Brain Mapping of Migraine Aura

Markus A. Dahlem

Research group: Nonlinear Dynamics in Physiology and Medicine

5min7min

0 10 20 30 40 50mm

5min7min

9min11min

23 min

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

Outline

IHS Classification ICHD-II – All Types

1.1. 1.2. 1.4. 1.5. 1.6.1.3.

1.2.1. 1.3.1. 1.5.1. 1.6.1.

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. 1.2.

1.2.1.

Migraine

Subtypes

1.2.1.

1.2.3.

Mainly two neural theories of migraine

”Migraine generator”-theory

Amyg Insula

”Spreading depression”-theory

Mainly two neural theories of migraine

”Migraine generator”-theory

Amyg Insula

”Spreading depression”-theory

”Migraine generator” in the brainstem

trigger

”Migraine generator” in the brainstem

trigger A

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

trigger A

trigger D

postdromeprodrome

headache

trigger C

trigger B

about 1 day about 1 day< 60 min 4−72h

trigger A

trigger B

trigger C

trigger D

SD is playing jazz – self-organizing dynamics

postdromeaura headache

delaytime

trigger

prodrome

heightened susceptibility

prodrome

Pathway of upstream and downstream events

headacheprodrome aura

trigger

edsusceptibility

delayed trigger

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

Migraine full-scale attack is more confined

(a) (b)

affected areatemporarily

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

SD wave in the cortex

log [cat] , M

0 10 20 30 s

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)

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

5min7min

0 10 20 30 40 50mm

5min7min

9min11min

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

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.

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

27 min

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

Mapped visual symptoms on cortex via fMRI retinotopy

23 min

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

1.3 1.32 1.34 1.36 1.38 1.4

torus outside

torus inside2

ring wave

∂P1D∂R∞

Nucleation failure on torus

Transient times in flat and curved geometry

1.3 1.32 1.34 1.36 1.38

with controlwithout control

torus outside

torus inside

ring wave

∂R∞

0 10 20 30 40 50 60 70 80

outside

inside

outside

inside

torus, without controltorus, with control

flat, without control

Simulation of an engulfing SD wave

In cooperation with Jens Dreier &

Denny Milakara, Charite

Migraine scotoma are well explained

Pattern matching

”Curved” retinotopic mapping

Dahlem & Tusch, submitted to J. Math Neuroscie.

Pattern matching ”Curved” retinotopic mapping

10Æ10Æ

m lv u10Ælingual gyrus uneus CS

2 4 6 8 10 12 14

20406080

100120140

2 4 6 8 10 12 14

1a 60Æ6Æ M=(a�1 )

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

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

nucleationcritical

But a global negative feedback keeps SD confined

slow dynamicstransient and

Cellular models. What about cortex (continuum limit)?

currents

ion gradient

conductance

activator−inhibitor dynamics

depolarization

firing rate

∂t= −m∞(V )INa − n∞(V )IK − I

(V )− IpumpNa

∂[ion]o

FVolo+ Idiff

∂[ion]i

Iion = V αF Pion[ion]i − [ion]o e−αV

1− e−αV

Ipumpion (V ) = βion Imax

)−2 (1 +

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

Cellular models. What about cortex (continuum limit)?

currents

ion gradient

conductance

pumpsout in

activator−inhibitor dynamics

depolarization

firing rate

neurovascular coupling

neural network activity

∂t= −m∞(V )INa − n∞(V )IK − I

(V )− IpumpNa

∂[ion]o

FVolo+ Dion∇

2[ion]o

∂[ion]i

Iion = V αF Pion[ion]i − [ion]o e−αV

1− e−αV

Ipumpion (V ) = βion Imax

)−2 (1 +

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

0 5 10 15 20 25 30 35time

collapse

SD nucleation

CSD break−up

long transient propagation

model−based

stimulation strategiestherapeutic TMS

neighboring points

collapse

16 min

31 min

nucleationrecordedslice not

neighboring points

16 min

31 min

recordedslice not

neighboring points 16 min

31 min

recordedslice not

31 min

recordedslice not

31 min

recordedslice not

time / m

Varying contact to the ghost

0 10 20 30 40 50 60

maximal instantaneous area (MIA)

0 50 100 150 200 250 300 350 400 450

total affected area (TAA)

0 80 160240

0 80 160240# Occurrences

β0 = 1.32

(2) (3)

0 30 60 90 120150180210240270time

0 10 20 30 40 50 60

0 50 100 150 200 250 300 350 400 450

0 100 200

0 100200300# Occurrences

β0 = 1.33

0 20 40 60 80 100120140160180time

0 10 20 30 40 50 60

0 50 100 150 200 250 300 350 400 450

0 250 500

β0 = 1.34

0 10 20 30 40 50 60 70 80 90time

1102030405060708090100110120130

IHS Classification ICHD-II – Major Types

with aura

without aura

typical aurawithout headache

1.1. 1.2.

1.2.1.

Migraine

Subtypes

1.2.1.

1.2.3.

Model-based hypothesis testing

1.1. 1.2.1

1.2.3Sub−threshold

aSurvival time

SD in migraine attack

0 5 10 15 20 25 30 35time

collapse

SD nucleation

CSD break−up

model−based

0 5 10 15 20 25 30 35time

sensory innervation

arachnoid

dura dural sinuses

cortex

0 5 10 15 20 25 30 35time

sensory innervation

arachnoid

SD is pronociceptive

dural sinuses

cortex

peak value

0 5 10 15 20 25 30 35time

sensory innervation

arachnoid

SD is pronociceptive

dural sinuses

cortex

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

Neuromodulation

Homo Neuromodulandus

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

0 5 10 15 20 25 30 35time

collapse

SD nucleation

CSD break−up

model−based

0 5 10 15 20 25 30 35time

collapse

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)

0 5 10 15 20 25 30 35

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

noise on

Permanent noise stimulation

0 5 10 15 20 25 30 35

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

noise on

Single pulse vs. constant noise stimulation

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

babili

Single pulse vs. constant noise stimulation

0 5 10 15 20 25 30 35survival time

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

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

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

27 min

Conclusion

Conclusions

headacheprodrome aura

trigger

susceptibility

delayed trigger

Conclusion

Conclusions

0 10 20 30 40 50 60

0 50 100 150 200 250 300 350 400 450

0 250 500

β0 = 1.34

0 10 20 30 40 50 60 70 80 90time

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

aura headache

trigger trigger

Conclusion ¡

aura headache

trigger trigger

Conclusion ¡

trigger A

trigger B

trigger C

trigger D

Conclusion ¡

trigger A

trigger C

trigger D

trigger B

Conclusion ¡

trigger A

trigger D

postdromeprodrome

headache

trigger C

trigger B

about 1 day about 1 day< 60 min 4−72h

Conclusion ¡

delaytime

trigger

prodrome

Conclusion ¡

trigger

delayed trigger

susceptibility

Conclusion ¡

trigger

delayed trigger

susceptibility

Conclusion ¡

trigger

delayed triggerSD

susceptibility

Conclusion ¡

trigger

delayed trigger

susceptibility

Conclusion ¡

Orchestrated vs self-organizing dynamics

delayed trigger

about 1 day about 1 day4−72h

trigger

< 60 min

susceptibility

Conclusion ¡

Orchestrated vs self-organizing dynamics

delaytime

trigger

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

Conclusion ¡

−π/2

Conclusion ¡

Visual migraine aura model

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

2D patterns with laser speckle-contrast imaging

(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

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)

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

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 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

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

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

Transcript of Brain Mapping of Migraine Aura

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