1
ARTERIAL SPIN LABELING (ASL)
Matthias van Osch, Associate Professor
C.J. Gorter Center for high field MRI, Dpt of RadiologyLeiden University Medical Center
The Netherlands
223 October 2013Quantification of ASL 2
Contents
• Introduction on perfusion
• Acute stroke, reactivity, flow territory mapping
• Introduction of arterial spin labeling MRI
• Pulse-sequences
• Image readout
• Background surpression
• Quantification
• (Flow territory mapping) (probably too little time)
3
Gray matter
White matter
Microvasculature
Cast of cerebral human vasculature
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4
Perfusion
Cerebral blood flow
amount of blood that enters the microvasculature per
secondml blood / min / 100 ml tissue
5Wednesday, October 23, 2013Arterial spin labeling 5
How can we measure perfusion?
• Exogenous contrast agents (next presentation)
Inject a bolus contrast agent and monitor dynamically the
concentration of the contrast agent in brain tissue,
microvasculature and arteries
Dynamic susceptibility contrast MRI (DSC-MRI) or
bolustracking MRI
Positron emission tomography (PET)
CT perfusion (CTP)
• Endogenous contrast agents
Label the blood magnetically and monitor the inflow
Arterial spin labeling (ASL)
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Acute stroke
• Identifying the perfusion/diffusion mismatch (“penumbra”?)
48-year old woman presenting within 6 hours after symptom onset
Bokkers, Hernandez, Merino, Mirasol, van Osch, Hendrikse, Warach, Latour: Stroke. 2012 May;43(5):1290-4
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7
66-year old woman presenting within 1 hour after symptom onset
Bokkers, Hernandez, Merino, Mirasol, van Osch, Hendrikse, Warach, Latour: Stroke. 2012 May;43(5):1290-4
Acute stroke
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Acute stroke
DSC (n = 64)
ASL Yes No
Yes 32 4
No 7 21
Perfusion deficits
Interrater agreement
• DSC: 0.64
• ASL: 0.6
Bokkers, Hernandez, Merino, Mirasol, van Osch, Hendrikse, Warach, Latour: Stroke. 2012 May;43(5):1290-4
DSC (n = 64)
ASL Yes No
Yes 18 6
No 2 38
Significant perf / diff mismatch
Interrater agreement
• DSC: 0.74
• ASL: 0.51
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ASL false negative for perfusion deficits in 7 patients
•5 cortical gray matter, in 4 ASL of poor quality
•2 lesions in the basal ganglia
ASL false positive for perfusion deficits in 4 patients
•3 of the DSC images were poor quality
In the 30 cases where DSC was not performed
•11 patients had clinically confirmed stroke
•ASL detected 6 perfusion deficits, 3 significant mismatches
Acute stroke
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ASL in Alzheimer’s Disease
Alzheimer’s Control
Axial Sagittal Coronal
In collaboration with:UT Southwest, Dallas, USA
Yezhuvath US, Uh J, Cheng Y, Martin-Cook K, Weiner M, Diaz-Arrastia R, van Osch M, Lu H. Neurobiol Aging. 2012 Jan;33(1):75-82Forebrain-dominant deficit in cerebrovascular reactivity in Alzheimer's disease.
11Wednesday, October 23, 2013Visit Philips LUMC 11
Brain tumor (Glioblastoma multiforme)
ASL DSC-MRI
Scanned by technicians, post-processing on the console
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Vasodilatory capacity (Acetazolamide)
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Vasodilatory capacity
Advantage of perfusion MRI: Reactivity in sub-regions, e.g. hypertensive SVD versus CAA
14Wednesday, October 23, 2013Visit Philips LUMC 14
Pharmacological MRI
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Superselective ASL:labeling of single small arteries
In collaboration with Kiel
2 cm
Tuneable labeling spot with effective labeling thickness of only 1-2 cm
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Arterio-venous malformation
Wednesday, October 23, 2013LIBC 16
http://www.avmsurgeon.com/aboutavms.html ASL angiography
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Patient with Arterio-Venous-Malformation
• 48yo ♂ patient, symptomatic AVM (severe headaches)
In collaboration with Kiel
In collaboration with Kiel
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Selective ASL of major brain feeding arteries did not provide the requested information:
• ICA right• ICA left• BA
Patient with Arterio-Venous-Malformation
In collaboration with Kiel
In collaboration with Kiel
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AVM
AVM AVM
Ø = 2.1 mm
Ø = 3.0 mm
TOF-MIP
ASL pre-surgery
Superselective ASL performed exclusively on feeding vessels of the AVM.
T1w
Patient with Arterio-Venous-Malformation
In collaboration with Kiel
In collaboration with Kiel
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Ø = 1.2 mm
Ø = 2.1 mm
T1w
ASL post-surgery
TOF-MIP
Superselective ASL performed on remained vessels (former feeding vessels of the AVM).
Patient with Arterio-Venous-Malformation
In collaboration with Kiel
In collaboration with Kiel
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T1w
ASL pre-surgery
ASL post-surgery
fMRI (language)
Temporal speech disorders of the patient after surgery.
Parts of Wernicke‘s area supplied by former feeding vessels of AVM (proved by fMRI).
2.
Changes of the territorial distribution of cerebral perfusion 24h after surgery.
Decreased steal effect after removal of AVM.
1.
Patient with Arterio-Venous-Malformation
In collaboration with Kiel
In collaboration with Kiel
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ASL in Meningeoma 3T 02/2011Patient 1
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ASL in Meningeoma 3T 02/2011Patient 1
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ASL in Meningeoma3T 06.10.2011
TOF TOF MIP
Patient 1
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25
T2
ICA ri + le
global
ICA + Menigia Media left
Patient 1
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T1 CE
T1 CE
10/2011
02/2011
Patient 1
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Principle of arterial spin labeling
• ASL is based on tracer kinetics to
measure blood flow, similar to the
nitrous oxide method, perfusion
CT and DSC-MRI
• Use blood as a tracer by inverting
its longitudinal relaxation: NO
CONTRAST AGENT
• Half-time of tracer governed by
the longitudinal relaxation time
• Freely diffusing tracer:
accumulation of tracer reflects
blood flow
Kety, S. S., and C. F. Schmidt. The nitrous oxide method for the quantitative determination of cerebral blood flow in man:
theory, procedure, and normal values. J. Clin. Invest. 27: 107–119, 1948.
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Arterial spin labeling (ASL)
Spatial selective inversion
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Arterial spin labeling (ASL)
Spatial selective inversion
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Label
Control
Arterial spin labeling (ASL)
-Spatial selective inversion
30×
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Arterial spin labeling (ASL)
Slab selective inversion pulse Adiabatic inversion plane
Pulsed Labeling (PASL)Continuous Labeling (CASL)Pseudo continuous (pCASL)
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Timing differences between PASL and CASL
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Half-time of tracer
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7 8 9
Time (s)
Sig
nal (
%)
The labeled spins decay with the longitudinal relaxation time T1
(T1,blood≈1650 ms @ 3Tesla)
16%
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•Transport time to imaging slice is
approximately 1 sec
•Probably takes another 1-1.5 s to
reach capillary bed
pCASL
PASL
Arrival-time of label
1-3 s
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Arrival-time of label vs decay of tracer
pCASL
PASL
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7 8 9
Time (s)
Signa
l (%
)
Wait long for arrival of spins in microvasculatureImage as quickly possible due to loss of label
1-3 s
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Loss of label: longitudinal relaxation
100 ms 300 ms 600 ms 1000 ms 1500 ms 2100 ms 2600 ms 3000 ms 3500 ms
Inflow of label Decay of label
The labeled spins decay with the longitudinal relaxation time T1
(T1,blood≈1650 ms @ 3Tesla)
Angiogram Perfusion Noise
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Problem in patients: delayed arrival
100 ms 300 ms 600 ms 1000 ms 1500 ms 2100 ms 2600 ms 3000 ms 3500 ms
Inflow of label Decay of label
The labeled spins decay with the longitudinal relaxation time T1
(T1,blood≈1650 ms @ 3Tesla)
Angiogram Perfusion Noise
MIP (merged)
MIP (ICA right)
MIP (ICA left)
MIP (BA)
MIP (TOF)
Example of ASL angiographyDelay = 400 ms
Example of ASL perfusion imagingDelay =1650 ms
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Magnetization transfer effect
• Macromoleculeshave much broader resonance frequency spectrum than water, but the influence of RF-pulses is transferred to the larger free water pool
• When RF-power between label and control differs than this can result in a non-CBF related signal difference
PASL-TILT (Pruessman/Golay)
Label
Control
slice selectiveinversion
acquisition
acquisition
+90°
acquisition
acquisition
+90°
+90° -90°
PASL-FAIR (Kim)
Label
Control
slice selectiveinversion
Non-selectiveinversion
acquisition
acquisition
acquisition
acquisition
180°
180ºVenous label
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Continuous ASL: single slice (Williams)
Label
Control
Inversion plane
Inversion planeAbove imaging
acquisition
acquisition
acquisition
acquisition
Pseudo continuous ASL
• Pseudo continuous ASL1
• Comparable to CASL
• Create a label bolus with a fixed duration of approx. 1.5 sec
• No continuous RF, therefore it is possible to use the body
transmit coil
• Use of a train of RF-pulses of 0.5 ms with 0.5 ms interval
1Garcia and Alsop, ISMRM 2005Labeling (1650 pulses)
Grz
RF
Steady-state for a series of RF-pulses
Garcia and Alsop, ISMRM 2005
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Manipulation of static state
Phase difference between RF and spins determines the steady state
1. By changing the phase of the RF pulses we can manipulate the
steady state
2. By changing the phase of the spins we can manipulate the steady
state
Phase change ∝ Gradient strength * x * ∆t
Magnetic field ~ rotating speed of spins
Gradientstrength
Pseudo continuous ASL
Between 2 RF pulses there is an extra gradient to create flow induced phase differences that takes the magnetization towards inversion
Gradient Phase
Gr z
Pseudo continuous ASL
With a correct
change in phase the
magnetization is
tipped to inversion
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Pseudo continuous ASL
Label
Grz
RF
Control
Grz
RF
Control situation
Control
Grz
RF
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delay
(p)CASL or PASL?
delay(p)CASL
0 sec 1 sec 2 sec 3 sec
PASL
0 sec 1 sec 2 sec 3 sec 4 sec?
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delay
(p)CASL or PASL?
delay(p)CASL
0 sec 1 sec 2 sec 3 sec
PASL
0 sec 1 sec 2 sec 3 sec 4 sec
FasterMore averages
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delay
(p)CASL or PASL?
delay(p)CASL
0 sec 1 sec 2 sec 3 sec
PASL
0 sec 1 sec 2 sec 3 sec 4 sec
1.5-2 sec of label
Spatial label, but how long in time?
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Input function in PASL
For PASL a large part of the vasculature is labeled. The amount of labeled spins is dependent on the volume of the arteries in the labeling plane (e.g. curved vessels, collateral pathways, etc).
Will be different for different vessels (especially anterior vs posterior)
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delay
(p)CASL or PASL?
delay(p)CASL
0 sec 1 sec 2 sec 3 sec
PASL
0 sec 1 sec 2 sec 3 sec 4 sec
1.5-2 sec of label
~500-800ms+ uncertainty!
SNR ×2declared“workhorse”
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Recommendation for labeling approach
23 October 2013Quantification of ASL 56pCASL labeling
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Readout of ASL
• The goal is to measure the amount of label, i.e. inverted spins
• Therefore, we need proton-density weighted sequence
• The label will decay with the T1 of blood/tissue and we are only allowed to start scanning after a sufficient delay to allow the label to reach the microvasculature: fast imaging
• ASL is a tiny signal: voxel size factor 10-50 smaller than anatomical imaging
• Requirements:
• Short echo-time
• Short readout (<300 ms)
• Whole brain coverage
• Single shot EPI
• Spiral (difficult)
• Single shot 3D (GRASE)
• Segmented 3D sequences
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slice 3slice 2slice 1
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2D Echo Planar Imaging, cartesian
Gent, 02-04-2010
• Readily available on most scanners
• Single shot � 1 slice per excitation, ~ 25 ms per slice
Gslice
RF
Gphase
Gread
Acq.
5959
3D GRASE
Gent, 02-04-2010
• Enables single shot whole brain imaging
• Relatively high signal to noise
• Blurring in slice encode direction
Gslice
RF
Gphase
Gread
Acq.
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Background suppression
• ASL is a subtraction technique
Static tissue Static tissueLabeled spins
• Due to movements, and respiratory and cardiac noise the
static tissue can show large signal variations
• Use background suppression to minimize noise
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6161
-1
-0.5
0
0.5
1
0 1000 2000 3000 4000
time (msec)
MZ
GM
-1
-0.5
0
0.5
1
0 1000 2000 3000 4000
time (msec)
MZ
GM
BStiming
satinv
Background suppression, principles
Arterial spin labeling
3200 ms
pCASL
-1
-0.5
0
0.5
1
0 1000 2000 3000 4000
time (msec)
MZ
GMWM
-1
-0.5
0
0.5
1
0 1000 2000 3000 4000
time (msec)
MZ
GMWMCSF
Reminder 1
Do not affect label
• Saturation is spatially selective on brain
• Inversion is global
Reminder 2
• BS affects different tissues equally
6262
BStiming
satinv
Background suppression, principles
Arterial spin labeling
Reminder 1
Do not affect label
• Saturation is spatially selective on brain
• Inversion is global
3200 ms
pCASL
-1
-0.5
0
0.5
1
0 1000 2000 3000 4000
time (msec)
MZ
GMWMCSF
Reminder 3
Equal sign for all tissues
• If not: intra voxel cancellation
Reminder 2
• BS affects different tissues equally
6363
-1
-0.5
0
0.5
1
0 1000 2000 3000 4000
time (msec)
MZ
GM
Background suppression, principles
Arterial spin labeling
3200 ms
pCASL
-1
-0.5
0
0.5
1
0 1000 2000 3000 4000
time (msec)
MZ
GMWM
-1
-0.5
0
0.5
1
0 1000 2000 3000 4000
time (msec)
MZ
GMWMCSF
BStiming
satinv1 inv2
Reminder 4
BS affects tissues equally
• To null more tissues, more inversion pulses are needed
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6464
BS and signal changes
Arterial spin labeling
-1
-0.5
0
0.5
1
MZ
GM
WM
CSF
6565
-0.5
0
0.5
time (msec)
MZ
GM
WM
CSF
Timing in Background Suppression
Arterial spin labeling
Reminder 5
• 2D imaging gives decrease of BS in subsequent slices
• effect on 3D less severe
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-0.5
0
0.5
time (msec)
MZ
GM
WM
CSF
Timing in Background Suppression
Reminder 5
• 2D imaging gives decrease of BS in subsequent slices
• effect on 3D less severe
2D-EPI
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Basics of quantification
• Correct for efficiency of
labeling
• Assume all label has arrived in
the imaging voxel
• Correct for loss of label due to
T1-relaxation
• Relate signal towards a
reference value, i.e. signal
within a voxel containing
100% arterial blood or a
proton density weighted scan
Wednesday, October 23, 2013Perfusion and permeability 67Arterial spin labeling
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What is recommended?
23 October 2013Quantification of ASL 68Quantification of ASLArterial spin labeling
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White paper recommendation
23 October 2013Quantification of ASL 69Quantification of ASLArterial spin labeling
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70
White paper recommendation
23 October 2013Quantification of ASL 70Quantification of ASLArterial spin labeling
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White paper recommendation
23 October 2013Quantification of ASL 71Quantification of ASLArterial spin labeling
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Recommendation
23 October 2013Quantification of ASL 72
Conversion to ml/100ml/min ∆M (ASL-signal)
ASL is based on inversion
Labeling efficiencyM0: reference for arbitrary scaling of signal intensities in MRI: proton density scan corrected for difference in proton content between water and tissue
Quantification of ASLArterial spin labeling
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73
Recommendation
23 October 2013Quantification of ASL 73
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Quantification of ASL
74
Half-time of tracer
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7 8 9
Time (s)
Sig
nal (
%)
The labeled spins decay with the longitudinal relaxation time T1
(T1,blood≈1650 ms @ 3Tesla)
16%
Arterial spin labeling
75
Recommendation
23 October 2013Quantification of ASL 75
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Quantification of ASL
labeling imagingPLD
T1-relaxation
Arterial spin labeling
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7623 October 2013Quantification of ASL 76
Labeling efficiency of PASL
• Check inversion effeciency and profile in phantoms
• Redo these experiments in vivo, because B1-distribution is different in vivo than in phantoms
• Acquire images at different delay times (inversion recovery)
7723 October 2013Quantification of ASL 77
Labeling efficiency of PASL
Remember: switch off pre-saturation pulses and post-labeling saturation
0
50
100
150
200
250
300
0 200 400 600 800 1000 1200 1400 1600
Inversion time (ms)
MR
-sig
nal (
a.u.
)
kl
7823 October 2013Quantification of ASL 78
Labeling efficiency of PASL
Remember: switch off pre-saturation pulses and post-labeling saturationRemember: modulus data rectifies noise
0
50
100
150
200
250
300
0 200 400 600 800 1000 1200 1400 1600
Inversion time (ms)
MR
-sig
nal (
a.u.
)
kl
27
7923 October 2013Quantification of ASL 79
Labeling efficiency of PASL
Labeling efficiency can be very close to 100% for PASL, but also check control condition
0
50
100
150
200
250
300
0 200 400 600 800 1000 1200 1400 1600
Inversion time (ms)
MR
-sig
nal (
a.u.
)
kl
80
Quantification of PASL
Wednesday, October 23, 2013Perfusion and permeability 80
Similar, but the temporal duration of the labeling needs to be known:1. Measure it via multi timepoint ASL (see later)2. Fix the duration by a saturation pulse TI1 ≈ 800 ms after the spatial selective
labeling pulse (QUIPSS)
150 300 450 600 750 900 1000 No QUIPSS
81Wednesday, October 23, 2013Perfusion and permeability 81
Alternative: scan dynamically the inflow of label
But at the cost of coverage and SNR (flipangle <90°)Arterial spin labeling
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82
Example of multi timepoint ASL
Wednesday, October 23, 2013Perfusion and permeability 82
Courtesy: Esben Petersen and Xavier Golay
Arterial spin labeling
Conclusions
• Arterial spin labeling is based on inversion of inflowing blood
• PCASL is the recommended approach
• Quantitative values are in line with gold standard (PET)
• Application areas include tumors, large vessel disease, acute
stroke, dementia, etc
• ASL can also be used for cognition research
• New techniques image the inflow of labeled spins dynamically
and can map flow territories
Wednesday, October 23, 2013Perfusion and permeability 131
13223 October 2013Quantification of ASL 132
Acknowledgements
• Leiden University Medical Center• Naj Mahani
• Wouter Teeuwisse• Sophie Schmid• Xingxing Zhang• Serge Rombouts• Jeroen van der Grond
• Amsterdam Medical Center, NL• Sanna Gevers• Dennis Heijtel• Aart Nederveen• Henk-Jan Mustaerts
• University Medical Center Utrecht
• Jeroen Hendrikse
• Reinoud Bokkers
• Esben Petersen
• Kiel University, Germany
• Michael Helle
• UT Southwestern, Dallas, USA
• Hanzhang Lu
• Vanderbildt University, USA
• Manus Donahue