LV’s
Impact & Applications
Scientific impact
a. To develop a completely new understanding of brain water balance
b. Virtual Physiological Brain (VP-Brain) is its target of the development of virtual optical instrumentation
Clinical impact
a. To improve diagnosis, intervention planning and therapy design
b. To facilitate targeted clinical interventions, which reduces the risk of ineffective, or harmful, treatment, and improves patient safety and clinical outcomes
Industrial impact
a. Three targeted industrial applications
1. Accurate characterisation of brain injury by modelling head impact
2. Development and deployment of a novel combined ICP-NIRS probe
3. Design of novel shunting devices
b. The pharmaceutical industry can realise new product development
Thanks !!
Questions, please!!
Acknowledgement
• FBG in Oxford
• ESI-Group