Ventricular displacement [m]CSF Pressure [Pa]

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)

http://blog.iilm.edu/2012/11/the -rest-is-history/footer_newton/

http://egoscueportland.wordpress.com/2010/12/26/the- cause-and-effect-of-football-tackling/

http://www.expertboxing.com/boxing-strategy/counter- punching/7-easy-boxing-counters-punches

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 



  

^      



 

2 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}





 

 

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)

k_e k_v

k_c k_a

Q_out

Q_in S_ac

S_cv

S_ce

S_ev

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

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

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

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

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)

k_e k_v

k_c k_a

Q_out

Q_in S_ac

S_cv

S_ce

S_ev

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



    



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



    



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



    



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



    



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 3^rdventricle 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 4^th ventricle (open case)

 (Right) Sagittal view of lines tangent to the instantaneous velocity vector in the 3^rd 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