Brain Ischemia: Physiology and Modeling

Koen Dijkstra
Applied Analysis

December 8, 2015

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Outline

The Nernst Potential and Donnan Equilibrium

The Hodgkin-Huxley Model
Physiology of Ischemia
Modeling and Examples

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Nernst Potentials

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Nernst Potentials

The Nernst potential ES of an ion species S is the membrane potential at

which the chemical and electrical force on S cancel each other out,
RT
[S]o
ES =
ln
.
zS F
[S]i

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Nernst Potentials

The Nernst potential ES of an ion species S is the membrane potential at

which the chemical and electrical force on S cancel each other out,
RT
[S]o
ES =
ln
.
zS F
[S]i
If the membrane potential is not equal to the Nernst potential, there is a
nonzero force acting on S, yielding a transmembrane current
IS = gS (V ES ) .
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The Donnan Equilibrium

Initial Condition
Extracellular Space

Neuron
[A ]i =

10 mM

[B+ ]i = 100 mM
[P ]i =

90 mM

[A ]o = 100 mM
[B+ ]o = 100 mM

V = 0 mV

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The Donnan Equilibrium

Initial Condition

Equilibrium State

Extracellular Space

Extracellular Space

Neuron

+ + +
+
+
+ +

+
+
+
Neuron

+
+

+
[A ]i = 10 mM + x +
+
+
+

[A ]i =

10 mM

[B+ ]i = 100 mM

[P ]i =

[B+ ]i = 100 mM + x

+
+
+

90 mM

[P ]i =

+
+ +
+
+
+ + +

Koen Dijkstra

90 mM

[A ]o = 100 mM

[A ]o = 100 mM x

[B+ ]o = 100 mM

[B+ ]o = 100 mM x

V = 0 mV

V = EA = EB

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+
+
+

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The Donnan Equilibrium

How big is x ?
EA = EB

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RT [A ]o
RT [B+ ]o
ln =
ln +
F
F
[A ]i
[B ]i
10 mM + x
100 mM x
=
100 mM x
100 mM + x

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The Donnan Equilibrium

How big is x ?
EA = EB

RT [A ]o
RT [B+ ]o
ln =
ln +
F
F
[A ]i
[B ]i
10 mM + x
100 mM x
=
100 mM x
100 mM + x

For = 2 this yields x = 20 mM. For bigger the concentration change x

decreases.

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The Hodgkin-Huxley Model: Equivalent Circuit

Outside

INa

+++ +++

IK

gNa

IL

gK

gL
V

+
+ ENa

+
EK

EL

Inside

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The Hodgkin-Huxley Model: Differential Equations

Membrane potential:
INa

IK

IL

z
}|
{ z
}|
{ z
}|
{
dV
C
= gNa m3 h (V ENa ) gK n4 (V EK ) gL (V EL )
dt

Gating variables:
dq
= q (V )(1 q) q (V )q,
dt

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q {m, h, n}

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The Hodgkin-Huxley Model: Differential Equations

Membrane potential:
INa

IK

IL

z
}|
{ z
}|
{ z
}|
{
dV
C
= gNa m3 h (V ENa ) gK n4 (V EK ) gL (V EL )
dt

Gating variables:
dq
= q (V )(1 q) q (V )q,
dt

q {m, h, n}

All (maximal) conductances and Nernst potentials are constants

ENa = 70 mV,

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EK = 90 mV,

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EL = 80 mV.

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The Hodgkin-Huxley Model: Equilibrium State

Computation of the resting potential:

dV
=0
dt

V =

gNa ENa + gK EK + gL EL
gNa + gK + gL

While the sum of all currents vanishes at rest, the individual currents do
not.

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The Hodgkin-Huxley Model: Equilibrium State

Computation of the resting potential:

dV
=0
dt

V =

gNa ENa + gK EK + gL EL
gNa + gK + gL

While the sum of all currents vanishes at rest, the individual currents do
not.
So even at rest, sodium leaks into and potassium out of the cell, but the
concentration gradients remain unchanged.

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The Hodgkin-Huxley Model: Equilibrium State

Computation of the resting potential:

dV
=0
dt

V =

gNa ENa + gK EK + gL EL
gNa + gK + gL

While the sum of all currents vanishes at rest, the individual currents do
not.
So even at rest, sodium leaks into and potassium out of the cell, but the
concentration gradients remain unchanged.
No Donnan equilibrium? Why is this still a very reasonable model?

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The Sodium-Potassium Pump

Active transport against the electrochemical gradient, therefore needs
energy (ATP) to run

Blausen.com staff. "Blausen gallery 2014". Wikiversity Journal of Medicine.

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Increasing [K+ ]o in Hodgkin-Huxley

If the Na+ /K+ -pumps stop working, the extracellular potassium

concentration (and the intracellular sodium concentration) will rise.

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Increasing [K+ ]o in Hodgkin-Huxley

If the Na+ /K+ -pumps stop working, the extracellular potassium

concentration (and the intracellular sodium concentration) will rise.
What happens if we increase [K+ ]o in the HH model?

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Increasing [K+ ]o in Hodgkin-Huxley

If the Na+ /K+ -pumps stop working, the extracellular potassium

concentration (and the intracellular sodium concentration) will rise.
What happens if we increase [K+ ]o in the HH model?
Systematic approach to this question: Bifurcation analysis!

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Increasing [K+ ]o in Hodgkin-Huxley

100

V (mV)

50
resting
state

autonomous
spiking

depolarization
block

50
physiological value
100

10

15

20

25

30

35

[K ]o (mM)

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Brain ischemia: Chain of Events

1 Oxygen and glucose deprivation

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Brain ischemia: Chain of Events

1 Oxygen and glucose deprivation

2 No ATP production

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Brain ischemia: Chain of Events

1 Oxygen and glucose deprivation

2 No ATP production
3 Failure of synapses and sodium-potassium pumps

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Brain ischemia: Chain of Events

1 Oxygen and glucose deprivation

2 No ATP production
3 Failure of synapses and sodium-potassium pumps
4 Breakdown of the ionic gradients, leading to depolarization

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Brain ischemia: Chain of Events

1 Oxygen and glucose deprivation

2 No ATP production
3 Failure of synapses and sodium-potassium pumps
4 Breakdown of the ionic gradients, leading to depolarization
5 Cell swelling

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Brain ischemia: Chain of Events

1 Oxygen and glucose deprivation

2 No ATP production
3 Failure of synapses and sodium-potassium pumps
4 Breakdown of the ionic gradients, leading to depolarization
5 Cell swelling
6 Cell death

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Modeling Ischemia
Second generation Hodgkin-Huxley: HH + ion & volume dynamics

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Modeling Ischemia
Second generation Hodgkin-Huxley: HH + ion & volume dynamics
Explicitly modeling the Na+ -K+ -pump:
IP = 

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Pmax
1+

3.5 mM
[K+ ]o

2 

1+

Brain Ischemia

10 mM
[Na+ ]i

3 ,

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Modeling Ischemia
Second generation Hodgkin-Huxley: HH + ion & volume dynamics
Explicitly modeling the Na+ -K+ -pump:
IP = 

Pmax
1+

3.5 mM
[K+ ]o

2 

1+

10 mM
[Na+ ]i

3 ,

Specifying the leak currents:



INa = gNa,L + gNa,G m3 h (V ENa ) +3IP



IK = gK,L + gK,G n4 (V EK ) 2IP

ICl = gCl,L (V ECl )

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Glial Buffering

Passive cells, regulating ion concentrations in the extracellular space

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Glial Buffering

Passive cells, regulating ion concentrations in the extracellular space

Buffering of extracellular K+ through multiple mechanims:
Na+ -K+ -pumps, potassium channels, and cotransporters.

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Glial Buffering

Passive cells, regulating ion concentrations in the extracellular space

Buffering of extracellular K+ through multiple mechanims:
Na+ -K+ -pumps, potassium channels, and cotransporters. Implemented as
a simple, phenomenological ion flux:
JG =

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Gmax
1 + exp

18 mM[K+ ]o
2.5 mM

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Extracellular Diffusion

Diffusion of extracellular K+ to and from the blood is modeled by

JD = D [K+ ]o B .

D : Diffusion constant
B : Blood or bath concentration

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Extracellular Diffusion

Diffusion of extracellular K+ to and from the blood is modeled by

JD = D [K+ ]o B .

D : Diffusion constant
B : Blood or bath concentration

Enables comparison of the model with brain slice experiments.

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Ion Dynamics
Electroneutrality in intra- and extracellular space
[Na+ ]i + [K+ ]i = [Cl ]i + [A ]i ,
[Na+ ]o + [K+ ]o = [Cl ]o + [A ]o .

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Ion Dynamics
Electroneutrality in intra- and extracellular space
[Na+ ]i + [K+ ]i = [Cl ]i + [A ]i ,
[Na+ ]o + [K+ ]o = [Cl ]o + [A ]o .
Assumption: Total amount of sodium in the system is conserved
[Na+ ]o = 140 mM [Na+ ]i 10 mM .

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Ion Dynamics
Electroneutrality in intra- and extracellular space
[Na+ ]i + [K+ ]i = [Cl ]i + [A ]i ,
[Na+ ]o + [K+ ]o = [Cl ]o + [A ]o .
Assumption: Total amount of sodium in the system is conserved
[Na+ ]o = 140 mM [Na+ ]i 10 mM .

Ion dynamics:
d[Na+ ]i

[Na+ ]i dwi
= INa
,
dt
wi
wi dt
d[K+ ]o

JG + JD [K+ ]o dwo
=
IK

,
dt
wo
wo
wo dt

[Cl ]i dwi
d[Cl+ ]i
= ICl
.
dt
wi
wi dt
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Volume Dynamics
Assumption: Total volume is constant
wi + wo = wtot .

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Volume Dynamics
Assumption: Total volume is constant
wi + wo = wtot .
Volume change is driven by a difference in osmolarity of the intra- and
extracellular volume
dwi
= pH2 O (Oi Oo ) ,
dt

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Volume Dynamics
Assumption: Total volume is constant
wi + wo = wtot .
Volume change is driven by a difference in osmolarity of the intra- and
extracellular volume
dwi
= pH2 O (Oi Oo ) ,
dt
where
A
i
,
wi
A
Oo = [Na+ ]o + [K+ ]o + [Cl ]o + o ,
wo
Oi = [Na+ ]i + [K+ ]i + [Cl ]i +

and the timescale is set by pH2 O , the permeability of the neuron to water.
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Model Summary
Hodgkin-Huxley core:
dV
1
= (INa + IK + ICl ) ,
dt
C
dq
= q (1 q) q q,
q = m, h, n.
dt

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Model Summary
Hodgkin-Huxley core:
dV
1
= (INa + IK + ICl ) ,
dt
C
dq
= q (1 q) q q,
q = m, h, n.
dt
Ion dynamics:
d[Na+ ]i

[Na+ ]i
= INa pH2 O (Oi Oo )
,
dt
wi
wi

d[K+ ]o
JG + JD
[K+ ]o
=
IK
+ pH2 O (Oi Oo )
,
dt
wo
wo
wo
d[Cl+ ]i

[Cl ]i
= ICl pH2 O (Oi Oo )
.
dt
wi
wi

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Model Summary
Hodgkin-Huxley core:
dV
1
= (INa + IK + ICl ) ,
dt
C
dq
= q (1 q) q q,
q = m, h, n.
dt
Ion dynamics:
d[Na+ ]i

[Na+ ]i
= INa pH2 O (Oi Oo )
,
dt
wi
wi

d[K+ ]o
JG + JD
[K+ ]o
=
IK
+ pH2 O (Oi Oo )
,
dt
wo
wo
wo
d[Cl+ ]i

[Cl ]i
= ICl pH2 O (Oi Oo )
.
dt
wi
wi
Volume dynamics:
dwi
= pH2 O (Oi Oo ) .
dt
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Example 1: Anoxic Depolarization

Computer simulaties en in-vitro metingen

Zandt et al. Single neuron dynamics during

experimentally induced anoxic depolarization J.
Neurophysiology, 2013

Zandt et al. Neural Dynamics during Anoxia

and the Wave of Death, PlosOne, 2011

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Example 2: Seizure-like Events in High K+ Bath

[K+ ]o (mM)

10
8
6

V (mV)

Jensen and Yaari, Role of Intrinsic Burst Firing, Potassium Accumulation, and Electrical Coupling in the Elevated Potassium
Model of Hippocampal Epilepsy, J Neurophysiol, 1997

60
0
-60
20

60

100

140

180

220

time (s)
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Questions?

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