brain mapping of migraine aura

Brain Mapping of Migraine Aura

Markus A. Dahlem

Research group: Nonlinear Dynamics in Physiology and Medicine

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1311

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Visual hemifield Primary visual cortex

Special Brain Mapping Center Seminar June 19, 2012

Markus A. Dahlem, TU Berlin

Outline

1 Localized spots traveling in human cortex

2 Linking SD patterns to symptoms

3 Towards migraine therapy


IHS Classification ICHD-II – All Types

1.

1.1. 1.2. 1.4. 1.5. 1.6.1.3.

1.2.1. 1.3.1. 1.5.1. 1.6.1.

Sub

form

s

Migraine

Subtypes

2 symptom, 3 combinations: both or either of them


IHS Classification ICHD-II – Major Types

with aura

without aura

typical aurawithout headache

1.

1.1. 1.2.

1.2.1.

Sub

form

s

Migraine

Subtypes

1.1.

1.2.1.

1.2.3.



Mainly two neural theories of migraine

”Migraine generator”-theory

S1

PFCTh

PPC

PAG

Amyg Insula

SMA

ACC

”Spreading depression”-theory


”Migraine generator” in the brainstem

SD

aura

trigger


”Migraine generator” in the brainstem

?

trigger A

SD

trigger B

?

trigger C

?

trigger D

postdromeprodrome aura headache

mysterious conductor

about 1 day about 1 day4−72h< 60 min


A conductor of a neural orchestra playing migraine

?

trigger A

?

trigger C

?

trigger D

postdromeprodrome headache


trigger B

SD

aura




?

trigger A

?

trigger D

postdromeprodrome


headache

trigger C

?SD

trigger B

aura

about 1 day about 1 day< 60 min 4−72h



?

trigger A

SD

trigger B

?

trigger C

?

trigger D





SD is playing jazz – self-organizing dynamics

SD

postdromeaura headache


delaytime

trigger

prodrome

heightened susceptibility

cort

ical

hom

eost

asis

prodrome


Pathway of upstream and downstream events

SD

headacheprodrome aura

trigger

heig

hten

edsusceptibility

delayed trigger

Only one upstream trigger?Silent aura?Delayed headache link?


Migraine full-scale attack is more confined

(a) (b)

(c)

LS

CS

(d)

affected areatemporarily

Dahlem et al. ”2D wave patterns ... ”. Physcia D 239 (2010) Special issue: Emerging Phenomena.


SD wave in the cortex

-1

-2

-3

-4-7

-8

1 min

20 mV

log [cat] , M

(mM)

VeNa+

Na+

K+

Ve

K+

Ca++

Ca++

H+

0 10 20 30 s

150

6050

31.5

0.08

unitact.

Lauritzen (1994) Brain 117:199.


Cerebral blood flow in migraine

Radionuclide xenon 133 method, used to image brain’s blood flow

Olesen, J. , Larsen, B. and Lauritzen, M., Focal hyperemia followed by

spreading oligemia and impaired activation of rCBF in classic migraine, Ann.

Neurol. 9, 344 (1981)


Migraine full-scale attack is more confined

(a) (b)

(c)

LS

CS

(d)

affected areatemporarily

Dahlem et al. ”2D wave patterns ... ”. Physcia D 239 (2010) Special issue: Emerging Phenomena.


What is a migraine aura?


Migraine visual field defects reported in 1941 by K. Lashley

visual field defect pattern on primary visual cortex

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Only about 2-10% but not 50% cortical surface area is affected!Dahlem & Hadjikhani (2009) PLoS ONE 4: e5007.


Tracking migraine aura symptoms

Vincent & Hadjikhani (2007) Cephalagia 27


Confined spatial patterns of spreading depression

Hadjikhani et al. (2001) PNAS

Dahlem & Hadjikhani (2009) PLoS ONEDahlem & Muller (1997) Exp. Brain Res.



neighboring points

collapse

?

16 min

31 min

1 cm

nucleationrecordedslice not





23 min18 min.

28 min.





23 min18 min.

28 min.

Open wave fronts move along

a rather straight line

preventing a reentry of SD





23 min18 min.

28 min.

Open wave fronts move along

a rather straight line

preventing a reentry of SD

Hadjikhani et al. (2001) PNASDahlem & Hadjikhani (2009) PLoS ONE

Dahlem & Muller (1997) Exp. Brain Res.



18 min.

23 min

28 min.

33 min.

38 min.

1 mm

Spiral waves (reentry) observed in retinal SDwith a rotation period of 2.45 min

Hadjikhani et al. (2001) PNASDahlem & Hadjikhani (2009) PLoS ONEDahlem & Muller (1997) Exp. Brain Res.


Clinical evidence


Mapped visual symptoms on cortex via fMRI retinotopy

1 cm

10°

1 357

15

1719

2123

25

27 min


Dahlem & Hadjikhani (2009) PLoS ONE 4: e5007.


Mapped visual symptoms on cortex via fMRI retinotopy

23 min

21

19

17

17

15

1311

975

10°

1 cm


Dahlem & Hadjikhani (2009) PLoS ONE 4: e5007.


Cortical geometry

positive (fender)

negative (saddle)

gyral crowns

entrance to sulci

gyral crowns

entrance to sulci


The surface of the brain (cortex) is curved


Traveling spots are unstable (w/o long-range inhibition)

Schenk, C. P. , Or-Guil, M. , Bode, M. and Purwins, H. -G. , Phys. Rev. Lett. 78, 3781 (1997)


Minimum threshold in a flat geometry

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1.3 1.32 1.34 1.36 1.38 1.4

S

β

torus outside

flat

torus inside2

21

1

ring wave

1

2

∂P1D∂R∞


Nucleation failure on torus


Transient times in flat and curved geometry

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with controlwithout control

torus outside

flat

torus inside

ring wave

∂R∞

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S

t

outside

inside

outside

inside

torus, without controltorus, with control

flat, without control


Simulation of an engulfing SD wave

Folds

Bumbs

In cooperation with Jens Dreier &

Denny Milakara, Charite


Migraine scotoma are well explained

Pattern matching

”Curved” retinotopic mapping

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913

A B

C

Dahlem & Tusch, submitted to J. Math Neuroscie.



Pattern matching ”Curved” retinotopic mapping

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913

A B

C

A

C

BHM

10Æ10Æ





47

913

A B

C

a d

b ce

m

m lv u10Ælingual gyrus uneus CS





47

913

A B

C

2 4 6 8 10 12 14

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20406080

100120140

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1a 60Æ6Æ M=(a�1 )

HM�=(%)K=(mm2 ) �=(rad)a�2 00:20:40:60:8

b d



Linking SD patterns to symptoms

Outline






Cortical homeostasis is stable

Hypothesis: Cortical susceptibility to SD depends on the size ofthe momentarily affected tissue.



Yet, too big a perturbation triggers SD




Yet, too big a perturbation triggers SD


nucleationcritical



But a global negative feedback keeps SD confined


slow dynamicstransient and



Cellular models. What about cortex (continuum limit)?

ion

currents

ion gradient

ion

conductance

ion

pumps

activator−inhibitor dynamics

depolarization

firing rate

C∂V

∂t= −m∞(V )INa − n∞(V )IK − I

pumpK

(V )− IpumpNa

(V )

∂[ion]o

∂t=

IionA

FVolo+ Idiff

∂[ion]i

∂t=

IionA

FVoli

with

Iion = V αF Pion[ion]i − [ion]o e−αV

1− e−αV

Ipumpion (V ) = βion Imax

(1 +

KmK

[K ]o

)−2 (1 +

KmNa

[Na]i

)−3

M. A. Dahlem, Models of cortical SD, Scholarpedia (invited)



Cellular models. What about cortex (continuum limit)?

ion

currents

ion gradient

ion

conductance

ion

pumpsout in

diffu

sion

activator−inhibitor dynamics

depolarization

firing rate

neurovascular coupling

neural network activity

C∂V

∂t= −m∞(V )INa − n∞(V )IK − I

pumpK

(V )− IpumpNa

(V )

∂[ion]o

∂t=

IionA

FVolo+ Dion∇

2[ion]o

∂[ion]i

∂t=

IionA

FVoli

with

Iion = V αF Pion[ion]i − [ion]o e−αV

1− e−αV

Ipumpion (V ) = βion Imax

(1 +

KmK

[K ]o

)−2 (1 +

KmNa

[Na]i

)−3

F (S)

M. A. Dahlem, Models of cortical SD, Scholarpedia (invited)



Simulation of transient SD wave segment

gray = cortical surface; red = SD wave



Typical trajectory: fast growth and collapse & bottleneck

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collapse

cort

ical

sur

face

are

a in

vade

d by

SD nucleation

CSD break−up

long transient propagation

model−based

stimulation strategiestherapeutic TMS




neighboring points

collapse

?

16 min

31 min

1 cm

nucleationrecordedslice not




neighboring points

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time

16 min

31 min

1 cm

recordedslice not




neighboring points 16 min

31 min

1 cm

recordedslice not




5cm

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6 24

time / m

in



Varying contact to the ghost

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tota

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maximal instantaneous area (MIA)

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total affected area (TAA)

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(2)

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β0 = 1.34

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1102030405060708090100110120130



IHS Classification ICHD-II – Major Types

with aura

without aura

typical aurawithout headache

1.

1.1. 1.2.

1.2.1.

Sub

form

s

Migraine

Subtypes

1.1.

1.2.1.

1.2.3.




Model-based hypothesis testing

1.1. 1.2.1

1.2.3Sub−threshold

Affe

cted

cor

tical

are

aSurvival time

SD in migraine attack




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20

25

0 5 10 15 20 25 30 35time

collapse

cort

ical

sur

face

are

a in

vade

d by

SD nucleation

CSD break−up


model−based





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5

10

15

20

25

0 5 10 15 20 25 30 35time

cort

ical

sur

face

are

a in

vade

d by

SD

sensory innervation

arachnoid

bone

blood

dura dural sinuses

cortex

pia




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15

20

25

0 5 10 15 20 25 30 35time

cort

ical

sur

face

are

a in

vade

d by

SD

sensory innervation

arachnoid

bone

blood

dura

SD is pronociceptive

dural sinuses

cortex

pia

peak value


Towards migraine therapy

Outline






Neuromodulation

”The headache future is bright for neuromodulation techniques ... if wemanage to understand how they work” (Jean Schoenen)

figure courtesy of Jean Schoenen



Homo Neuromodulandus

”The headache future is bright for neuromodulation techniques ... if wemanage to understand how they work” (Jean Schoenen)

figure courtesy of Jean SchoenenMarkus A. Dahlem, TU Berlin


Control of spreading depression

From bench to bedside

!

!"#$%&'$()'#"*(

+,-+,."(!"#$%&/*#(

0&1'2(3"'$#(

4#&5$1"(!"#$%&'$()'#"*( 6/&'7/2%1"(!"#$%&'$()'#"*(

Cooperation with Stephen Schiff & Bruce Gluckman Courtesy of Neuralieve



From bifurcation bench to bedside




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collapse

cort

ical

sur

face

are

a in

vade

d by

SD nucleation

CSD break−up


model−based





0

5

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15

20

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0 5 10 15 20 25 30 35time

collapse

cort

ical

sur

face

are

a in

vade

d by

SD nucleation

CSD break−up


noise!

model−based




Single-pulse transcranial magnetic stimulation

Lipton et al. Lancet Neurology 9,373, 2010



Single-pulse transcranial magnetic stimulation



Double pulse stimulation (current TMS strategy)

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noise sample 1 k=0.010noise sample 1 k=0.100noise sample 1 k=0.300noise sample 2 k=0.010noise sample 2 k=0.100noise sample 2 k=0.300

without noise

time

noise on

wav

e si

ze



Permanent noise stimulation

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noise sample 1 k=0.030noise sample 1 k=0.040noise sample 1 k=0.050noise sample 2 k=0.030noise sample 2 k=0.040noise sample 2 k=0.050

without noise

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Single pulse vs. constant noise stimulation

0 5 10 15 20 25 30 35survival time of unstable solitons

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pro

babili

ty



Single pulse vs. constant noise stimulation

0 5 10 15 20 25 30 35survival time

0.0

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pro

babili

tyMigraine aura duration

without noiseon t=5, k = 0.050on t=5, k = 0.100noise 0.050pulse t=5, k = 0.100pulse t=5, k = 0.500



Noise sensitivity of transient wave segments

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without noisenoise k=0.010noise k=0.015noise k=0.020noise k=0.025noise k=0.030noise k=0.035noise k=0.040

wav

e si

ze

time

How to escape quicklyfrom the ”ghost” plateau?


Conclusion

(i) Persistent migraine w/o infarction, (ii) Migrainousinfarction, (iii) ischemia-induced migraine

Dahlem et al. Physica D 239, 889 (2010)


Conclusion

Clinical evidence for localized SD

Cortical perfusion measurement by indocyanine-green videoangiography inpatients undergoing hemicraniectomy for malignant stroke

cf. Woitzik J et al., Stroke 37,1549 (2006)


Conclusion

Conclusions

We need more non-invasive magingdata of the aura!

The predicted plateau (”ghost ofsaddle-node”) theory can be testedclinically with non-invasive imaging

Sef-organizing patterns provide aunifying concept including silent aura,migraine w or w/o headache/aura

Insights pattern formation may refineneuromodulation strategies:

Being close to a saddle-nodebifurcation (”ghost” plateau)Design (feedback) control tointelligently target certain propertiesof SD in migraine

1 cm

10°

1 357

15

1719

2123

25

27 min



Conclusion

Conclusions






SD

headacheprodrome aura

trigger

heig

hten

ed

susceptibility

delayed trigger


Conclusion

Conclusions






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450

tota

laff

ecte

dare

a(T

AA

)

(1)

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150

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exci

tati

ond

ura

tion

(ED

)

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(2)

(3)

(4)

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(1)

(2)

(3)

(4)

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240

#O

ccu

rren

ces

0 250 500


β0 = 1.34

(1)

(2)

(3)

(4)

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1102030405060708090100110120130


Conclusion ¡

Cooperation & Funding

Nouchine Hadjikhani(EPFL & Martinos Center for Biomedical Imaging, MGH)

Paul Van Valkenburgh

Jens Dreier(Department of Neurology, Charite; University Medicine, Berlin)

Steve Schiff(Penn State Center for Neural Engineering)

Klaus Podoll(University Hospital Aachen)

Thomas Isele

berlin

Migraine Aura Foundation


Conclusion ¡

2 symptoms, 3 combinations: both or either of them

SD ?

aura headache

trigger trigger


Conclusion ¡


SD ?

aura headache


trigger trigger


Conclusion ¡


?

trigger A

SD

trigger B

?

trigger C

?

trigger D





Conclusion ¡


?

trigger A

?

trigger C

?

trigger D



trigger B

SD

aura



Conclusion ¡


?

trigger A

?

trigger D

postdromeprodrome


headache

trigger C

?SD

trigger B

aura

about 1 day about 1 day< 60 min 4−72h


Conclusion ¡


SD



delaytime

trigger

prodrome


cort

ical

hom

eost

asis

prodrome


Conclusion ¡


SD


trigger

delayed trigger


heig

hten

ed

susceptibility


Conclusion ¡



trigger

delayed triggerSD


heig

hten

ed

susceptibility


Conclusion ¡



trigger

SD

?

delayed trigger


heig

hten

ed

susceptibility


Conclusion ¡

Orchestrated vs self-organizing dynamics


?

delayed trigger

about 1 day about 1 day4−72h

trigger

SD

< 60 min

aura

heig

hten

ed

susceptibility


Conclusion ¡

Orchestrated vs self-organizing dynamics

SD



delaytime

trigger

prodrome


cort

ical

hom

eost

asis

prodrome


Conclusion ¡

Localized stimulation: sampling of phase space

Retinotopic”A”-”Z”,”0”-”9” (36 patterns), 4 sizes, 10 stimulation strengths =33 420 stimulation patterns (elevation of activator concentration u)

12.56.25


Conclusion ¡


Orientation selective

−π/2

0

π/2


Conclusion ¡



0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9


Conclusion ¡

Visual migraine aura model

b

a

c

e

d

Dahlem et al. (2000) Eur. J. Neurosci. 12:767.

Dahlem and Chronicle (2004) Prog. Neurobiol. 74:351.


Conclusion Open wave segments - fMRI evidence & retinal SD

Tracking migraine aura symptoms

Vincent & Hadjikhani (2007) Cephalagia 27



2D patterns with laser speckle-contrast imaging

SG

EG

KCLMG

(a)

(b) 5 min 37s (c) 9 min 07s

Dahlem et al. 239, 889 (2009) Physica D



Re-entrant SD waves with anatomical block

Reshodko, L. V. and Bures, J Biol. Cybern. 18,181 (1975)



Drugs adjust excitability:retracting & collapsing waves

a b c

d e f

g h i

j k l

Dahlem et al. 2D wave patterns ... . (2010) Physcia D



Drugs adjust excitability:retracting & collapsing waves

What happens if SD wave fragments with open ende occur inhuman pathophysiology during migraine?

Do they form spirals?

Do fragments quickly retract?

Or: can wave fragments propagte some distance?



SD triggers trigeminal meningeal afferents, ie, headache

see e.g.: Bolay et al. Nature Medicine 8, 2002Review: Eikermann-Haerter & Moskowitz, Curr Opin Neurol. 21, 2008

Figure: Dodick & Gargus SciAm, August 2008



Parameter space of excitability

Classifications of excitabile elements and excitability in activemedia.

Schneider, Scholl & Dahlem, Chaos 19 015110, (2009)



Characteristic time scale due to bottleneck

Three spatiotempral SD patterns:2 short lasting patterns: large and low amplitude (∼90%)long lasting wave with characteristic shape (∼10%)

0 10 20 30 40 50 600

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40

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600.00.20.40.60.81.01.21.4

0.00.20.40.60.81.01.21.4



Noise sensitivity of transient wave segments

0

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20

25

0 5 10 15 20 25 30 35

without noisenoise k=0.010noise k=0.015noise k=0.020noise k=0.025noise k=0.030noise k=0.035noise k=0.040

wav

e si

ze

time

How to escape quicklyfrom the ”ghost” plateau?




Retinotopic”A”-”Z”,”0”-”9” (36 patterns), 4 sizes, 10 stimulation strengths =33 420 stimulation patterns (elevation of activator concentration u)

12.56.25





−π/2

0

π/2





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fMRI patterns is more diffuse than SD patterns

reference (min 0)

start (min 20)

end (min 30)

What if the the blood flow provides along-range or global negative feedback?

modified from Hadjikhani et al. (2001) PNAS 98



fMRI patterns is more diffuse than SD patterns

reference (min 0)

start (min 20)

end (min 30)

What if the the blood flow provides along-range or global negative feedback?modified from Hadjikhani et al. (2001) PNAS 98




”A”-”Z”,”0”-”9” (36 patterns), 4 sizes, 10 stimulation strengths =1440 stimulation patterns (elevation of activator concentration u)

12.56.25


brain mapping of migraine aura

Health & Medicine

tu berlin

migraine therapy markus

pnas markus

pnas dahlem hadjikhani

h markus

sd trigger b aura

depressiontheory markus

classic migraine