Brain Mapping of Migraine Aura
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Brain Mapping of Migraine Aura
Markus A. Dahlem
Research group: Nonlinear Dynamics in Physiology and Medicine
0
5
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5min7min
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11min
15min
0 10 20 30 40 50mm
5min7min
9min11min
15min
23 min
21
19
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17
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1311
975
10°
1 cm
Visual hemifield Primary visual cortex
Special Brain Mapping Center Seminar June 19, 2012
Markus A. Dahlem, TU Berlin
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Outline
1 Localized spots traveling in human cortex
2 Linking SD patterns to symptoms
3 Towards migraine therapy
Markus A. Dahlem, TU Berlin
![Page 3: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/3.jpg)
Outline
1 Localized spots traveling in human cortex
2 Linking SD patterns to symptoms
3 Towards migraine therapy
Markus A. Dahlem, TU Berlin
![Page 4: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/4.jpg)
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
Markus A. Dahlem, TU Berlin
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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.
2 symptom, 3 combinations: both or either of them
Markus A. Dahlem, TU Berlin
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Mainly two neural theories of migraine
”Migraine generator”-theory
S1
PFCTh
PPC
PAG
Amyg Insula
SMA
ACC
”Spreading depression”-theory
Markus A. Dahlem, TU Berlin
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Mainly two neural theories of migraine
”Migraine generator”-theory
S1
PFCTh
PPC
PAG
Amyg Insula
SMA
ACC
”Spreading depression”-theory
Markus A. Dahlem, TU Berlin
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”Migraine generator” in the brainstem
SD
aura
trigger
Markus A. Dahlem, TU Berlin
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”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
Markus A. Dahlem, TU Berlin
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A conductor of a neural orchestra playing migraine
?
trigger A
?
trigger C
?
trigger D
postdromeprodrome headache
mysterious conductor
trigger B
SD
aura
about 1 day about 1 day4−72h< 60 min
Markus A. Dahlem, TU Berlin
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A conductor of a neural orchestra playing migraine
?
trigger A
?
trigger D
postdromeprodrome
mysterious conductor
headache
trigger C
?SD
trigger B
aura
about 1 day about 1 day< 60 min 4−72h
Markus A. Dahlem, TU Berlin
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A conductor of a neural orchestra playing migraine
?
trigger A
SD
trigger B
?
trigger C
?
trigger D
postdromeprodrome aura headache
mysterious conductor
about 1 day about 1 day4−72h< 60 min
Markus A. Dahlem, TU Berlin
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SD is playing jazz – self-organizing dynamics
SD
postdromeaura headache
about 1 day about 1 day4−72h< 60 min
delaytime
trigger
prodrome
heightened susceptibility
cort
ical
hom
eost
asis
prodrome
Markus A. Dahlem, TU Berlin
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Pathway of upstream and downstream events
SD
headacheprodrome aura
trigger
heig
hten
edsusceptibility
delayed trigger
Only one upstream trigger?Silent aura?Delayed headache link?
Markus A. Dahlem, TU Berlin
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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.
Markus A. Dahlem, TU Berlin
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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.
Markus A. Dahlem, TU Berlin
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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)
Markus A. Dahlem, TU Berlin
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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.
Markus A. Dahlem, TU Berlin
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What is a migraine aura?
Markus A. Dahlem, TU Berlin
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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.
Markus A. Dahlem, TU Berlin
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Tracking migraine aura symptoms
Vincent & Hadjikhani (2007) Cephalagia 27
Markus A. Dahlem, TU Berlin
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Tracking migraine aura symptoms
Vincent & Hadjikhani (2007) Cephalagia 27
Markus A. Dahlem, TU Berlin
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Confined spatial patterns of spreading depression
Hadjikhani et al. (2001) PNAS
Dahlem & Hadjikhani (2009) PLoS ONEDahlem & Muller (1997) Exp. Brain Res.
Markus A. Dahlem, TU Berlin
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Confined spatial patterns of spreading depression
neighboring points
collapse
?
16 min
31 min
1 cm
nucleationrecordedslice not
Hadjikhani et al. (2001) PNAS
Dahlem & Hadjikhani (2009) PLoS ONEDahlem & Muller (1997) Exp. Brain Res.
Markus A. Dahlem, TU Berlin
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Confined spatial patterns of spreading depression
23 min18 min.
28 min.
Hadjikhani et al. (2001) PNAS
Dahlem & Hadjikhani (2009) PLoS ONEDahlem & Muller (1997) Exp. Brain Res.
Markus A. Dahlem, TU Berlin
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Confined spatial patterns of spreading depression
23 min18 min.
28 min.
Open wave fronts move along
a rather straight line
preventing a reentry of SD
Hadjikhani et al. (2001) PNAS
Dahlem & Hadjikhani (2009) PLoS ONEDahlem & Muller (1997) Exp. Brain Res.
Markus A. Dahlem, TU Berlin
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Confined spatial patterns of spreading depression
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.
Markus A. Dahlem, TU Berlin
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Confined spatial patterns of spreading depression
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.
Markus A. Dahlem, TU Berlin
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Clinical evidence
Markus A. Dahlem, TU Berlin
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Mapped visual symptoms on cortex via fMRI retinotopy
1 cm
10°
1 357
15
1719
2123
25
27 min
Visual hemifield Primary visual cortex
Dahlem & Hadjikhani (2009) PLoS ONE 4: e5007.
Markus A. Dahlem, TU Berlin
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Mapped visual symptoms on cortex via fMRI retinotopy
23 min
21
19
17
17
15
1311
975
10°
1 cm
Visual hemifield Primary visual cortex
Dahlem & Hadjikhani (2009) PLoS ONE 4: e5007.
Markus A. Dahlem, TU Berlin
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Cortical geometry
positive (fender)
negative (saddle)
gyral crowns
entrance to sulci
gyral crowns
entrance to sulci
Markus A. Dahlem, TU Berlin
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The surface of the brain (cortex) is curved
Markus A. Dahlem, TU Berlin
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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)
Markus A. Dahlem, TU Berlin
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Minimum threshold in a flat geometry
0
20
40
60
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∞
Markus A. Dahlem, TU Berlin
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Nucleation failure on torus
Markus A. Dahlem, TU Berlin
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Transient times in flat and curved geometry
0
10
20
30
40
50
1.3 1.32 1.34 1.36 1.38
S
β
with controlwithout control
torus outside
flat
torus inside
ring wave
∂R∞
0
10
20
30
0 10 20 30 40 50 60 70 80
S
t
outside
inside
outside
inside
torus, without controltorus, with control
flat, without control
Markus A. Dahlem, TU Berlin
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Simulation of an engulfing SD wave
Folds
Bumbs
In cooperation with Jens Dreier &
Denny Milakara, Charite
Markus A. Dahlem, TU Berlin
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Migraine scotoma are well explained
Pattern matching
”Curved” retinotopic mapping
47
913
A B
C
Dahlem & Tusch, submitted to J. Math Neuroscie.
Markus A. Dahlem, TU Berlin
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Migraine scotoma are well explained
Pattern matching ”Curved” retinotopic mapping
47
913
A B
C
A
C
BHM
10Æ10Æ
Dahlem & Tusch, submitted to J. Math Neuroscie.
Markus A. Dahlem, TU Berlin
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Migraine scotoma are well explained
Pattern matching ”Curved” retinotopic mapping
47
913
A B
C
a d
b ce
m
m lv u10Ælingual gyrus uneus CS
Dahlem & Tusch, submitted to J. Math Neuroscie.
Markus A. Dahlem, TU Berlin
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Migraine scotoma are well explained
Pattern matching ”Curved” retinotopic mapping
47
913
A B
C
2 4 6 8 10 12 14
0.1
0.2
0.3
2 4 6 8 10 12 14
20406080
100120140
2 4 6 8 10 12 14
0.2
0.4
0.6
0.8
1a 60Æ6Æ M=(a�1 )
HM�=(%)K=(mm2 ) �=(rad)a�2 00:20:40:60:8
b d
Dahlem & Tusch, submitted to J. Math Neuroscie.
Markus A. Dahlem, TU Berlin
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Linking SD patterns to symptoms
Outline
1 Localized spots traveling in human cortex
2 Linking SD patterns to symptoms
3 Towards migraine therapy
Markus A. Dahlem, TU Berlin
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Linking SD patterns to symptoms
Cortical homeostasis is stable
Hypothesis: Cortical susceptibility to SD depends on the size ofthe momentarily affected tissue.
Markus A. Dahlem, TU Berlin
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Linking SD patterns to symptoms
Yet, too big a perturbation triggers SD
Hypothesis: Cortical susceptibility to SD depends on the size ofthe momentarily affected tissue.
Markus A. Dahlem, TU Berlin
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Linking SD patterns to symptoms
Yet, too big a perturbation triggers SD
Hypothesis: Cortical susceptibility to SD depends on the size ofthe momentarily affected tissue.
nucleationcritical
Markus A. Dahlem, TU Berlin
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Linking SD patterns to symptoms
But a global negative feedback keeps SD confined
Hypothesis: Cortical susceptibility to SD depends on the size ofthe momentarily affected tissue.
slow dynamicstransient and
Markus A. Dahlem, TU Berlin
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Linking SD patterns to symptoms
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)
Markus A. Dahlem, TU Berlin
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Linking SD patterns to symptoms
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)
Markus A. Dahlem, TU Berlin
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Linking SD patterns to symptoms
Simulation of transient SD wave segment
gray = cortical surface; red = SD wave
Markus A. Dahlem, TU Berlin
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Linking SD patterns to symptoms
Typical trajectory: fast growth and collapse & bottleneck
0
5
10
15
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
long transient propagation
model−based
stimulation strategiestherapeutic TMS
Markus A. Dahlem, TU Berlin
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Linking SD patterns to symptoms
Confined spatial patterns of spreading depression
neighboring points
collapse
?
16 min
31 min
1 cm
nucleationrecordedslice not
Markus A. Dahlem, TU Berlin
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Linking SD patterns to symptoms
Confined spatial patterns of spreading depression
neighboring points
0
4
8
12
16
20
32
28
24
time
16 min
31 min
1 cm
recordedslice not
Markus A. Dahlem, TU Berlin
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Linking SD patterns to symptoms
Confined spatial patterns of spreading depression
neighboring points 16 min
31 min
1 cm
recordedslice not
Markus A. Dahlem, TU Berlin
![Page 55: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/55.jpg)
Linking SD patterns to symptoms
Confined spatial patterns of spreading depression
neighboring points 16 min
31 min
1 cm
recordedslice not
Markus A. Dahlem, TU Berlin
![Page 56: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/56.jpg)
Linking SD patterns to symptoms
Confined spatial patterns of spreading depression
neighboring points 16 min
31 min
1 cm
recordedslice not
Markus A. Dahlem, TU Berlin
![Page 57: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/57.jpg)
Linking SD patterns to symptoms
Confined spatial patterns of spreading depression
5cm
00
0 0
32 16
6 24
time / m
in
Markus A. Dahlem, TU Berlin
![Page 58: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/58.jpg)
Linking SD patterns to symptoms
Varying contact to the ghost
0
50
100
150
200
250
300
350
400
450
tota
laff
ecte
dar
ea(T
AA
)
(1)
(2)
(3)
(4)
0 10 20 30 40 50 60
maximal instantaneous area (MIA)
0
50
100
150
200
250
300
exci
tati
on
du
rati
on(E
D)
(1)
(2)
(3)
(4)
0 50 100 150 200 250 300 350 400 450
total affected area (TAA)
(1)
(2)
(3)
(4)
0
80
160
240
#O
ccu
rren
ces
0 80 160240
0 80 160240# Occurrences
β0 = 1.32
(1)
(2) (3)
(4)
0 30 60 90 120150180210240270time
1
10
20
30
40
50
60
70
80
Markus A. Dahlem, TU Berlin
![Page 59: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/59.jpg)
Linking SD patterns to symptoms
Varying contact to the ghost
0
50
100
150
200
250
300
350
400
450
tota
laff
ecte
dar
ea(T
AA
)
(1)
(2)
(3)
(4)
0 10 20 30 40 50 60
maximal instantaneous area (MIA)
0
50
100
150
200
250
300
exci
tati
on
du
rati
on(E
D)
(1)
(2)
(3)
(4)
0 50 100 150 200 250 300 350 400 450
total affected area (TAA)
(1)
(2)
(3)
(4)
0
80
160
240
#O
ccu
rren
ces
0 100 200
0 100200300# Occurrences
β0 = 1.33
(1)
(2)
(3)
(4)
0 20 40 60 80 100120140160180time
1
10
20
30
40
50
60
70
80
90
Markus A. Dahlem, TU Berlin
![Page 60: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/60.jpg)
Linking SD patterns to symptoms
Varying contact to the ghost
0
50
100
150
200
250
300
350
400
450
tota
laff
ecte
dar
ea(T
AA
)
(1)
(2)
(3)
(4)
0 10 20 30 40 50 60
maximal instantaneous area (MIA)
0
50
100
150
200
250
300
exci
tati
on
du
rati
on(E
D)
(1)
(2)
(3)
(4)
0 50 100 150 200 250 300 350 400 450
total affected area (TAA)
(1)
(2)
(3)
(4)
0
80
160
240
#O
ccu
rren
ces
0 250 500
0 150 300# Occurrences
β0 = 1.34
(1)
(2)
(3)
(4)
0 10 20 30 40 50 60 70 80 90time
1102030405060708090100110120130
Markus A. Dahlem, TU Berlin
![Page 61: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/61.jpg)
Linking SD patterns to symptoms
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.
2 symptom, 3 combinations: both or either of them
Markus A. Dahlem, TU Berlin
![Page 62: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/62.jpg)
Linking SD patterns to symptoms
Model-based hypothesis testing
1.1. 1.2.1
1.2.3Sub−threshold
Affe
cted
cor
tical
are
aSurvival time
SD in migraine attack
Markus A. Dahlem, TU Berlin
![Page 63: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/63.jpg)
Linking SD patterns to symptoms
Typical trajectory: fast growth and collapse & bottleneck
0
5
10
15
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
long transient propagation
model−based
stimulation strategiestherapeutic TMS
Markus A. Dahlem, TU Berlin
![Page 64: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/64.jpg)
Linking SD patterns to symptoms
Typical trajectory: fast growth and collapse & bottleneck
0
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
Markus A. Dahlem, TU Berlin
![Page 65: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/65.jpg)
Linking SD patterns to symptoms
Typical trajectory: fast growth and collapse & bottleneck
0
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
SD is pronociceptive
dural sinuses
cortex
pia
peak value
Markus A. Dahlem, TU Berlin
![Page 66: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/66.jpg)
Linking SD patterns to symptoms
Typical trajectory: fast growth and collapse & bottleneck
0
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
SD is pronociceptive
dural sinuses
cortex
pia
peak value
Markus A. Dahlem, TU Berlin
![Page 67: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/67.jpg)
Towards migraine therapy
Outline
1 Localized spots traveling in human cortex
2 Linking SD patterns to symptoms
3 Towards migraine therapy
Markus A. Dahlem, TU Berlin
![Page 68: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/68.jpg)
Towards migraine therapy
Neuromodulation
”The headache future is bright for neuromodulation techniques ... if wemanage to understand how they work” (Jean Schoenen)
figure courtesy of Jean Schoenen
Markus A. Dahlem, TU Berlin
![Page 69: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/69.jpg)
Towards migraine therapy
Neuromodulation
”The headache future is bright for neuromodulation techniques ... if wemanage to understand how they work” (Jean Schoenen)
figure courtesy of Jean Schoenen
Markus A. Dahlem, TU Berlin
![Page 70: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/70.jpg)
Towards migraine therapy
Neuromodulation
”The headache future is bright for neuromodulation techniques ... if wemanage to understand how they work” (Jean Schoenen)
figure courtesy of Jean Schoenen
Markus A. Dahlem, TU Berlin
![Page 71: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/71.jpg)
Towards migraine therapy
Neuromodulation
”The headache future is bright for neuromodulation techniques ... if wemanage to understand how they work” (Jean Schoenen)
figure courtesy of Jean Schoenen
Markus A. Dahlem, TU Berlin
![Page 72: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/72.jpg)
Towards migraine therapy
Neuromodulation
”The headache future is bright for neuromodulation techniques ... if wemanage to understand how they work” (Jean Schoenen)
figure courtesy of Jean Schoenen
Markus A. Dahlem, TU Berlin
![Page 73: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/73.jpg)
Towards migraine therapy
Neuromodulation
”The headache future is bright for neuromodulation techniques ... if wemanage to understand how they work” (Jean Schoenen)
figure courtesy of Jean Schoenen
Markus A. Dahlem, TU Berlin
![Page 74: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/74.jpg)
Towards migraine therapy
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
![Page 75: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/75.jpg)
Towards migraine therapy
Control of spreading depression
From bench to bedside
!
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+,-+,."(!"#$%&/*#(
0&1'2(3"'$#(
4#&5$1"(!"#$%&'$()'#"*( 6/&'7/2%1"(!"#$%&'$()'#"*(
Cooperation with Stephen Schiff & Bruce Gluckman Courtesy of Neuralieve
Markus A. Dahlem, TU Berlin
![Page 76: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/76.jpg)
Towards migraine therapy
From bifurcation bench to bedside
Markus A. Dahlem, TU Berlin
![Page 77: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/77.jpg)
Towards migraine therapy
From bifurcation bench to bedside
Markus A. Dahlem, TU Berlin
![Page 78: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/78.jpg)
Towards migraine therapy
From bifurcation bench to bedside
Markus A. Dahlem, TU Berlin
![Page 79: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/79.jpg)
Towards migraine therapy
From bifurcation bench to bedside
Markus A. Dahlem, TU Berlin
![Page 80: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/80.jpg)
Towards migraine therapy
Typical trajectory: fast growth and collapse & bottleneck
0
5
10
15
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
long transient propagation
model−based
stimulation strategiestherapeutic TMS
Markus A. Dahlem, TU Berlin
![Page 81: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/81.jpg)
Towards migraine therapy
Typical trajectory: fast growth and collapse & bottleneck
0
5
10
15
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
long transient propagation
noise!
model−based
stimulation strategiestherapeutic TMS
Markus A. Dahlem, TU Berlin
![Page 82: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/82.jpg)
Towards migraine therapy
Single-pulse transcranial magnetic stimulation
Lipton et al. Lancet Neurology 9,373, 2010
Markus A. Dahlem, TU Berlin
![Page 83: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/83.jpg)
Towards migraine therapy
Single-pulse transcranial magnetic stimulation
Markus A. Dahlem, TU Berlin
![Page 84: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/84.jpg)
Towards migraine therapy
Double pulse stimulation (current TMS strategy)
0
5
10
15
20
25
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
time
noise on
wav
e si
ze
Markus A. Dahlem, TU Berlin
![Page 85: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/85.jpg)
Towards migraine therapy
Permanent noise stimulation
0
5
10
15
20
25
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
time
noise on
wav
e si
ze
Markus A. Dahlem, TU Berlin
![Page 86: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/86.jpg)
Towards migraine therapy
Single pulse vs. constant noise stimulation
0 5 10 15 20 25 30 35survival time of unstable solitons
0.0
0.1
0.2
0.3
0.4
0.5
pro
babili
ty
Markus A. Dahlem, TU Berlin
![Page 87: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/87.jpg)
Towards migraine therapy
Single pulse vs. constant noise stimulation
0 5 10 15 20 25 30 35survival time
0.0
0.1
0.2
0.3
0.4
0.5
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
Markus A. Dahlem, TU Berlin
![Page 88: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/88.jpg)
Towards migraine therapy
Noise sensitivity of transient wave segments
0
5
10
15
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?
Markus A. Dahlem, TU Berlin
![Page 89: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/89.jpg)
Conclusion
(i) Persistent migraine w/o infarction, (ii) Migrainousinfarction, (iii) ischemia-induced migraine
Dahlem et al. Physica D 239, 889 (2010)
Markus A. Dahlem, TU Berlin
![Page 90: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/90.jpg)
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)
Markus A. Dahlem, TU Berlin
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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
Visual hemifield Primary visual cortex
Markus A. Dahlem, TU Berlin
![Page 92: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/92.jpg)
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
SD
headacheprodrome aura
trigger
heig
hten
ed
susceptibility
delayed trigger
Markus A. Dahlem, TU Berlin
![Page 93: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/93.jpg)
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
0
50
100
150
200
250
300
350
400
450
tota
laff
ecte
dare
a(T
AA
)
(1)
(2)
(3)
(4)
0 10 20 30 40 50 60
maximal instantaneous area (MIA)
0
50
100
150
200
250
300
exci
tati
ond
ura
tion
(ED
)
(1)
(2)
(3)
(4)
0 50 100 150 200 250 300 350 400 450
total affected area (TAA)
(1)
(2)
(3)
(4)
0
80
160
240
#O
ccu
rren
ces
0 250 500
0 150 300# Occurrences
β0 = 1.34
(1)
(2)
(3)
(4)
0 10 20 30 40 50 60 70 80 90time
1102030405060708090100110120130
Markus A. Dahlem, TU Berlin
![Page 94: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/94.jpg)
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
Markus A. Dahlem, TU Berlin
![Page 95: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/95.jpg)
Conclusion ¡
2 symptoms, 3 combinations: both or either of them
SD ?
aura headache
trigger trigger
Markus A. Dahlem, TU Berlin
![Page 96: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/96.jpg)
Conclusion ¡
A conductor of a neural orchestra playing migraine
SD ?
aura headache
mysterious conductor
trigger trigger
Markus A. Dahlem, TU Berlin
![Page 97: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/97.jpg)
Conclusion ¡
A conductor of a neural orchestra playing migraine
?
trigger A
SD
trigger B
?
trigger C
?
trigger D
postdromeprodrome aura headache
mysterious conductor
about 1 day about 1 day4−72h< 60 min
Markus A. Dahlem, TU Berlin
![Page 98: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/98.jpg)
Conclusion ¡
A conductor of a neural orchestra playing migraine
?
trigger A
?
trigger C
?
trigger D
postdromeprodrome headache
mysterious conductor
trigger B
SD
aura
about 1 day about 1 day4−72h< 60 min
Markus A. Dahlem, TU Berlin
![Page 99: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/99.jpg)
Conclusion ¡
A conductor of a neural orchestra playing migraine
?
trigger A
?
trigger D
postdromeprodrome
mysterious conductor
headache
trigger C
?SD
trigger B
aura
about 1 day about 1 day< 60 min 4−72h
Markus A. Dahlem, TU Berlin
![Page 100: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/100.jpg)
Conclusion ¡
SD is playing jazz – self-organizing dynamics
SD
postdromeaura headache
about 1 day about 1 day4−72h< 60 min
delaytime
trigger
prodrome
heightened susceptibility
cort
ical
hom
eost
asis
prodrome
Markus A. Dahlem, TU Berlin
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Conclusion ¡
SD is playing jazz – self-organizing dynamics
SD
postdromeprodrome aura headache
trigger
delayed trigger
about 1 day about 1 day4−72h< 60 min
heig
hten
ed
susceptibility
Markus A. Dahlem, TU Berlin
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Conclusion ¡
SD is playing jazz – self-organizing dynamics
SD
postdromeprodrome aura headache
trigger
delayed trigger
about 1 day about 1 day4−72h< 60 min
heig
hten
ed
susceptibility
Markus A. Dahlem, TU Berlin
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Conclusion ¡
SD is playing jazz – self-organizing dynamics
postdromeprodrome aura headache
trigger
delayed triggerSD
about 1 day about 1 day4−72h< 60 min
heig
hten
ed
susceptibility
Markus A. Dahlem, TU Berlin
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Conclusion ¡
SD is playing jazz – self-organizing dynamics
postdromeprodrome aura headache
trigger
SD
?
delayed trigger
about 1 day about 1 day4−72h< 60 min
heig
hten
ed
susceptibility
Markus A. Dahlem, TU Berlin
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Conclusion ¡
Orchestrated vs self-organizing dynamics
postdromeprodrome headache
?
delayed trigger
about 1 day about 1 day4−72h
trigger
SD
< 60 min
aura
heig
hten
ed
susceptibility
Markus A. Dahlem, TU Berlin
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Conclusion ¡
Orchestrated vs self-organizing dynamics
SD
postdromeaura headache
about 1 day about 1 day4−72h< 60 min
delaytime
trigger
prodrome
heightened susceptibility
cort
ical
hom
eost
asis
prodrome
Markus A. Dahlem, TU Berlin
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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
Markus A. Dahlem, TU Berlin
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Conclusion ¡
Localized stimulation: sampling of phase space
Orientation selective
−π/2
0
π/2
Markus A. Dahlem, TU Berlin
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Conclusion ¡
Localized stimulation: sampling of phase space
Orientation selective
−π/2
0
π/2
Markus A. Dahlem, TU Berlin
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Conclusion ¡
Localized stimulation: sampling of phase space
Orientation selective
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Markus A. Dahlem, TU Berlin
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Conclusion ¡
Localized stimulation: sampling of phase space
Orientation selective
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Markus A. Dahlem, TU Berlin
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Conclusion ¡
Localized stimulation: sampling of phase space
Orientation selective
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Markus A. Dahlem, TU Berlin
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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.
Markus A. Dahlem, TU Berlin
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Conclusion Open wave segments - fMRI evidence & retinal SD
Tracking migraine aura symptoms
Vincent & Hadjikhani (2007) Cephalagia 27
Markus A. Dahlem, TU Berlin
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Conclusion Open wave segments - fMRI evidence & retinal SD
Tracking migraine aura symptoms
Vincent & Hadjikhani (2007) Cephalagia 27
Markus A. Dahlem, TU Berlin
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Conclusion Open wave segments - fMRI evidence & retinal SD
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
Markus A. Dahlem, TU Berlin
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Conclusion Open wave segments - fMRI evidence & retinal SD
Re-entrant SD waves with anatomical block
Reshodko, L. V. and Bures, J Biol. Cybern. 18,181 (1975)
Markus A. Dahlem, TU Berlin
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Conclusion Open wave segments - fMRI evidence & retinal SD
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
Markus A. Dahlem, TU Berlin
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Conclusion Open wave segments - fMRI evidence & retinal SD
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?
Markus A. Dahlem, TU Berlin
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Conclusion Open wave segments - fMRI evidence & retinal SD
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
Markus A. Dahlem, TU Berlin
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Conclusion Open wave segments - fMRI evidence & retinal SD
Parameter space of excitability
Classifications of excitabile elements and excitability in activemedia.
Schneider, Scholl & Dahlem, Chaos 19 015110, (2009)
Markus A. Dahlem, TU Berlin
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Conclusion Open wave segments - fMRI evidence & retinal SD
Parameter space of excitability
Classifications of excitabile elements and excitability in activemedia.
Schneider, Scholl & Dahlem, Chaos 19 015110, (2009)
Markus A. Dahlem, TU Berlin
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Conclusion Open wave segments - fMRI evidence & retinal SD
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
10
20
30
40
50
600.00.20.40.60.81.01.21.4
0.00.20.40.60.81.01.21.4
Markus A. Dahlem, TU Berlin
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Conclusion Open wave segments - fMRI evidence & retinal SD
Noise sensitivity of transient wave segments
0
5
10
15
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?
Markus A. Dahlem, TU Berlin
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Conclusion Open wave segments - fMRI evidence & retinal SD
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
Markus A. Dahlem, TU Berlin
![Page 126: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/126.jpg)
Conclusion Open wave segments - fMRI evidence & retinal SD
Localized stimulation: sampling of phase space
Orientation selective
−π/2
0
π/2
Markus A. Dahlem, TU Berlin
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Conclusion Open wave segments - fMRI evidence & retinal SD
Localized stimulation: sampling of phase space
Orientation selective
−π/2
0
π/2
Markus A. Dahlem, TU Berlin
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Conclusion Open wave segments - fMRI evidence & retinal SD
Localized stimulation: sampling of phase space
Orientation selective
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Markus A. Dahlem, TU Berlin
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Conclusion Open wave segments - fMRI evidence & retinal SD
Localized stimulation: sampling of phase space
Orientation selective
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Markus A. Dahlem, TU Berlin
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Conclusion Open wave segments - fMRI evidence & retinal SD
Localized stimulation: sampling of phase space
Orientation selective
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Markus A. Dahlem, TU Berlin
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Conclusion Open wave segments - fMRI evidence & retinal SD
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
Markus A. Dahlem, TU Berlin
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Conclusion Open wave segments - fMRI evidence & retinal SD
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
Markus A. Dahlem, TU Berlin
![Page 133: Brain Mapping of Migraine Aura](https://reader033.fdocuments.in/reader033/viewer/2022042602/55823b5dd8b42a0d368b4ea5/html5/thumbnails/133.jpg)
Conclusion Open wave segments - fMRI evidence & retinal SD
Localized stimulation: sampling of phase space
”A”-”Z”,”0”-”9” (36 patterns), 4 sizes, 10 stimulation strengths =1440 stimulation patterns (elevation of activator concentration u)
12.56.25
Markus A. Dahlem, TU Berlin