Brain Mapping of Migraine Aura

Brain Mapping of Migraine Aura
Markus A. Dahlem
Research group: Nonlinear Dynamics in Physiology and Medicine
0
5
10
15
5min
7min
9min
11min
15min
0 10 20 30 40 50
mm
5min
7min
9min
11min15min
23 min
21
19
17
17
15
13
11
97
5
10°
1 cm
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.
Subforms
Migraine
Subtypes

IHS Classiﬁcation ICHD-II – Major Types
with aura
without aura
typical aura
without headache
1.
1.1. 1.2.
1.2.1.
Subforms
Migraine
Subtypes
1.1.
1.2.1.
1.2.3.
2 symptom, 3 combinations: both or either of them

Mainly two neural theories of migraine
”Migraine generator”-theory
S1
PFC
Th
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
delay
time
trigger
prodrome
heightened susceptibility
corticalhomeostasis
prodrome

Pathway of upstream and downstream events
SD
headacheprodrome aura
trigger
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 area
temporarily
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)
Ve
Na
+
Na
+
K
+
Ve
K
+
Ca++
Ca++
H
+
0 10 20 30 s
150
60
50
3
1.5
0.08
unit
act.
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)

What is a migraine aura?

Migraine visual field defects reported in 1941 by K. Lashley
visual field defect pattern on primary visual cortex
0
5
10
15
5min
7min
9min
11min
15min
0 10 20 30 40 50
mm
5min
7min
9min
11min15min
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

neighboring points
collapse
?
16 min
31 min
1 cm
nucleation
recorded
slice not

23 min
18 min.
28 min.

23 min
18 min.
28 min.
Open wave fronts move along
a rather straight line
preventing a reentry of SD

23 min
18 min.
28 min.
Open wave fronts move along
a rather straight line
preventing a reentry of SD
Dahlem & Hadjikhani (2009) PLoS ONE

18 min.
23 min
28 min.
33 min.
38 min.
1 mm
Spiral waves (reentry) observed in retinal SD
with a rotation period of 2.45 min
Dahlem & Hadjikhani (2009) PLoS ONE
Dahlem & M¨uller (1997) Exp. Brain Res.

Clinical evidence

Mapped visual symptoms on cortex via fMRI retinotopy
1 cm
10°
1
3
5
7
15
17
19
21
23
25
27 min

Mapped visual symptoms on cortex via fMRI retinotopy
23 min
21
19
17
17
15
13
11
97
5
10°
1 cm

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
0
20
40
60
1.3 1.32 1.34 1.36 1.38 1.4
S
β
torus outside
flat
torus inside
2
21
1
ring wave
1
2
∂P1D∂R∞

Nucleation failure on torus

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 control
without 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 control
torus, with control
flat, without control

Simulation of an engulﬁng SD wave
Folds
Bumbs
In cooperation with Jens Dreier &
Denny Milakara, Charit´e

Migraine scotoma are well explained
Pattern matching
4
7
9
13
A B
C
Dahlem & Tusch, submitted to J. Math Neuroscie.

Pattern matching ”Curved” retinotopic mapping
4
7
9
13
A B
C
ÀÅ
½¼Æ
½¼Æ

4
7
9
13
A B
C
a d
b c
e
m
m
Ð
Ú
Ù
½¼Æ
Ð Ò Ù Ð ÝÖÙ×

ÙÒ Ù×
Ë

4
7
9
13
A B
C
2 4 6 8 10 12 14
0.1
0.2
0.3
2 4 6 8 10 12 14
20
40
60
80
100
120
140
2 4 6 8 10 12 14
0.2
0.4
0.6
0.8
1
¼Æ
Æ
Å´ ½µ
ÀÅ
¯´±µÃ´ÑÑ¾µ
´Ö µ
¾ ¼
¼ ¾¼¼¼


Linking SD patterns to symptoms
Outline

Cortical homeostasis is stable

Yet, too big a perturbation triggers SD

Yet, too big a perturbation triggers SD
nucleation
critical

But a global negative feedback keeps SD conﬁned
Hypothesis: Cortical susceptibility to SD depends on the size of
the momentarily aﬀected tissue.
slow dynamics
transient 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
pump
K
(V ) − I
pump
Na
(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
I
pump
ion
(V ) = βionImax 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
diffusion
activator−inhibitor dynamics
depolarization
firing rate
neurovascular coupling
neuralnetworkactivity
C
∂V
∂t
= −m∞(V )INa − n∞(V )IK − I
pump
K
(V ) − I
pump
Na
(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
I
pump
ion
(V ) = βionImax 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
0
5
10
15
20
25
0 5 10 15 20 25 30 35
time
collapse
corticalsurfaceareainvadedbySD
nucleation
CSD break−up
long transient propagation
model−based
stimulation strategies
therapeutic TMS

neighboring points
collapse
?
16 min
31 min
1 cm
nucleation
recorded
slice not

neighboring points
0
4
8
12
16
20
32
28
24
time
16 min
31 min
1 cm
recorded
slice not

neighboring points 16 min
31 min
1 cm
recorded
slice not

5cm
00
0 0
32 16
6 24
time/min

Varying contact to the ghost
0
50
100
150
200
250
300
350
400
450
totalaﬀectedarea(TAA)
(1)
(2)
(3)
(4)
0 10 20 30 40 50 60
maximal instantaneous area (MIA)
0
50
100
150
200
250
300
excitationduration(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
#Occurrences
0 80 160240
0 80 160240
# Occurrences
β0 = 1.32
(1)
(2) (3)
(4)
0 30 60 90 120150180210240270
time
1
10
20
30
40
50
60
70
80

0
50
100
150
200
250
300
350
400
450
(1)
(2)
(3)
(4)
0 10 20 30 40 50 60
0
50
100
150
200
250
300
(1)
(2)
(3)
(4)
0 50 100 150 200 250 300 350 400 450
(1)
(2)
(3)
(4)
0
80
160
240
#Occurrences
0 100 200
0 100200300
# Occurrences
β0 = 1.33
(1)
(2)
(3)
(4)
0 20 40 60 80 100120140160180
time
1
10
20
30
40
50
60
70
80
90

0
50
100
150
200
250
300
350
400
450
(1)
(2)
(3)
(4)
0 10 20 30 40 50 60
0
50
100
150
200
250
300
(1)
(2)
(3)
(4)
0 50 100 150 200 250 300 350 400 450
(1)
(2)
(3)
(4)
0
80
160
240
#Occurrences
0 250 500
0 150 300
# Occurrences
β0 = 1.34
(1)
(2)
(3)
(4)
0 10 20 30 40 50 60 70 80 90
time
1
10
20
30
40
50
60
70
80
90
100
110
120
130

IHS Classiﬁcation ICHD-II – Major Types
with aura
without aura
typical aura
without headache
1.
1.1. 1.2.
1.2.1.
Subforms
Migraine
Subtypes
1.1.
1.2.1.
1.2.3.
2 symptom, 3 combinations: both or either of them

Model-based hypothesis testing
1.1. 1.2.1
1.2.3Sub−
threshold
Affectedcorticalarea
Survival time
SD in migraine attack

0
5
10
15
20
25
0 5 10 15 20 25 30 35
time
sensory innervation
arachnoid
bone
blood
dura dural sinuses
cortex
pia

0
5
10
15
20
25
0 5 10 15 20 25 30 35
time
sensory innervation
arachnoid
bone
blood
dura
SD is pronociceptive
dural sinuses
cortex
pia
peak value

Towards migraine therapy
Outline

Neuromodulation

Homo Neuromodulandus
”The headache future is bright for neuromodulation techniques ... if we
manage to understand how they work” (Jean Schoenen)
ﬁgure courtesy of Jean SchoenenMarkus A. Dahlem, TU Berlin

Control of spreading depression
From bench to bedside

!
Cooperation with Stephen Schiﬀ Bruce Gluckman Courtesy of Neuralieve

From bifurcation bench to bedside

Typical trajectory: fast growth and collapse bottleneck
0
5
10
15
20
25
0 5 10 15 20 25 30 35
time
collapse
nucleation
CSD break−up
model−based
therapeutic TMS

Typical trajectory: fast growth and collapse bottleneck
0
5
10
15
20
25
0 5 10 15 20 25 30 35
time
collapse
nucleation
CSD break−up
noise!
model−based
therapeutic TMS

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
0 5 10 15 20 25 30 35
noise sample 1 k=0.010
without noise
time
noise on
wavesize

Permanent noise stimulation
0
5
10
15
20
25
0 5 10 15 20 25 30 35
without noise
time
noise on
wavesize

Single pulse vs. constant noise stimulation
0 5 10 15 20 25 30 35
survival time of unstable solitons
0.0
0.1
0.2
0.3
0.4
0.5
probability

Single pulse vs. constant noise stimulation
0 5 10 15 20 25 30 35
survival time
0.0
0.1
0.2
0.3
0.4
0.5
probability Migraine aura duration
without noise
on t=5, k = 0.050
on t=5, k = 0.100
noise 0.050
pulse t=5, k = 0.100
pulse t=5, k = 0.500

Noise sensitivity of transient wave segments
0
5
10
15
20
25
0 5 10 15 20 25 30 35
without noise
noise k=0.010
noise k=0.015
noise k=0.020
noise k=0.025
noise k=0.030
noise k=0.035
noise k=0.040
wavesize
time
How to escape quickly
from the ”ghost” plateau?

Conclusion
(i) Persistent migraine w/o infarction, (ii) Migrainous
infarction, (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 in
patients undergoing hemicraniectomy for malignant stroke
cf. Woitzik J et al., Stroke 37,1549 (2006)

Conclusion
Conclusions
We need more non-invasive maging
data of the aura!
The predicted plateau (”ghost of
saddle-node”) theory can be tested
clinically with non-invasive imaging
Sef-organizing patterns provide a
unifying concept including silent aura,
migraine w or w/o headache/aura
Insights pattern formation may reﬁne
neuromodulation strategies:
Being close to a saddle-node
bifurcation (”ghost” plateau)
Design (feedback) control to
intelligently target certain properties
of SD in migraine
1 cm
10°
1
3
5
7
15
17
19
21
23
25
27 min

Conclusion
Conclusions
data of the aura!
of SD in migraine
SD
headacheprodrome aura
trigger
heightened
susceptibility
delayed trigger

Conclusion
Conclusions
data of the aura!
of SD in migraine
0
50
100
150
200
250
300
350
400
450
(1)
(2)
(3)
(4)
0 10 20 30 40 50 60
0
50
100
150
200
250
300
(1)
(2)
(3)
(4)
0 50 100 150 200 250 300 350 400 450
(1)
(2)
(3)
(4)
0
80
160
240
#Occurrences
0 250 500
0 150 300
# Occurrences
β0 = 1.34
(1)
(2)
(3)
(4)
0 10 20 30 40 50 60 70 80 90
time
1
10
20
30
40
50
60
70
80
90
100
110
120
130

Conclusion ¡
Cooperation Funding
Nouchine Hadjikhani
(EPFL Martinos Center for Biomedical Imaging, MGH)
Paul Van Valkenburgh
Jens Dreier
(Department of Neurology, Charit´e; 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
about 1 day about 1 day4−72h 60 min

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
delay
time
trigger
prodrome
corticalhomeostasis
prodrome

Conclusion ¡
SD
trigger
delayed trigger
heightened
susceptibility

Conclusion ¡
trigger
delayed triggerSD
heightened
susceptibility

Conclusion ¡
trigger
SD
?
delayed trigger
heightened
susceptibility

Conclusion ¡
Orchestrated vs self-organizing dynamics
?
delayed trigger
about 1 day about 1 day4−72h
trigger
SD
60 min
aura
heightened
susceptibility

Conclusion ¡
Orchestrated vs self-organizing dynamics
SD
delay
time
trigger
prodrome
corticalhomeostasis
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
KCL
MG
(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 Bureˇs, 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 in
human 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, 2002
Review: 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 active
media.
Schneider, Sch¨oll 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
10
20
30
40
50
60
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
0.00.20.40.60.81.01.21.4

Noise sensitivity of transient wave segments
0
5
10
15
20
25
0 5 10 15 20 25 30 35
without noise
noise k=0.010
noise k=0.015
noise k=0.020
noise k=0.025
noise k=0.030
noise k=0.035
noise k=0.040
wavesize
time
How to escape quickly
from 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

0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9

fMRI patterns is more diﬀuse than SD patterns
reference (min 0)
start (min 20)
end (min 30)
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 a
long-range or global negative feedback?
modified from Hadjikhani et al. (2001) PNAS 98

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