DISSERTATION submitted to Aix-Marseille University Doctoral School of Life and Health Sciences for the degree of Doctor of Philosophy (Ph.D.) Characterization of spinal cord compression: Development of 7Tesla Magnetic Resonance techniques for human spinal cord perfusion imaging and biomechanical simulation of Degenerative Cervical Myelopathy put forward by Simon LÉVY, Eng., M.A.Sc. Oral examination: September 24, 2020
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DISSERTATION
submitted to
Aix-Marseille University
Doctoral School of Life and Health Sciences
for the degree of
Doctor of Philosophy (Ph.D.)
Characterization of spinal cord compression:
Development of 7 Tesla Magnetic Resonance
techniques for human spinal cord perfusion imaging
and biomechanical simulation of Degenerative
Cervical Myelopathy
put forward by
Simon LÉVY, Eng., M.A.Sc.
Oral examination: September 24, 2020
Simon LÉVY, Eng., M.A.Sc.
Characterization of spinal cord compression:
Development of 7 Tesla Magnetic Resonance techniques for human spinal cord perfusion imaging and
biomechanical simulation of Degenerative Cervical Myelopathy
DISSERTATION, September 24, 2020
Reviewers: Dr. Alexandre VIGNAUD and Pr. Éric WAGNAC
Examiners: Dr. Alan SIEFERT, Dr. Thomas TROALEN and Pr. Pierre-Hugues ROCHE
Supervisors: Dr. Virginie CALLOT and Dr. Pierre-Jean ARNOUX
Aix-Marseille University
Center for Magnetic Resonance in Biology and Medicine (CRMBM)
Laboratory of Applied Biomechanics (LBA)
Faculty of Medicine
Doctoral School of Life and Health Sciences
27 Boulevard Jean Moulin
13385 Marseille
UNIVERSITÉ D’AIX-MARSEILLE
ÉCOLE DOCTORALE Sciences de la Vie et de la Santé
Partenaires de recherche
Siemens Healthineers & Assistance Publique Hôpitaux de Marseille
Laboratoires
Centre de Résonance Magnétique en Biologie et Médecine (CRMBM)
Unité Mixte de Recherche 7339 CNRS/AMU
Laboratoire de Biomécanique Appliquée (LBA)
Unité Mixte de Recherche T24 AMU/Université Gustave Eiffel
International Laboratory for Imaging and Biomechanics of the Spine (iLab-Spine)
Thèse présentée pour obtenir le grade universitaire de docteur
Discipline : Neurosciences
Simon LÉVY, Eng., M.A.Sc.
Caractérisation des compressions médullaires :
Développement de techniques d’Imagerie par Résonance Magnétique de
perfusion de la moelle épinière humaine à 7 Tesla et simulation
biomécanique des Myélopathies Cervicales Dégénératives
Characterization of spinal cord compressions:
Development of 7 Tesla Magnetic Resonance techniques for human spinal cord
perfusion imaging and biomechanical simulation of Degenerative Cervical Myelopathy
Soutenue le 24/09/2020 devant le jury composé de :
Alexandre VIGNAUD, HDR. Neurospin, CEA, Saclay, France Rapporteur
Éric WAGNAC, Pr. École de Technologie Supérieure, Montréal, Canada Rapporteur
Alan SEIFERT, PhD. Icahn School of Medicine, New York, USA Examinateur
Thomas TROALEN, PhD. Siemens Healthineers, Saint-Denis, France Examinateur
Pierre-Hugues ROCHE, MD.,Pr. Hopital Nord, APHM, Marseille, France Examinateur
Virginie CALLOT, HDR. CRMBM, CNRS/AMU, Marseille, France Directrice de thèse
Pierre-Jean ARNOUX, HDR. LBA, Univ Gustave Eiffel/AMU, Marseille, France Co-directeur de thèse
Numéro national de thèse/suffixe local : 2017AIXM0001/001ED62
To my grand-parents,
Lucie, Nicole, Emile and Georges,
Résumé
Les compressions médullaires induites par la dégénérescence du rachis sont une cause
fréquente de dysfonctionnement de la moelle épinière. Des recherches antérieures ont
démontré des signes d’ischémie déclenchant l’apoptose des cellules, exacerbés par la
suite par un processus d’inflammation, menant finalement à la myélopathie et l’altération
fonctionnelle. Cependant, la durée des processus dégénératifs et leur interaction restent
peu connues. Si la chirurgie de décompression est recommandée pour les Myélopathies
Cervicales Dégénératives (DCM) sévères, le suivi et la prise en charge des cas légers
sont plus problématiques. Un biomarqueur du déficit de perfusion serait d’une aide
particulièrement précieuse dans la prise de décision.
Ce travail de thèse s’inscrit dans un projet plus global visant à combiner la simulation
biomécanique des contraintes induites avec des mesures de perfusion in-vivo par IRM.
Plus particulièrement, ce travail visait à développer une technique IRM de cartographie
de la perfusion médullaire et à concevoir des simulations par éléments finis réalistes de
cas de compressions DCM typiques.
Compte tenu des faibles niveaux de perfusion et de la petite taille de la moelle épinière
humaine, les développements ont été réalisés à 7T pour bénéficier de la sensibilité accrue
à ultra-haut champ. La technique de Mouvement Incohérent Intra-Voxel (IVIM) a tout
d’abord été étudiée. Le rapport signal/bruit a été maximisé et les erreurs obtenues in-vivo
ont été évaluées à l’aide de simulations de Monte-Carlo. L’imagerie par Contraste de
Susceptibilité Dynamique (DSC), basée sur l’injection d’un agent de contraste, a ensuite
été explorée. Un protocole d’acquisition et de post-traitement a été mis en place pour
minimiser les biais physiologiques (battements cardiaques, respiration, mouvement).
Enfin, des caractéristiques géométriques typiques des compressions DCM ont été extraites
de la littérature et d’IRM anatomiques de patients. Des simulations biomécaniques ont
été implémentées à l’aide d’un modèle détaillé du rachis et les contraintes résultantes ont
été quantifiées au long du processus de compression, le long de la moelle ainsi que par
région médullaire.
La technique IVIM a démontré une faible sensibilité malgré le rapport signal/bruit
élevé obtenu. En revanche, des cartes bien définies de volume et flux sanguin relatifs
ont été obtenues chez des volontaires sains par DCM, mettant en évidence la perfusion
plus élevée de la substance grise par rapport à la substance blanche. La sensibilité a
été plus limitée chez les patients DCM, mais de nouvelles consignes pour améliorer
la robustesse de la technique ont pu être identifiées. Les simulations biomécaniques
pourraient expliquer l’ischémie fréquemment observée chez les patients DCM dans la
substance grise, mais elles ne peuvent expliquer directement la démyélinisation de la
voie corticospinale si l’on se base sur la distribution des contraintes uniquement.
En conclusion, la technique DSC a un grand potentiel pour la cartographie de la
perfusion de la moelle épinière humaine en routine clinique. Étant donné la grande
variabilité des motifs de compression DCM et des symptômes qui en résultent, la définition
de simulations standards est complexe. Dans ce contexte, une approche spécifique au
patient est recommandée pour pouvoir établir de manière fiable une relation entre la
compression mécanique et l’ischémie induite.vii
Abstract
Spinal cord compression induced by spine degeneration is a common cause of spinal
cord dysfunction. Previous research has shown evidence of ischemia firing cell apoptosis
exacerbated by inflammation, which eventually results in myelopathy and functional
impairment. However, little is known about the timescale of the processes and their
interaction. If decompression surgery is recommended for severe Degenerative Cervical
Myelopathy (DCM), the progression and management of mild cases is more challenging.
Biomarker of perfusion deficit would particularly help to make decision.
This PhD is part of a global project aiming at associating biomechanical simulations of
the induced constraints to in-vivo measurements of perfusion using MRI. More specifically,
this work aimed at developing an MRI technique to map spinal cord perfusion and at
designing realistic finite element simulations of typical DCM compressions.
Given the low perfusion levels and small size of the human spinal cord, developments
were conducted at 7T to benefit from ultra-high field sensitivity. The Intra-Voxel Incoherent
Motion (IVIM) technique was first investigated. Signal-to-noise ratio was maximized
and errors from in-vivo data were assessed using Monte-Carlo simulations. Dynamic
Susceptibility Contrast (DSC) imaging, which makes use of contrast injection, was then
explored. Acquisition and post-processing pipelines were implemented to address phys-
iological biases (heartbeat, breathing, motion). Finally, geometrical features of typical
DCM compressions were synthesized from literature and anatomical MRI of patients.
Simulations were performed using a detailed spine model and resulting constraints were
quantified along the compression process, spinal cord length and across spinal pathways.
The IVIM technique showed poor sensitivity despite the high signal-to-noise ratio
obtained. By contrast, well-defined relative blood volume and flow maps were obtained
in healthy volunteers with DSC, depicting the higher perfusion of gray matter with respect
to white matter. Sensitivity was mitigated in DCM patients, however new guidelines to
improve robustness of the technique could be identified. Based on stress distribution
only, biomechanical simulations could explain the gray matter infarction reported in DCM
patients but not directly the demyelination of the corticospinal tract.
In conclusion, the DSC technique has a great potential for human spinal cord per-
fusion mapping in clinical routine. Given the large variability of DCM patterns and
resulting symptoms, the definition of standard simulation designs is complex. In this con-
text, a patient-specific approach is advised to reliably establish the relationship between
mechanical compression and resulting ischemia.
ix
Acknowledgement
First of all, I want to thank all the people who worked so that the DOC2AMU doctoral
program takes shape and offers a fruitful and enlightening PhD environment. In particular,
I would like to thank Pr. Mossadek Talby and Sarah Sawyer for coordinating the program
and for their goodwill along those three years, as well as A*MIDEX and the Regional
Council Provence-Alpes-Côte d’Azur for funding the program along with Aix-Marseille
University.
Obviously, I want to thank Virginie Callot and Pierre-Jean Arnoux for setting up this
exciting project and trusting me for carrying it out. Thank you for your commitment and
positiveness, and for the skills I have learned along those three years. I also want to truly
thank Stanislas Rapacchi from who I learned so much. Thank you for your support, your
enthusiasm, your generosity and above all, your precious help. We both know that I owe
you much more than this.
I am also extremely grateful to Thomas Troalen for his tutorship and valuable help.
Along with Siemens Healthineers, I would like to thank Thorsten Feiweier for the support.
I am sincerely grateful to Tangi Roussel, Olivier Girard, Ludovic De Rochefort and Arnaud
Le Troter for the stimulating discussions and for everything they helped me figure out.
Thank you for your openness. Many thanks also to Christophe Vilmen for his amazing
help on the conception of the phantom. And thank you very much to Laure Balasse for
welcoming us at the CERIMED and for your time.
Furthermore, I am sincerely grateful to Sylviane Confort-Gouny, Véronique Gimenez-
Derderian, Lauriane Pini and Patrick Viout for their devotion to the lab and its activity,
and for their previous help all along those three years. Thank you also to Monique
Bernard and Maxime Guye for sympathetically welcoming me in this lab and supporting
my initiatives and projects. Thank you to Jean-Philippe Ranjeva for taking care of the
exchange within the group with zeal. I am extremely grateful to Magatte Sarr and
Danielle Rousseau for all the administrative burden that my missions outside the lab
generated. Thank you very much also to all the students of the lab for constantly working
for a warmer and more cohesive group. In particular, I would like to thank Emyra Trabelsi
for her limitless kindhearted and generous support. And many thanks to all the people of
the lab I could not name here!
xi
From the side of the LBA, I would like to particularly thank Patrice Sudres, Tristan
Tarrade, Maxime Llari and Morgane Evin for their help and useful discussions. I am also
extremely grateful to all the students for the warm and stimulating atmosphere they
constantly fuel in the lab. Many thanks also to Pierre-Hugues Roche for your time, your
support and your heated interest for the project.
From abroad, I would like to truly thank Maryam Seif, Patrick Freund and Johanna
Vannesjö for their hearty welcome in Zurich and their interest in my work. I am also
extremely grateful to Alan Seifert for his commitment and support to make my research
exchange in New York come true despite the circumstances. And I would like to express
my sincere appreciation and thanks to Laura Bell and Steven Sourbron for all the energy
and devotion you have dedicated, and continue to dedicate, to OSIPI.
Finally, I would like to thank all the DOC2AMU fellows who became my second family
during those three years in Marseille. And I will end by thanking the most essential
support: my family, including Michaela. I am endlessly grateful for your sound advice,
ardent encouragement and constant presence despite the distance.
Figure 2.4.: Atlas of major white matter spinal tracts. In red are the motor de-scending pathways, in blue are the sensory ascending pathways (fromMikael Häggström (https://commons.wikimedia.org/wiki/User:Mikael_H%C3%
A4ggstr%C3%B6m#/media/File:Spinal_cord_tracts_-_English.svg) on June18, 2020).
2.1.4 Vascular network
Spinal cord vascular network is very complex. It was first studied in 1881 by the Polish
pathologist Albert Wojciech Adamkiewicz, who the great radicular artery was named
after. The spinal cord vascular network includes an important collateral component which
can provide compensatory flow in case of occlusion of the main arteries Griepp et al.,
2012. As an example, according to Adamkiewicz’s partial flow theory, flow in the anterior
spinal artery (see below) arriving to the cord in two currents (cranial and caudal), a
pressure change or occlusion of one route can revert the flow in anterior spinal artery
(Thron, 1988).
Arterial supply
Lumbar arteries at lumbar level, intercostal arteries at thoracic level and subclavian
arteries for cervical levels branch from the aorta (Figure 2.5).
Lumbar arteries and intercostal arteries generally show three main bifurcations before
reaching the cord (see zoom box in Figure 2.5 and Figure 2.6). The first bifurcation gives
rise, on one side, to the spinal branch and, on the other side, to dorsal and vertebral
branches. The spinal branch then divides into the radicular branch (or segmental
arteries) and ventral epidural artery. The radicular branch then bifurcates into the
Figure 2.5.: Anatomy of spinal arterial supply and zoom around thoracic region with arteryof Adamkiewicz. The vertebral column and the aorta were shaded for a betterobservation of the arteries (Adapted from: Amato et al., 2015) ).
anterior and posterior radicular arteries (or radiculomedullary artery and radiculopial
artery in Figure 2.6), and the dorsal epidural artery (dedicated to supply the paraspinal
musculature). Anterior radicular arteries follow the ventral spinal nerve roots while
vector with a direction called the spin polarization. Parti-
cles with non-null spin, such as protons, exhibit a magnetic
moment ~µ pointing in a collinear direction to the spin polar-
ization. For a sample of protons in the absence of magnetic
field, the distribution of magnetic moments is isotropic. Now
when applying a magnetic field on the sample, due to their
angular momentum ~J , spins starts to move around the field
in a cone with constant angle (Figure 2.8). This motion is
called precession.
20 Chapter 2
The frequency of precession ω0 = 2πf0 (in radians/s and f0 the frequency in Hz)
depends on the magnetic field amplitude B0 and the gyromagnetic ratio defined as γ = Jµ .
For nuclear spins, this frequency of precession is called the nuclear Larmor frequency and
is:
ω0 = −γB0
Most nuclei have a positive gyromagnetic ratio (267.52 × 106 rad/s/T or 42.58 MHz/Tesla
for 1H), meaning their spins precess in the clockwise direction around B0 (the counter-
clockwise direction being defined positive by convention) (Levitt, 2001).
The proton Larmor frequency (absolute value) therefore equals 802.61 × 106 rad/s or
127.74 MHz at 3T and 1872.77 × 106 rad/s or 298.06 MHz at 7T.
Magnetization
In the human body, free protons are mostly found within the water molecules H2O.
The 1H nucleus has spin quantum number of 12 , thus two energy levels are possible
(Zeeman effect): ms = +s = 12 (spin-up) or ms = −s = −1
2 (spin-down). The energy
difference is ∆E = ~ω0 = ~γB0 (with ~ = h/2π =1.38 × 10−34 the reduced Planck’s
constant) and therefore depends on the field strength.
In absence of a magnetic field, the macroscopic magnetic moment of the sample (sum
of all spins magnetic moment, ~Mequilibrium =∑
spins ~µi, called the magnetization) is close
to 0 (isotropic distribution of the spins polarization).
In the presence of a magnetic fields, the protons’ molecular environment add micro-
scopic magnetic fields fluctuating due to thermal agitation at the human body temperature.
Protons therefore experience a total magnetic field slightly fluctuating in amplitude and
direction. A system of spins in a magnetic field then follows a Boltzmann distribution
where the states with lower energy (spin-up) have a slightly higher probability of being
occupied, according to:N+
N−= e−∆E/kT
where N+ and N− are the number of spins in the higher (spin-down) and lower (spin-
up) energy states, k=1.38 × 10−23 J/K is Boltzmann’s constant and T is the temperature
(310 K in the human body). Instead of having all spins magnetic moment aligned in the
direction of the magnetic field, these fluctuations induce an anisotropic distribution of
the spins polarization, with a slightly higher probability for the configuration with lower
2.2 Magnetic Resonance Imaging acquisition 21
magnetic energy, i.e. with the spins magnetic moment aligned in the direction of the
magnetic field.
The probability of finding a spin within the system with energy ǫ is:
P (ǫ) =e−ǫ/kT
∑ǫ
e−ǫ/kT(2.1)
The net magnetization of the system at equilibrium is the sum of individual magnetizations
that is:
M0 = ρ0
∑
ms=s,−s
P (ǫ(ms))µ(ms) (2.2)
where ρ0 is the spin density, ǫ(ms) = −ms~ω0 is the energy for state ms and µ(ms) =
msγ~ is the magnetization for state ms, leading to:
M0 = ρ0γ~
∑ms=s,−s
msems~ω0
kT
∑ms=s,−s
ems~ω0
kT
= ρ0γ~
∑ms=s,−s
msemsu
∑ms=s,−s
emsu(2.3)
with u = ~ω0
kT . Since the nuclear magnetic energies are much smaller than the thermal
energies at the human body temperature, u << 1 , we have emsu ≈ 1 + msu (Taylor
expansion), simplifying to:
M0 =ρ0γ2
~2
4kTB0 (2.4)
The net magnetization amplitude therefore depends on the field strength B0, gyromag-
netic ratio γ, environment temperature T (in Kelvin) and proton density ρ0.
Longitudinal and transverse relaxations
Let us consider a sample of water molecules protons in the human body in a magnet
with magnetic field ~B0 = B0~z. The macroscopic net magnetization is aligned in the
direction of the field (~z), with spins precessing around this direction at the Larmor
frequency at the microscopic scale. This magnetization is called longitudinal magnetization~Mz.
The longitudinal magnetization is almost undetectable. The NMR strategy is to measure
it in the perpendicular plane to the field.
22 Chapter 2
If a Radio-frequency (RF) pulse is applied with an excitation coil, spins will experience
both a static field ( ~B0) and an oscillating field, called transmit or ~B1+
field. Although
of a much lower amplitude than the static field, if the coil transmit field oscillates at
the Larmor frequency, the effect of the RF pulse on the spins accumulate with time and
a large change in the spins polarization state can be applied, similarly to little push in
the back of a child on a swing finally result in large oscillations with accumulation. The
transmit field is resonant, hence the Nuclear Magnetic Resonance phenomenon.
With an application of the RF pulse for several microseconds (hundreds of Larmor
precession cycles), the magnetization can be tilted in the transverse (~x, ~y) plane with
angle α = γB1τ (with B1 and τ the amplitude and duration of the RF pulse applied),
giving rise to a non-null transverse magnetization ~Mxy, precessing around the ~z axis with
the Larmor frequency (Figure 2.9).
Figure 2.9.: Nuclear magnetic resonance experience in the frame rotating at the Larmor frequency(Source: Levitt, 2001, adapted from Figure 2.19, page 34).
Once the RF pulse is stopped, as the magnetic field at the microscopic scale is
fluctuating, the individual spins experience a slightly different magnetic field, leading to
a loss of coherence in spins precession frequency. The magnetization distribution finally
becomes totally random and the total transverse magnetization disappears, following the
law:
Mx = M0sin(ω0t)e−
tT2 My = −M0cos(ω0t)e
−t
T2 (2.5)
The characteristic time of the transverse magnetization decay is the transverse relaxation
time T2. It is the time required for the transverse magnetization to fall under ∼37% (1/e)
of its initial value after the end of the RF excitation. In the human body, this relaxation
time is attributable to thermodynamics effects related to the sample (homogeneity, shape,
size, orientation, magnetic properties). We talk about spin-spin interactions.
2.2 Magnetic Resonance Imaging acquisition 23
Local field inhomogeneities, related to the system (field non-uniformity, shimming), add
to the spins loss in frequency coherence. This process is associated with the time constant
T ′
2 and results in an apparent relaxation with time T ∗
2 (< T2) according to:
1
T2=
1
T ∗
2
+1
T ′
2
(2.6)
While the spins get out of phase in the transverse plan, the spin distribution progressively
comes back to equilibrium along the static ~B0 field and the longitudinal magnetization
growths until recovering its initial amplitude, according to:
Mz = M0(1 − e−
tT1 ) (2.7)
The characteristic time of the longitudinal magnetization recovery is the longitudinal
relaxation time T1. It is the time required for the longitudinal magnetization to regrow at
∼63% (1 − 1/e) of its initial value after the end of the RF excitation. In the human body,
this relaxation time is attributable to interactions between spins and their environment
(spin-lattice interactions).
In living tissue, T1 ranges from around 100 to 4500 ms while T2 ranges from around
20 (excluding ultra-short T2 components) to 2000 ms.
Equation (2.5) and Equation (2.7) were established by Felix Bloch as a result of his
famous experiment on “Nuclear inducion” (Bloch, 1946; Block et al., 1946). Note that T1
and T2 were defined phenomenologically and not derived from fundamental principles.
NMR signal acquisition
The NMR signal is measured thanks to a receive coil element (e.g., loop) positioned
perpendicular to the transverse plane (Figure 2.10).
According to Faraday’s law of induction, the rotating magnetic field produced by the
precessing transverse magnetization is accompanied by a rotating electric field which
induces an oscillating electric current in the coil wire. The electromotive force emf is
given by:
emf(t) = − d
dt
∫
sample
~M(~r, t) ~B−
1 (~r)d3r (2.8)
24 Chapter 2
Figure 2.10.: NMR signal acquisition (Source: Levitt, 2001, adapted from Figure 2.23, page 36).
where ~M is the net magnetization and ~B−
1 is the "receive" field of the detection coil,
which is the magnetic field per unit current that would be produced by the detection coil
(reciprocal principle). The oscillating current induced in the coil by the ~M after an RF
excitation pulse was applied, measures the NMR signal, also called the Free-Induction
Decay (FID). Although this current is very low, it can be detected using an RF detector
thanks to its well-known frequency.
Bloch’s equations as a function of time t and position ~r for a series of pulses are:
The magnitude Mxy(~r, t = 0) and phase φ0(~r) of the transverse magnetization are
determined by the RF pulse conditions at t = 0.
Feeding Equation (2.9) into Equation (2.8) and after further manipulations and
simplifications (especially knowing that ω0 is at least four order of magnitude larger than
1/T1 and 1/T2 for B0 around 1 T, allowing the derivative of the e1/T1(~r) and e1/T2(~r) to be
neglected), it can be shown that (Haacke et al. (1999), chapter 7.3):
signalemf (t) ∝ ω0
∫
samplee−t/T2(~r)Mxy(~r, t = 0)B−
1,xy(~r)sin(ω0t + θB−
1
(~r) − φ0(~r))d3r
(2.11)
2.2 Magnetic Resonance Imaging acquisition 25
where Mxy and B−
1,xy are the transverse components of the magnetization and receive
field, and θB−
1
is the angle between the receive field and the magnetization. The signal is
then demodulated into two channels, called the real and imaginary channel, multiplying
signalemf by a reference signal, sin(ω0 + δω)t for the real channel and −cos(ω0 + δω)t
for the imaginary channel. After filtering of the high frequency component (2ω0 + δω),
we obtain the complex demodulated signal:
signaldemodulated ∝ ω0
∫
samplee−t/T2(~r)Mxy(~r, t = 0)B−
1,xy(~r)ei((Ω−ω0)t−θ
B−
1
(~r)+φ0(~r))d3r
(2.12)
with Ω the frequency of the reference signal used for demodulation (most often set to
ω0 + δω).
MR sequences
There exist two main families of RF pulse sequences to produce an NMR signal
(Figure 2.11).
The first one is the Gradient-echo (GRE), also called gradient-recalled echoes, gradient-
refocused echoes or field echoes. It consists of an RF pulse, tilting the magnetization in the
transverse plane followed by the application of two consecutive opposite magnetic field
gradients of equal duration and amplitude (de-phasing and re-phasing gradients). The
first gradient artificially de-phases the spins (but by a well-defined phase) whereas the
second gradient gets them back in phase to produce a signal echo. The signal decays with
T ∗
2 relaxation time.
The second family of sequences is the Spin-echo (SE), invented by Erwin Hahn (Hahn,
1950): in addition to a first excitation RF pulse, a second inversion pulse is applied to the
sample at time TE/2 in order to flip spins magnetization by 180º in transverse plane. The
direction of precession of the spins is reversed so that the phase accumulation due to
static field inhomogeneities is reversed and spins will come back in phase at time TE since
they will experience the same inhomogeneities as between TE/2 and TE. This type of
sequence therefore gets rid of T ′
2 relaxation. Signal decays exponentially from excitation
(first RF pulse) and TE with time constant T2 relaxation.
26 Chapter 2
90º RF pulse Signal echot=0 t=TE
90º RF pulse Signal echot=0 t=TEt=TE/2
Gradient-echo sequence
Spin-echo sequence
180º RF pulse
De-phasing and re-phrasing
magnetic field gradients
FID
FID
Figure 2.11.: Gradient-echo and spin-echo sequences diagrams (assuming perfect 90° and 180°pulses) for illustration purposes. TE: Echo time. TE is usually shorter in gradient-echo sequences to minimize the signal loss with T2* dephasing.
2.2 Magnetic Resonance Imaging acquisition 27
2.2.2 Image acquisition and reconstruction
For Magnetic Resonance Imaging, it is necessary to encode the signal as a function
of the position in space. Only the concepts used in this PhD work and/or relevant to its
discussion will be introduced here. More details can be found in the excellent books from
Levitt (2001) or Haacke et al. (1999).
K-space
Spatial encoding It is possible to encode the signal as a function of the spins position ~r
with the use of magnetic field gradients ~G(t).
If we consider the transmitting and receiving RF coil fields sufficiently uniform in
Equation (2.12), the initial phase φ0, the receiving RF coil field directional phase θB−
1
and transverse amplitude B−
1,xy can be assumed independent from the position. To turn
Equation (2.12) from proportionality to equality, all gain factors from the electronic
detection system can be included in a constant factor Λ. In addition, the constant
phases φ0 and θB−
1
can be set to 0 with loss of generality. The demodulated signal can
consequently be expressed as:
s(t) = ω0ΛB−
1,xy
∫ +∞
−∞
e−t/T2(~r)Mxy(~r, t = 0)ei(Ωt+φ(~r,t))d3r (2.13)
with Ω the demodulation frequency and φ(~r, t) = −∫ t
0 ω(~r, t′)dt′ is the accumulated phase
with time. Here, we assume that variation of φ with position is only due to a magnetic
field gradient ~G(t) and if ~G(t) = 0, φ(~r, t) = −ω0t as the static field is considered
homogeneous.
For clarity purpose, the relaxation effects can be ignored and we can define the « effective
» spin density ρ(~r) = ω0ΛB−
1,xyMxy(~r, t = 0) such that:
s(t) =
∫ +∞
−∞
ρ(~r)ei(Ωt+φ(~r,t))d3r (2.14)
The goal of MR imaging is to measure the spin density as a function of the position to form
an image of the object. Let us now consider the effect of a magnetic field gradient in one
dimension ~x: ~G(t) = Gx(t)~x = ∂Bx
∂x (t)~x. The 1D spin density is ρ(x) =∫
sample ρ(~r)dydz.
28 Chapter 2
Along ~x, the magnetic field varies linearly as a function of the position and so does the
frequency:
Bx(x, t) = B0 + xG(t) = B0 + xGx(t) (2.15)
ω(x, t) = ω0 + γxG(t) = ω0 + γxGx(t) (2.16)
The gradient is used to establish a relation between the spins position and their precession
rate. This technique is referred as frequency encoding. The accumulated phase up to time
t is therefore:
φ(~r, t) = −∫ t
0ω(~r, t′)dt′ = −ω0t − γx
∫ t
0Gx(t)dt (2.17)
With a frequency modulation Ω = ω0, we get following relation between the signal and
the spatial frequency:
s(kx(t)) =
∫ +∞
−∞
ρ(x)e−i2πkx(t)xdx (2.18)
with kx(t) = γ2π
∫ t0 Gx(t′)dt′ the spatial frequency. The effective spin density can then be
obtained by inverse Fourier transform which is the link between the frequency domain
(s(kx)) and the image domain (ρ(x)):
ρ(x) =
∫ +∞
−∞
s(kx)e+i2πkx(t)xdkx (2.19)
The expression of the signal as a function of the spatial frequencies induced by gradients
can be generalized to three dimensions:
s(kx, ky, kz) =
∫ +∞
−∞
ρ(x, y, z)e−i2π(kxx+kyy+kzz)dx dy dz = F [ρ(x, y, z)] (2.20)
Figure 2.12.: Relation between k-space and image space sampling parameters in two dimensions.The number of sampled points in each direction (i.e. 2kx,max × 2ky,max) is oftenreferred as the matrix size.
The k-space can be traveled by varying (kx, ky, kz) through the variation of gradients
(Gx, Gy, Gz) to sample it. Different trajectories to sample k-space, cartesian (i.e., on
a squared grid) or not, are possible. During the sampling of the k-space, the signal is
recorded with an Analog/Digital Converter (ADC). This sampling period is often called
the readout.
For imaging a 3D volume, two approaches to sample the k-space are possible: multiple
acquisitions of 2D slices with or without gap in-between (2D multi-slice imaging) or
acquisition of a 3D volume (3D imaging).
30 Chapter 2
2D multi-slice imaging In 2D multi-slice imaging, multiple slices are acquired succes-
sively with multiple RF pulses. To do so, the spins of the slice to be acquired need to
be selected using the same principle as spatial encoding but at the moment of the RF
excitation: by means of a gradient Gz (slice-selection gradient) applied in the slice-encoding
direction(commonly ~z), the Larmor frequency is linearly varied as a function of the posi-
tion: ω(z) = γ(B0 + Gzz) as illustrated in Figure 2.13. Consequently, the RF excitation at
the frequency ωslice = γ(B0 + Gzzslice) with bandwidth (BW) ∆ω will only affect spins
with Larmor frequency within ω0 + γGzzslice ± ∆ω/2 , corresponding to spins at positions
within zslice ± ∆ω2γGz
(the slice thickness being ∆ωγGz
).
Position along slice-encoding direction
z
Larmor frequency
ω
zslice
ω 0+
γG zz
0
ω0 + γGzzslice
ω0
Δω
Δz =Δω
γGz
Figure 2.13.: Relation between position and frequency with application of a slice-selection gradi-ent.
Once only one slice has been selected by the RF excitation pulse along ~z, the k-space
has to be sampled only along ~x and ~y. Different trajectories to sample the entire k-space,
using a single RF excitation or multiple ones (e.g., reading only one line by RF excitation),
are possible. Figure 2.14 shows an example of possible trajectory with the associated
sequence diagram. Along one axis (~x), the gradient Gx is turned on to travel from one
side of the k-space to the other while the gradient along the other axis (Gy) is turned off
( 0 → 1 on Figure 2.14). Once one kx line has been recorded, Gy is turned on to add
a phase to spins to increment one line of ky ( 1 → 2 ). For this ky line, the frequency
of spins will be varied by Gx in the other way as a function of position x ( 2 → 3 ) but
they will have a phase specific to this line Nphaseky = Nphase∆Gyτy, hence the name of
frequency-encoding direction for ~x and phase-encoding direction for ~y.
2.2 Magnetic Resonance Imaging acquisition 31
(a) Sequence diagram (b) k-space trajectory
Figure 2.14.: Example of k-space trajectory (b) with associated pulse sequence diagram(a). Ts isthe sampling period when the Analog/Digital Converter (ADC) is open for signalrecording (source: Haacke et al., 1999). Note here that gradients Gx and Gy arefirst turned on right after the RF excitation to travel at one extremity of the k-space— here (kx, ky) = (0, 0) — at the beginning of the signal sampling (point 0 ). Thisk-space sampling scheme is the one used for Echo-Planar Imaging (EPI), detailedin section 2.2.2.
3D imaging In 3D imaging, signal spatial-encoding follows essentially the same principle
as for 2D multi-slice imaging. The difference is that a larger volume called slab is selected
during the RF pulse. Afterwards, as shown by Equation (2.20), k-space can be sampled
with the application of gradients in 3D. A second phase encoding is used in the third
dimension kz, also called the partition-encoding direction.
Common accelerated acquisition strategies
Hermitian symmetry of k-space Due to its construction by demodulation of the signal
with cosine and sine functions into real and imaginary channels, the k-space has an
hermitian symmetry, as shows the signal expression as a Fourier transform of the spin
density in Equation (2.20). An hermitian symmetry in 2D means that s(−kx, −ky) =
s(kx, ky)∗ where ∗ denotes the conjugate. This means that only half of the k-space
can theoretically be acquired and missing data are retrieved by hermitian symmetry,
called phase-conjugate symmetry techniques, which can take different names according to
vendors such as partial Fourier (Siemens), fractional NEX (General Electrics), Half Scan
(Philips) or Asymmetric Fourier Imaging (Canon). In practice, B0 inhomogeneities can
lead to phase errors; a little more than half of the k-space is thus acquired to minimize
those errors and still get a good estimation of phase (arctan Imaginary part(s)Real part(s) ).
32 Chapter 2
Such technique help reducing the total readout time. Note however that SNR varies
by the square root of the number of acquired lines. Different algorithms are available for
estimation of the missing lines — e.g, Projection Onto Convex Set, Margosian (McGibney
et al., 1993) — but the most commonly used is zero filling. Nonetheless, this technique
leads to a loss in actual resolution (blurring and loss of fine structures depiction). Indeed,
the center of k-space, where low spatial frequencies and center of the echoes are, con-
tains most of the image SNR and contrast, while peripheral k-space, with high spatial
frequencies, contains information for depiction of fine details.
to the vendor, it is called the EPI factor in Siemens and Philips systems and the Echo Train
Length for General Electrics.
Note that EPI is generally not considered as a cartesian trajectory because, in practice
(and contrary to the schematic of Figure 2.14), k-space points are also acquired during
the ramp-up and ramp-down periods of the gradients and not only during the constant
plateau. Consequently, the spacing ∆kx between points is not regular as in a cartesian
grid.
Such k-space sampling trajectory can be used in conjunction with parallel imaging
reconstruction methods such as GRAPPA and partial Fourier.
Spiral EPI Spiral EPI (Ahn et al., 1986) fills k-space with a spiral trajectory(Figure 2.16)
from the center to the outer of k-space (spiral-out) or from the outer to the center of
k-space (spiral-in).
(a) Sequence diagram
(b) k-space trajectory
Figure 2.16.: Sequence diagram (a) and k-space trajectory (b) for circular spiral EPI (source:Haacke et al., 1999). θ(t) is the angle of rotation of the trajectory, kθ is thesampling dimension defining the number of points per rotation and kr is thesampling dimension defining the number of rotations.
2.2 Magnetic Resonance Imaging acquisition 35
For 2D circular spiral trajectory, the two gradients are turned on simultaneously with
sinusoidal trajectories such that (Ahn et al., 1986):
Gx(t) = α1 sin α2t + α1α2t cos α2t for kx(t) = γα1t sin α2t + φ
Gy(t) = α1 cos α2t − α1α2t sin α2t and ky(t) = γα1t cos α2t + φ
Values for α1, α2 and φ are determined by the number of rotations and the number of
points per rotation (see (Ahn et al., 1986)) which have to respect the Nyquist criterion
(i.e., the sampling frequency 1/∆k needs to be greater than twice the highest sampled
frequency 1/∆kmax).
As for standard EPI due to sampling during gradients ramp periods, circular spiral EPI
requires a re-gridding on a cartesian grid. This makes the implementation and image
reconstruction not trivial. Moreover, spiral readout is more affected by incorrect gradient
timing, concomitant field gradients and B0 heterogeneity inducing trajectory errors. At
3T in the brain, B0 field probes were required to correct for spiral trajectory errors
(Dietrich et al., 2016). However, as frequency- and phase-encoding dimensions are
not independent, artifacts are different from standard EPI (e.g., curvilinear bands, ring-
shaped blurring instead of shearing) and they might only affect the periphery of the field
of view. Figure 2.17 shows the different types of artifacts obtained with a spiral readout
in spinal cord, compared to a standard EPI readout.
Finally, spiral EPI usually offers a significant reduction in the readout and echo time,
resulting in lower T ∗
2 decay effects in readout and a higher SNR efficiency.
Standard or spiral EPI are specific readout strategies. They can be used with any
sequence preparation such as Spin-echo or Gradient-echo, yielding the common acronyms
SE-EPI or GRE-EPI, respectively.
36 Chapter 2
(a) GRE sequence with circular spiral readout (b) GRE sequence with standard EPI readout
Figure 2.17.: Differences in the type of artifacts obtained in spinal cord with a Gradient-echo(GRE) sequence and spiral EPI (FOV=95×95mm2, matrix=128×128, TE=1.7ms)(a) or standard EPI readout (FOV=132×131mm2, matrix=178×176, TE=21.8ms)(a). Ring-shaped blurring can be observed with spiral EPI whereas the main artifactswith standard EPI are distortions in the phase-encoding direction (horizontal here).Those are images from exploratory non-optimized data acquired at the CRMBM.
2.3 Ultrahigh field MRI
In the context of clinical MRI, Ultrahigh Field (UHF) MRI refers to 7T MRI, while
high field MRI would refer to 3T MRI and low field MRI would describe field strength
of 1.5T and lower. The first 7T human MRI scanner appeared in the 2000s. Since
then, a hundred of them has been installed worldwide. The highest operational MRI
field strengths for human today (2020) are 9.4 T (five operational scanners across the
world) and 10.5 T (CMRR, University of Minnesota, Minneapolis). The Iseult project is
an ongoing French-German project aiming to build and use a human MRI scanner with
field strength 11.7 T in Paris-Saclay (Neurospin, CEA), by the 2021 horizon.
Up to now, clinical field strengths in use are 1.5 T and 3 T MRI. However, since 2017,
Siemens 7 T MRI (Magnetom Terra) has been approved for clinical use in Europe (Staff
News Brief, 2017) and the United-States (United States Food and Drug Administration,
2017). Even though it mostly remains at the stage of clinical research, new 7T installations
have skyrocketed across the world since then, making 7T MRI slowly but surely coming
to clinical routine.
2.3 Ultrahigh field MRI 37
A synthetic table of pros and cons of UHF MRI can be found in Ladd et al., 2018 and
in Cohen-Adad et al., 2014 or Barry et al. (2018) for spinal cord-oriented applications.
Table 2.1 briefly summarizes them.
Table 2.1.: Brief overview of potentials pros and cons of Ultrahigh Field MRI.
Characteristic Pros Cons
SNR ↑resolution ↑, scan time ↓, CNR↑, X-nuclei (31P, 23Na) possible
None
T1 ↑ ASL, TOF, DCE TR and scan time ↑
T2 ↓ SE-DSC DWI, DTI
T2* ↓ BOLD, GRE-DSC
GRE imaging (sig-nal dephasing ↑)
SAR ↑ NoneNumber of slices ↓, flip angle
restrictions ↑, TR and scan time ↑
Transmit field homogeneity ↓Parallel imaging(*),
parallel transmissionNon-uniform flip angle
in image, poor inversion
Coil sensitivity ↓ None Difficulty to image deep regions ↑
(*): The benefit of parallel imaging in UHF is not obvious. It comes from the theoretical reduction ofthe minimum achievable geometry factor (so called g-factor) of the receive coil array with increasing fieldstrength, and the consequent increase of the critical acceleration factor (Wiesinger et al., 2004a). It is dueto complex phase patterns generated by the RF at UHF which help suppressing spatially dependent noiseamplification (Wiesinger et al., 2004b; Wiesinger et al., 2006; Pruessmann, 2004; Ugurbil, 2014).
38 Chapter 2
2.3.1 Advantages of UHF MRI
Signal-to-Noise Ratio (SNR)
SNR dependency on field strength According to Equation (2.8) introduced in Sec-
tion 2.2.1, the NMR signal is detected by the electro-magnetic field emf induced by
the transverse magnetization Mxy precession in the coil after excitation by an RF pulse:
emf(t) = − d
dt
∫
sample
~M(~r, t) ~B−
1 (~r)d3r
where ~M is the net magnetization and ~B−
1 is the "receive" field of the detection coil
(magnetic field per unit current that would be produced by the detection coil).
Assuming an homogeneous sample and static field, with perfect and homogeneous RF
excitation, and ignoring the relaxation effects and the electronic amplification factors,
the signal amplitude expression can be simplified to:
|S| = ω0M0| ~B−
1 |xyVsample
with Vsample the volume of the sample and | ~B−
1 |xy =√
B−
1,x2
+ B−
1,y2 is the norm of ~B−
1
in the transverse plane. Signal amplitude is therefore proportional to B02.
Now, the noise (i.e., the perturbations coming from the system, the electronic compo-
nents or the sample) in NMR, is directly related to the effective resistance Reff "seen" by
the signal-receiving electronics. This resistance is the sum of the resistance of the sample,
the coil and the electronics. In particular, Hoult et al. (1979) studied the dieletric and
inductive losses in the human body. At low frequencies, the coil and electronics resistance
dominate whereas at high frequencies (B0 ≥ 0.5 T), the sample resistance dominates and
is proportional to ω02.
According to the Nyquist-Johnson theorem (Nyquist, 1928; Johnson, 1928), the vari-
ance of the fluctuating noise voltage σnoise is proportional to 4kT · Reff · BW with
BW the bandwidth of the reception coil, which is determined in NMR by the cutoff
frequency of the anti-aliasing low pass filter. Consequently, the Signal-to-Noise Ratio
(SNR)= S/σnoise = S/σthermal is proportional to B0 such that:
SNR ∝ B20√
B20
= B0 (2.21)
2.3 Ultrahigh field MRI 39
By increasing the field strength from 3 to 7T, the SNR would therefore be theoretically
increased by a factor of ∼2.3, provided that coil design and resistance remain the same,
which is not the case in practice (Pohmann et al., 2016). This increase in SNR can be
traded either for a higher resolution or a shorter acquisition time (less averages or k-space
sampling).
Ultimate intrinsic SNR To go further, at UHF the dependency of SNR on B0 becomes a
complex function of the object shape, size and composition (Ladd et al., 2018). However,
such result is difficult to verify experimentally because comparison across field strength
is biased by differences in RF coils and other hardware considerations. Therefore, a
theoretical concept that can be used is the ultimate intrinsic SNR (uiSNR) (Ocali et al.,
1998). It is the maximum theoretically achievable SNR for a given object, independently
from the RF coil. It is basically determined by body noise.
Thanks to recent advances in numerical simulations, uiSNR could be computed for
realistic body models with different electromagnetic properties for different tissue types
(Guérin et al., 2017). Results for brain simulations suggest that uiSNR would increase
linearly with B0 close to the surface of the head but in the center of the head, uiSNR
would increase proportionally to B02.1 (Figure 2.18). Such results are compatible with
the B01.65 field-dependency of SNR measured in the same three subjects at 3T, 7T and
9.4T by Pohmann et al. (2016) (Figure 2.19(a)).
An additional interesting result from Guérin et al. (2017) is that the SNR increase
with field strength is greater at higher acceleration factors than for acquisition without
parallel imaging. However, this result was poorly supported by the in-vivo experiments of
Pohmann et al. (2016) (Figure 2.19(b)).
Relaxation and susceptibility
For most biological tissues, empirical measurements suggest that T1 increases with
field strength approximately according to B01/3. Plotting T1 over multiple field strength
measurement, Rooney et al. (2007) estimated that T1 for all brain tissues increased as
B0x with x between 0.34 and 0.38.
The T1 increase with field strength can be explained with the principle of dipole-dipole
interaction which is related to the molecular tumbling frequency ω (Figure 2.20) and the
40 Chapter 2
Figure 2.18.: Ultimate intrinsic SNR as a function of the position in human head model (Source:Guérin et al., 2017). (a) In a uniform sphere, (a’) is the same graph but with ay-axis scale to zoom in on the inner positions. (b) and (b’) are similar graphs butin the Duke head model. (c) uiSNR average in gray and white matter with theDuke head model as a function of field strength. For graphs (a), (a’), (b), (b’),POS#1,#2,#3 and #4 are located at 1, 2, 3 and 9 cm away from the top edge ofthe sphere/head. For all graphs, dashed lines represent the linear extrapolationfrom low fields.
(b)(a)
Figure 2.19.: In-vivo SNR (a) and g-factor (b) in brain as a function of field strength measuredin three healthy volunteers (source: Pohmann et al., 2016). (a) The B0
x model fityielded to x = 1.65. (b) The mean g-factor was measured in brain and phantomfor different GRAPPA acceleration factors at 3T, 7T and 9.4T.
rotational correlation time τC (time to rotate by ∼1 radian). The proportion of molecules
tumbling at a given frequency ω is given by the spectral density function:
J(ω) =τC
1 + ω2τC2
(2.22)
2.3 Ultrahigh field MRI 41
The proportion of molecules tumbling at frequency ω therefore decreases as this frequency
increases. According to the theory progressively established by Solomon-Bloembergen
equations (Solomon et al., 1956; Bloembergen et al., 1948):
1
T1=
6
20
~2γ4
r6(J(ω) + 4J(2ω)) (2.23)
T1 is essentially defined by its minimum value which is obtained when the molecular
tumbling frequency matches the resonance frequency. By increasing the field strength
and thus, this resonance frequency, the proportion of molecules minimizing the T1 is
therefore decreased and the T1 is increased.
This increase in T1 is more or less pronounced according to the molecules state. For
protons in highly mobile molecules (e.g., free water), T1 will be much less affected than
for molecules with intermediate or low mobility (e.g., bound protons).
Figure 2.20.: Proportion of tumbling molecules according to the frequency and effect of fieldstrength (i.e., resonance frequency) increase (Source: http://mriquestions.com/
bo-effect-on-t1--t2.html on July 15, 2020).
In MRI, increase in T1 is, for instance, advantageous for Time-Of-Flight (TOF) tech-
niques (higher signal from inflowing protons) or Arterial Spin Labeling (ASL) (slower
relaxation of labeled blood).
According to the dipole-dipole interaction model of Bloembergen, Purcell and Pound
(Solomon et al., 1956; Bloembergen et al., 1948), T2 is independent from field strength.
However, at UHF (≥7 T) a substantial shortening of T2 was measured (Graaf et al., 2006).
This is supposed to be due to exacerbated microscopic diffusion, susceptibility effects and
chemical exchange at UHF. Moreover, the measured values depends on the particular
Chemical shift refers to the little differences in Larmor frequencies of protons induced
by the different molecular environments. The most common example in MRI is the
chemical shift between fat protons and water protons. Fat protons are covered by electron
clouds coming from the long-chain triglycerides they are nestled in and which act as
a shield to the external magnetic field. Water protons are less shielded because of the
highly electronegative oxygen atom pulling away the electrons. Fat protons therefore
have a lower Larmor frequency by 3.4 parts per million (ppm) than water protons. This
can lead to chemical shift artifact caused by an incorrect position of the fat signal with
respect to water signal in the frequency-encoding direction (or phase-encoding direction
in EPI). Increasing B0 thus linearly increases the chemical shift.
In some applications however, the chemical shift is an advantage as source of contrast.
Indeed, the chemical shift between metabolites (e.g., to differentiate glutamate (Glu)
and glutamine (Gln)) is the fundamental of Magnetic Resonance Spectroscopy (MRS).
UHF therefore increases the spectral resolution, helping the separation of the different
metabolites. Chemical Exchange Saturation Transfer (CEST) (Ward et al., 2000) is
another technique benefiting from the increased chemical shift at UHF, as separation of
CEST peaks between diluted molecules is made easier.
The increased chemical shift between fat and water protons at UHF is also an advan-
tage for fat saturation techniques prior to imaging.
2.3.2 Disadvantages and challenges of UHF MRI
Static field inhomogeneities
B0 field inhomogeneities originate from two sources. The first one is related to
hardware. Imperfections of the static field produced by the magnet are more important
at UHF as it becomes more and more challenging to build magnets with uniform static
field when the field strength increases, as for wide bores and short magnets. As a result,
7T magnets show a static field homogeneous over a reduced volume around the isocenter
compared to 3T, and are longer with narrower bores (e.g., 270 cm×60 cm for Siemens
Magnetom Terra 7T versus 173 cm×70 cm Siemens Magnetom Skyra 3T).
44 Chapter 2
The second source of inhomogeneity is the object or subject introduced in the magnet.
The inhomogeneities in magnetic susceptibility related to tissue proportionally convert
into field inhomogeneities, which scale with B0. Susceptibility inhomogeneities can be
static (e.g., between air and tissue) or dynamic (e.g., fluctuating air volume in lungs with
breathing).
In spinal cord, static inhomogeneities are high because of the different tissue types
in immediate vicinity (CSF, vertebrae bone, intervertebral disks, soft tissue) and the
longitudinal tubular shape of the cord. But in addition, the close proximity of the lungs
and trachea, filled of air with a volume that fluctuates with breathing, is a source of
dynamic inhomogeneities (Verma et al., 2014; Vannesjo et al., 2018). CSF pulses with
heartbeat during the acquisition bring additional dynamic field inhomogeneities (Hu
et al., 1995).
Even at 3T, and even at the highest cervical levels, breathing-induced B0 variations were
measured, with a great variability across subjects (Figure 2.22). Such variations are
increased at 7T up to 95 Hz in average (Vannesjo et al., 2018) or higher (Pennell et al.,
2014), compared to 75 Hz at 3T. In comparison, breathing-induced B0 fluctuations in
brain at 7T were estimaged at 7 Hz during deep breathing (Duerst et al., 2016). According
to Vannesjo et al. (2018), the B0 shift between inspiration and expiration can go up to
more than 200 Hz.
Those increased B0 inhomogeneities at 7T are particularly detrimental to sequences
such as single-shot EPI, which has a very low BW in the phase-encoding direction,
resulting in large geometric distortions. If identical gradient strength is used, a BW 2.3
times higher than what is used at 3T would be necessary to obtain the same level of
distortions at 7T. However, this would considerably lower the SNR. Fortunately, new 7T
systems include gradient coils capable of higher gradient strengths compared to 3T.
Field inhomogeneities are local strong gradients, of the same order as the maximum
gradient strength of current 7T gradient coils. By way of example, the susceptibility
difference between air and soft-tissue is 9.4 ppm, corresponding to a frequency shift
of 2.8 kHz whereas the maximum gradient strength of 7T systems such as the Siemens
Terra scanner is 80 mT/m, which is equivalent to a frequency shift of 3.4 kHz/mm. B0
shimming is thus used to correct for field inhomogeneity using dedicated shim coils
inserted in the magnet bore. Standard B0 shimming procedures measure frequency
shifts by means of a B0 field map (or a set of projections in different orientations) and
then apply an algorithm in order to determine the external magnetic field to apply (and
corresponding currents for the shim coil) to counteract those local inhomogeneities. As
2.3 Ultrahigh field MRI 45
(a) At 3T (Verma et al., 2014)
(b) At 7T (Vannesjo et al., 2018)
Figure 2.22.: Measured B0 difference in the spinal cord between expired and inspired breath-hold field map acquisitions according to the vertebral level at 3T in seven healthysubjects (a) and at 7T in nine subjects (b).
the field variations in space get sharper at UHF, combination of linear gradients are not
enough and second or third order shim harmonics are necessary. In spinal cord, static
inhomogeneity is typically reduced from around 400 Hz to 50 Hz with shimming (Barry
et al., 2018). A trade-off has to be found when defining the volume where to compute
shim settings as a too tight volume can deteriorate field homogeneity outside it and
interfere with excitation profile or fat suppression, while a too large volume would reduce
the homogeneity inside it. Siemens’s algorithm to calculate the shimming harmonics
is not open-source but several choices for the field mapping sequences are available to
the user, among them GRE and DESS (Dual-Echo Steady State). However, for spinal
cord imaging at 7T, vendors solutions have shown poor robustness (Barry et al., 2018),
especially for small shim volumes (dimensions of the order of the spinal canal in the
transverse plane). The fit of second- or third-order shim harmonics is ill-conditioned
with small volumes. Moreover, shimming algorithm do not take into account the shim
current limits and the actual field profiles produced by shim coils, assuming perfect shim
harmonics profile. There is consequently room for improvements. Current technologies
46 Chapter 2
consider arrays of small shim coils placed close to the subject, which have demonstrated
improved shimming performance at 7T in the brain (Juchem et al., 2011)). Such set-up
was also adopted for spinal cord coil design (Topfer et al., 2016) and is very promising.
Those systems however fail to correct for dynamic field inhomogeneity or drastic
field variations along the inferior-superior direction as occur in spinal cord imaging at
7T when dealing with large FOV (e.g., from C1 to C7). Several strategies have been
proposed to address these problems. The first approach is to correct the inhomogeneity
during acquisition using dynamic shimming system in order to adjust the corrective field
(shimming settings) for each slice (slice-wise shimming) (Juchem et al., 2010; Sengupta
et al., 2011). Even the dynamic update of first-order shim along inferior-superior axis
has shown significant improvement for multi-slice spinal cord acquisitions (Finsterbusch
et al., 2013). To correct for time-fluctuating inhomogeneities like breathing-induced
variations, an adaptation of shim currents in real-time is necessary (real-time shimming).
However, real-time control of shim settings requires specific hardware (Topfer et al.,
2018) or modifications of current hardware (Gelderen et al., 2007). The second approach
is to correct the data retrospectively during reconstruction. FID navigators are used to
monitor the spatiotemporal B0 field changes in real time and then incorporate them
into a restrospective iterative reconstruction to improve 2D GRE images of the brain
(Wallace et al., 2019). In spinal cord, Vannesjo et al. (2019) proposed a method to
correct the acquired k-space data by the phase offset induced by breathing. This phase
offset was deduced from the respiratory belt signal and reference field maps acquired
beforehand and used to calibrate the relation between respiratory belt signal and B0 offset
individually for each slice and each subject. Finally, the third approach is to use pads
filled with specific materials matching the susceptibility of human tissue and to position
them in the vicinity of the subject (passive B0 shimming), which would mostly mitigate
inhomogeneities close to the shoulder but would not help with dynamic variations. Lee
et al. (2015) demonstrated an improved field homogeneity at 3T in the spinal cord with
pyrolytic graphite foam placed around the neck of the subject. A fourth option would be
to synchronize B0 shimming and EPI acquisitions with respiration.
Transmit field inhomogeneities and energy deposition
As the transmit field frequency increases with static field strength, the wavelength
of excitation pulses is reduced and becomes comparable to the human body and head
dimensions. At 7T the electromagnetic wavelength is close to the human body and head
2.3 Ultrahigh field MRI 47
dimensions (λRF ≈ 13.4 cm in brain tissue at 300 MHz) (Collins et al., 2011). Reflection
and scattering effects of the electromagnetic wave entering the body are thus increased
and lead to higher transmit field inhomogeneity with substantial local voids. The energy
of the electromagnetic wave is also increased (E = hf0). In addition, while the magnetic
component of the transmit RF field interact with the spin to flip the magnetization, the
spatially varying non-conservative electric component ~E that accompanies it displaces
charges in the tissue, creating electric currents, which convert into heating and energy
deposition with the natural resistive losses of the human tissue. The Specific Absorption
Rate (SAR) quantifies the energy deposition in the tissue according to:
SAR =σ| ~E(~r)|
2ρ
with σ the conductivity and ρ the mass density of the tissue. According to Faraday’s law,
the electric component is related to the temporal derivative of the magnetic component
by:
∇ × ~E = −∂ ~B
∂t
As the frequency of the RF pulse is increased at higher field, the magnetic component
changes faster with time, hence the increased electric field and SAR at higher field.
For field strengths up to 3T, SAR approximately increases as B02. At UHF, the electric
field distribution becomes more inhomogeneous with so-called hot spots that can induce
local SAR peaks compared to surrounding tissue. The local-to-global SAR ratio may be
substantially increased. Therefore, the extrapolation of SAR distribution at UHF is non-
trivial and may deviate from the quadratic increase with field strength. Although active
research is looking at reliable solutions to measure temperature and SAR with MRI (MRI
thermometry), since SAR is caused by the electric field and not the magnetic component,
measurements are mainly performed with numerical eletromagnetic simulations with
virtual coil and human body model.
In summary, not only does the RF power necessary to tilt the magnetization by the desired
flip angle increase at UHF, leading to SAR restrictions, but also the SAR distribution
gets more heterogeneous with local heating spots that can potentially cause tissue
damage. To ensure patients’ safety, the maximum SAR exposure is limited by regulatory
authorities (International Electrotechnical Commission, 2015; United States Food and
Drug Administration, 2014). In European Union for example, the global SAR is limited to
an average value of 3.2 W/kg by 6-minute time periods. The local SAR for each 10g of
tissue is limited to a maximum of 10 W/kg, and 30 W/kg over any 10-second period.
48 Chapter 2
Those limitations are the same regardless of the field strength but are more restricting
at UHF for the reasons aforementioned. In practice, workarounds are to lengthen RF
pulses, prescribe smaller flip angle, reduce the number of slices or lengthen repetition
time at the cost of the scan duration. Nevertheless, those workarounds are quickly limited.
To fully unlock the potential of UHF MRI, the independent usage of different transmit
coil channels emerged as a solution (Katscher et al., 2006; Zhu, 2004; Katscher et al.,
2003). Thanks to individual design of the pulse profiles of each transmission channel of
the coil, parallel transmission (pTx) techniques take advantage of the higher degrees of
freedom to improve the spatial homogeneity of the resultant transmit field in the region
of interest and to reduce SAR.
Furthermore, as proposed for static field heterogeneity, transmit field homogeneity
and efficiency at UHF can be improved with dieletric pads filled with high-permittivity
materials (Teeuwisse et al., 2012). Those pads are positioned between the coil and the
subject. However, as with pTx, the transmit field distribution of the coil is modified and
therefore requires a validation (e.g., using electromagnetic numerical simulations) to
ensure that no local SAR hot spots are created that could induce tissue damage.
Physiological effects of UHF
Physiological effects on patients pointed out during the development stage of 7T MRI
are of critical importance for the clinical acceptance of UHF. Beyond the local SAR hotspots
that are more likely at high field strength, dizziness, nausea, vertigo, magnetophosphenes
or metallic taste have been reported (Heilmaier et al., 2011). Disturbance of the vestibular
system leading to an incongruence between sensory, proprioceptive and visual information
received by the brain are suspected to be responsible for dizziness, nausea and vertigo
(Mian et al., 2016; Thormann et al., 2013). An increased blood pressure due to increased
static field strength was also investigated. Magnetohydrodynamic models have estimated
an increased pressure by less than 0.2% for a 10T field change (Keltner et al., 1990) and
experimental measurements in human and large animals did not find significant effects
(Atkinson et al., 2007).
If the aforementioned effects are categorized as transitory effects, permanent effect
with negative long-term health consequences of UHF, and more generally of MRI, have
been investigated. The main concern regards DNA damage and especially double-strand
breaks (DSB) which can lead to cell death or degeneration and cancerogenesis. Such
damage would mainly result from the interaction of high-energy photons with H2O
2.3 Ultrahigh field MRI 49
generating free radicals (e.g., OH-). Two out of seven studies reported increase in
staining for DSB in blood before and after MRI exposure. However, the studies with the
largest sample size, highest field strength (up to 7T) and including frequently exposed
subjects did not find any significant effect, concluding that DNA damage induced by MRI
up to 7T is not a relevant concern (Brand et al., 2015; Lancellotti et al., 2015; Reddig
et al., 2015).
Either it exist or not, these effects might be close to the limit of detection of the
current techniques or similar to the variations with everyday life activities. The RF
quantum energy (10−6 eV at 7T) is much smaller than the Boltzmann thermal energy at
the human body temperature (about 27 × 10−3 eV) or than the ionization or excitation
energies in molecules (about 1 eV). Thus, potential effects during medical MR exams in
clinics (clinical exposure) should not be reconsidered. Concerns are for research practice
(research exposure) where subject are exposed without direct benefit for them. Regarding
the exposure of workers to higher magnetic fields (occupational exposure), activities
which require approaching the bore or reaching into it should be monitored as limits
have been defined by the European Union Electromagnetic Field Directive (2 T for normal
working conditions, 8 T for localized exposure of the limbs, 8T for controlled working
conditions) (European Parliament and Council, 2013).
2.3.3 UHF MRI in spinal cord
The main centers deeply involved in 7T spinal cord imaging across the world are
currently Vanderbilt University Institute of Imaging Science (Nashville, USA), Oxford
Centre for Functional MRI of the Brain (Oxford, UK), Athinoula A. Martinos Center for
Biomedical Imaging (MGH, Charlestown, USA), Icahn School of Medicine at Mount
Sinai (New York, USA) and Center for Magnetic Resonance in Biology and Medicine (Aix-
Marseille University, Marseille, France), recently joined by Montreal Neurological Institute
(Montreal, Canada) and the Balgrist Spinal Cord Injury Center (Zurich, Switzerland).
7T spine coil arrays
Several designs have been proposed for spinal cord MRI coils at 7T. A comprehensive
review is available in Barry et al., 2018 (see Figure 2).
50 Chapter 2
Figure 2.23.: Cervical spine coil array for 7T MRI designed by RAPID Biomedical (source: Massireet al., 2016). (a) A power splitter enables either to combine the Tx channels intoa single one or to use them independently for parallel transmission. (b) The coilarray is made of 8 Tx-Rx channels with respective pre-fixed relative phase values.(c) The transmit field coverage along inferior-superior axis (for transmission insingle-channel mode) can be appreciated on a sagittal localizer. Nonetheless, thecoverage extent largely depends on the subject’s morphology. The acceptablecoverage also depends on the application.
To date, the only spine coil array approved for clinical use (in Europe only, limited
to investigational use in the United-States) is a 8-channel Transmit (Tx) and Receive
(Rx) cervical spine coil array designed by RAPID Biomedical as a prototype for the
CRMBM-CEMEREM, which is now commercialized with Siemens 7T Magnetom Terra
scanner (Figure 2.23). The 8 channels can be either combined into one for single-channel
Tx or used independently for parallel transmission. The "sensitive area" is from C1 to
C7 (Figure 2.23), however, the extent of the transmit field acceptable coverage largely
depends on the subject’s morphology and the application (Massire et al., 2018).
Another spine coil array of interest is the two-panel array with 4 Tx/Rx and 18 Rx-only
elements, encircling head and neck for imaging from brainstem to C7, built by Zhang
et al. (2017) (Figure 2.24). Designed based on electromagnetic simulations, the posterior
panel is made of 2 central Tx/Rx elements surrounded by 12 Rx-only elements, while the
anterior panel is made of 2 central Tx/Rx elements surrounded by 6 Rx-only elements.
Finally, a promising design, including a 3-dipole Tx array and a 15-channel Rx
array with AC/DC technology allowing for real-time B0 shimming and compensation of
breathing-induced fluctuations, was proposed by Lopez Rios et al. (2019) for cervical
spine (Figure 2.25). Although not yet operational at 7T, it demonstrated useful reduction
in B0 static heterogeneity and temporal variations at 3 T (32% and 27% respectively).
2.3 Ultrahigh field MRI 51
(a) Coil exterior(b) Sagittal GRE image showing
the coil inferior-superiorcoverage
Figure 2.24.: Two-panel coil array proposed by Zhang et al. (2017) for 7 T MRI of the brainstemand cervical spinal cord. (a) The exterior of posterior (2 Tx/Rx elements in thecenter, 12 Rx-only elements around) and posterior array (2 Tx/Rx elements in thecenter, 6 Rx-only elements around). (b) Sagittal GRE image showing the arrayinferior-superior coverage from brainstem to C7.
UHF applications to spinal cord
In the beginning of the twenty-first century, given the increased sensitivity to suscepti-
bility effects with field strength, functional MRI (in brain) has been a driving force for
UHF development. Functional MRI is therefore also one of the main axis of UHF research
applications in the spinal cord (Barry et al., 2014; Barry et al., 2016) (Figure 2.26).
With the SNR gain, high-resolution Diffusion Tensor Imaging (DTI) (Figure 2.27a),
high-resolution T1 and T2* relaxometry (Massire et al., 2016; Massire et al., 2018;
Massire et al., 2020), as well as quantitative Magnetization Transfer (qMT) (Dortch
et al., 2012) mapping in the spinal cord have also benefited from 7 T MRI. Attracted
by the higher spectral resolution, the first application in the spinal cord using parallel
transmission has been Magnetic Resonance Spectroscopy (MRS) (Henning et al., 2016).
Also benefiting from the higher spectral resolution at 7T, Chemical Exchange Saturation
52 Chapter 2
Figure 2.25.: Integrated AC/DC 15-channel Rx and 3-dipole Tx array design for 7T MRI ofcervical spine (source: Lopez Rios et al., 2019). Rx elements are represented bywhite loops while Tx dipoles are represented by yellow lines. (a) Sagittal view, (b)Coronal view.
Transfer (CEST) has been applied at 7T in the spinal cord for imaging of the glutamate in
healthy volunteers (Kogan et al., 2013) (Figure 2.27b) and in multiple sclerosis patients
(Dula et al., 2016). Last but not least, multiple studies have pushed the resolution for
multi-echo gradient-echo imaging to depict the exquisite anatomical details of healthy
spinal cord (nerve roots, ligaments, anterior and posterior spinal arteries, dura mater, pia
mater, see Figure 2.27c) (Zhao et al., 2014; Massire et al., 2016; Zhang et al., 2017).
UHF MRI in the spinal cord is an emerging field, with application mainly at the
cervical level. This field has to take up the multiple challenges described earlier but
research makes fast progress and a high potential to improve patient care is expected.
2.3 Ultrahigh field MRI 53
Figure 2.26.: Reproducibility of resting state functional MRI in spinal cord at 7T (from Barryet al., 2016). Example of spatial correlations for ventral (motor, first row) anddorsal (sensory, second row) resting state networks at C3/C4 vertebral level for 4healthy subjects and two distinct runs. The second column shows the results withfiltering including higher frequencies (0.01 to 0.13 Hz instead of 0.10 to 0.13 Hz).
54 Chapter 2
(a) High-resolution (400×400 µm2 in-plane) FA maps of healthy spinal cord.
(b) CEST imaging of glutamate inhealthy spinal cord at 7T.
(c) High-resolution (180×180 µm2 in-plane) anatomicalimaging of healthy spinal cord
Figure 2.27.: Examples of applications benefiting from 7T MRI. (a) High-resolution(400×400 µm2 in-plane) FA maps obtained at 7T in healthy spinal cord by Massireet al. (2018), showing different diffusion properties across spinal pathways such asCorticospinal Tracts (CST), fasciculus gracilis and cuneatus, at cervical levels fromC1 to C5. (b) Quantitative map of the CEST asymmetry attributed to glutamateamide protons obtained at 7T in healthy spinal cord by Kogan et al. (2013). (c)Sum of squares of multi-echo gradient-echo images of a healthy spinal cord withhigh in-plane resolution (180×180 µm2) obtained at 7T by Massire et al. (2016)and allowing thin structures to be depicted, as shown by the color arrows (blue:nerve roots, purple: ligaments, red: anterior and posterior spinal arteries, green:dura mater, yellow: pia mater).
2.3 Ultrahigh field MRI 55
2.4 Perfusion MRI
Several MR techniques to measure (or to be sensitive to) perfusion and vasculature
have been developed. On the one hand, vascular MRI refers to Magnetic Resonance
Angiography (MRA) and is performed to reveal arteries and veins anatomy and dysfunc-
tions. It relies either on endogenous contrast, such as Time-Of-Flight (TOF) techniques
or phase-contrast MRA (Miyazaki et al., 2012), or exogenous contrast agent, referred as
contrast-enhanced MRA (Marchal et al., 1992). As it is not the main focus of this PhD
work, the main principles were briefly described in Appendix A.1. Perfusion MRI, on the
other hand, refers to microvasculature and blood supply to the capillaries.
Historically, perfusion techniques were first developed in the brain. While develop-
ments in brain are still ongoing, research has then focused to translate those techniques
to other organs (e.g., kidneys, heart, liver, etc.). Two main types of techniques stand out:
exogenous techniques, with injection of a contrast agent, and endogenous techniques,
without it. Due to their higher sensitivity to perfusion/vasculature and short acquisition
times, exogenous techniques are today the reference technique in clinics.
2.4.1 Exogenous techniques
Contrast agent effects
Exogenous techniques consist in detecting Contrast agent (CA) after one or two
intravenous injections in a peripheral vein (usually antecubital vein). The most frequently
used CA are paramagnetic and based on Gadolinium (Gd), which is encapsulated in
chelates to limit toxicity. Several chelates are commercialized (e.g., gadoteric acid for
Dotarem®, gadobutrol for Gadovist®). Other types of CA exist but only Gd-based CA will
be considered here. For such CA, the standard "single" dose is 0.1 mmol/kg body weight
or 0.2 ml/kg.
In the central nervous system, when CA arrives in vascular network, the apparent
relaxation rates R1, R2 and R∗
2 increase. T1 shortening provides more signal for short TR
acquisitions, T2 and T ∗
2 shortening induces a signal drop for identical TE.
Figure 2.28 shows the R1 increase of human blood at 37°C with the increase of
injected Dotarem® concentration. For the same concentration, R1 decreases with higher
56 Chapter 2
field strengths, along with the difference in R1 between blood with and without the CA.
R1 is intrinsically lower at higher field and CA relaxivity (in mM-1s-1) is also reduced
(Figure 2.29). As reference, T1 in blood was estimated around 1480, 1649 and 2087 ms
at 1.5T, 3T and 7T (Zhang et al., 2013).
Figure 2.28.: Dotarem® Relaxation rate R1 of Dotarem® in human blood at 37°C according toGd concentration and field strength (Source: Shen et al., 2015).
Literature is less clear-cut regarding R2 dependency on field strengths, although T2
theoretically does not depend on field strength (see Section 2.3.1). Rohrer et al. (2005)
measured a rough decrease in r2 relaxivity with increasing field strengths for Dotarem®
in human plasma and most tested CA, with higher r2 at 3T compared to 1.5T and 4.7T.
Although absolute values were slightly different, Vignaud et al. (2014) came up with the
same results, with a decrease in r2 from 1.5 to 3T to 7T for Dotarem® but a higher r2 at
3T for other CA . Pintaske et al. (2006) measured a decrease in r2 from 0.2 to 1.5 to 3T
for other CA (Gd-DTPA, Gd-BT-DO3A, Gd-BOPTA) in human plasma at 37°C. Finally, the
most recent study which focused on in-vitro r2 relaxivities of Gd-based CA in human blood
found higher values at 3T compared to 1.5T (Shen et al., 2019). Therefore, although
similar trends were found in human plasma, results at 7T might differ in oxygenated
human blood and in-vivo because of the physiological environment (e.g., interstitial fluids,
intracellar space) and binding of CA to macromolecules (protein binding).
2.4 Perfusion MRI 57
Figure 2.29.: Contrast agent r1 dependency on field strength in human blood at 37°C for differentchelates (Source: Shen et al., 2015).
According to Rohrer et al. (2005), r1/r2 ratio decreased with increasing field strength,
dominated by r1 dynamic. Vignaud et al. (2014) only reported a weak change for
Gd-DOTA (Dotarem®).
As for R∗
2 dependency on field strength, literature is sparse. Only one group reported
values in a journal article in oxygenated human blood (Kalavagunta et al., 2014).Based
on those results, the increase in blood R∗
2 with Gd concentration is expected to be higher
at 7T than at 3T.
Considering those results, increasing field strength would increase the sensitivity to
R∗
2 change with CA arrival in tissue, not because of the increased r2 relaxivity (spin-
spin interactions) but rather because of the reduced T ′
2 (increased sensitivity to B0
inhomogeneities at higher fields).
58 Chapter 2
(a) Vignaud et al. (2014)
(b) Shen et al. (2019)
Figure 2.30.: T2 relaxivities in distilled water and human plasma at 1.5T, 3T and 7T (a) and inhuman blood at 1.5T and 3T (b).
Dynamic Susceptibility Contrast (DSC) imaging
Principle The Dynamic Susceptibility Contrast (DSC) technique is based on the mon-
itoring of the CA transit into the vascular and microvascular network of the tissue of
interest, by use of a dynamic series of T2- or T2*-weighted images (SE or GRE pulse
2of Magnevist™(Gd-DTPA) in bovine blood and oxygenated human blood at 37°C
according to Kalavagunta et al. (2010) and Kalavagunta et al. (2014).
sequence). The magnetic effects of the paramagnetic CA induce a signal drop in the
signal intensity-time curve (Figure 2.32).
Figure 2.32.: CA bolus effect on MRI signal intensity in DSC imaging, along with effect of CAleakage in extravascular space in case of disrupted blood-brain barrier. The firstpassage of the CA in brain tissue (tumor in that case), inducing a large signalintensity drop can be observed, as well as the second passage or recirculation(second small signal drop). CA extravasation effects on signal can either be asignal intensity increase after bolus (T1-dominant effects), mostly observed inlow-grade tumor (e.g., astrocytoma), or a signal intensity that is not coming backto baseline (T2*-dominant effects), more often observed in high-grade tumors (e.g.,glioblastoma) (Source: Goo et al., 2017)
.
60 Chapter 2
This curve can then be converted to variations in R2 or R∗
2 according to:
∆R(∗)2 (t) = − 1
TEln
(S(t)
S0
)
where S(t) is the signal intensity, S0 is the baseline signal (before CA injection) and
TE is the echo time. Assuming that relaxation rate change is directly proportional
to CA concentration change, normalizing by the CA relaxivity converts it into the CA
concentration of the tissue:
∆R(∗)2 (t)
r(∗)2
= fvascularCvascular = Ctissue
with r(∗)2 the CA relaxivity in human blood, fvascular the volume fraction of vascular
compartment (0≤fvascular≤1) in the tissue and Cvascular the CA concentration in vascular
compartment.
Perfusion indices From the concentration-time curve, several perfusion indices can be
derived.
For these indices to quantify perfusion with absolute values, the profile of CA arrival
into the tissue by the arterial supply network is necessary. This is named the Arterial
Input Function (AIF). AIF is extracted in a few voxels in the most direct artery or arteries
supplying the tissue of interest. On the one hand, the ideal location to extract AIF is the
small arterioles directly supplying the tissue of interest. However, because of their small
size with respect to the typical spatial resolution of DSC-MRI (∼2×2×5 mm3), Partial
Volume Effects (PVE) can lead to large errors in the extracted AIF (loss of sharpness and
amplitude). On the other hand, extracting AIF in large artery, more distal from the region
of interest, would help to minimize PVE but would lead to an erroneous representation of
the bolus ultimately entering the tissue, especially regarding timings (e.g., Bolus Arrival
Time (BAT)) and peak because of the multiple bifurcations occurring in-between. For
brain perfusion, a medium-size artery such as the first segment of the middle cerebral
artery is typically chosen, as a compromise between minimising PVE and bolus delay and
dispersion (Calamante, 2013).
The deconvolution of the concentration-time curve by the AIF allows the following
perfusion indices to be extracted:
2.4 Perfusion MRI 61
• the residue function: the tissue retention of CA, given the AIF (assuming an ideal
instantaneous bolus injection), i.e. the deconvolved tissue-concentration curve
• the Blood Volume (BV): the fraction of tissue volume occupied by blood (in
milliliters per 100g of tissue), calculated as the area under the deconvolved tissue-
concentration curve
• the Blood Flow (BF): the blood volume passing through the tissue vasculature per
time unit (in milliliters per minute per 100g of tissue), calculated as the maximum
value of the deconvolved tissue-concentration curve
• the Mean Transit Time (MTT): the average time its takes CA to pass through the
Average across references 4.9±0.9 2.4±0.8 63.9±16.7 24.3±5.8 4.6±1.6 5.5±1.7
Pulse sequence To properly depict the dynamic of the CA passage in the tissue, a
minimum temporal resolution of 1.5 seconds is required (Welker et al., 2015). This
2.4 Perfusion MRI 63
requires rapid imaging technique. Echo-Planar Imaging (EPI) is therefore the most used
for readout. Regarding sequence contrast, as a signal drop with CA passage is wanted,
the lowest T1-weighting is desired and the highest T2 or T2* weighted is sought-after.
Consequently, SE-EPI for T2-weighted signal and GRE-EPI for T2*-weighted signal are
used.
Gadolinium r2∗ being higher than r2, a higher Contrast-to-Noise Ratio (CNR) can
be obtained with GRE. However, because of more pronounced susceptibility artefacts
with GRE, SE is advised at high field strengths (Welker et al., 2015) or for imaging
regions close to tissue interfaces such as paranasal sinuses, skull base or hematomas
(Figure 2.34).
Besides, GRE signal (∆R∗
2) was shown to be more sensitive to large vessels than SE
signal (∆R2) with equal sensitivity to smaller vessels (Figure 2.35). This difference is
explained by the sensitivity of SE to spin diffusion (Weisskoff et al., 1994). For small
vessel sizes (<4-5 µm), spin diffusion is fast enough to dephase before the refocusing
pulse, yielding similar sensitivity between GRE and SE. However, for larger vessel sizes,
spin diffusion is slower and is refocused with SE, while ∆R2∗ in GRE is dominated by
intra-voxel dephasing and becomes independent from vessel size (dephasing due to spin
diffusion has become negligible). SE signal is therefore more related to capillary perfusion
as confirmed in-vivo (Speck et al., 2000).
In case of disrupted blood-brain barrier, CA extravasates in the tissue and reduces its
T1 relaxation time. Some studies have proposed double-echo GRE or SE sequences to
mitigate the T1 effects due to CA extravasation (Vonken et al., 1999; Newbould et al.,
2007). ∆R2 or ∆R∗
2 is directly estimated using the two echoes of each acquisition,
independently from T1 effects.
Combining double-echo GRE and SE in the same pulse sequence was also pro-
posed (Schmiedeskamp et al., 2012; Donahue et al., 2000). In addition to provide
T1-independent DSC data, such technique combines the higher sensitivity to CA of GRE
and the better microvascular selectivity of SE, without additional scan time or a second
injection. It additionally enables a vessel size index map to be calculated.
Finally, two-dimensional multislice acquisitions are generally preferred over 3D for
the shorter TR (Welker et al., 2015).
Main applications in brain The main indications for DSC MRI in brain are diagnosis and
characterization of tumor and ischemia assessment. It is, inter alia, used to guide surgical
64 Chapter 2
Figure 2.34.: Relative cerebral BF maps from GRE and SE along with anatomical image. Thesignal drop near the ears (first row) is larger with GRE than with SE. White arrowspoint the different appearance between the two methods for large vessels. Whilearteries and veins show high BF values with GRE, they are less visible with SE. Noneof the draining veins appear with SE but the GM delineation is clearer. (Source:Speck et al., 2000)
interventions towards the highest grade tumor regions (Lefranc et al., 2012), evaluate
response to therapy or monitor tumor progression (Hu et al., 2012). In cerebral ischemia
assessment (e.g., acute stroke), DSC MRI is useful to delineate the ischemic penumbra
2.4 Perfusion MRI 65
Figure 2.35.: ∆R2 and ∆R∗
2dependency on polystyrene microsphere diameter in a solvent made
of aqueous solution and Dy-DTPA (Source: Weisskoff et al., 1994). Above 4µm, GEand SE sensitivity diverge.
(critically underperfused tissue that has not yet infarcted) (Wintermark et al., 2013) or to
evaluate hemodynamic function in vascular steno-occlusive diseases (Apruzzese et al.,
2001; Kavec et al., 2004).
Dynamic Contrast-Enhanced (DCE) imaging
Dynamic Contrast-Enhanced (DCE) is a perfusion imaging technique dedicated to
assess blood-brain barrier deficiency. It is commonly referred as permeability MRI or T1
perfusion MRI. As for DSC, it consists in acquiring a temporal dynamic series of images
before, during and after the paramagnetic CA intravenous injection in the patient. The
main differences with DSC regards the MRI contrast used, the temporal sampling and the
model applied. The extraction of an Arterial Input Function is also necessary for absolute
parameter quantification.
DCE uses T1-weighted images. Several microvascular permeability models exist
but the classical 2-compartment (plasma space and extravascular extracellular space)
pharmacokinetic extended Toft’s model is the most frequently used to assess permeability
of brain tumors or lesions (Figure 2.36). The main indices of interest are:
• the volume transfer constant Ktrans (measure of microvascular permeability)
• the total blood plasma volume Vp
66 Chapter 2
• the total extravascular extracelluar volume Ve
• the rate constant from extravascular extracellular space to plasma space Kep =
Ktrans/Ve
Figure 2.36.: Example of 2-compartment pharmacokinetic models of DCE and derived perfusionparameters, Toft’s model being the most frequently used. The difference betweenToft and extended Toft’s models is that the latest additionally estimate the bloodplasma volume Vp (source: Gaddikeri et al., 2016)
.
Because of the higher relaxivity r2 of Gd-based CA compared to r1, indices directly
related to perfusion (e.g. BF, BV, MTT) are preferably estimated based on T2-weighted
images given the consequent higher sensitivity. When permeability needs to be assessed,
for instance to delineate tumor or characterize vessel functionality in neoangiogenesis,
T1-weighted images are preferred over T2-weighted EPI sequences, which potentially
come with limited spatial resolution and image distortion. Nonetheless, DSC MRI can
provide indices of CA extravasation (Schmainda et al., 2004). Conversely, a few studies
also showed that perfusion-related indices could also be extracted from T1-weighted
dynamic image series, providing prior acquisition of a quantitative T1 map. Table 2.3 lists
those studies and the BF and BV obtained in brain. (Haroon et al., 2007) and (Zakariaee
et al., 2018) acquired both DCE and DSC protocols in patients with brain tumors. An
example of the obtained BV and BF maps are presented in Figure 2.37 and a comparison
of values in WM, GM and tumors is presented in Table 2.4.
2.4 Perfusion MRI 67
Table 2.3.: Healthy BV and BF values obtained in literature with DCE MRI in brain.
Reference BV (mL/100g) BF (mL/100g/min)
GM WM GM WM
Zakariaee et al. (2018) 5.0±1.4 1.8±0.7 60.5±12.7 32.0±6.0
Nael et al. (2015) 2.4±1 1.3±0.6 68.7±23.1 19.4±6.4
Singh et al. (2007) 6.9±1.7 2.6±1.1 65.9±23.8 36.5±14.8
Bulte et al. (2007) 3.9±0.9 2.5±0.8
Shin et al. (2006) with fast water exchange model 5.8 2.73
Shin et al. (2006) with no water exchange model 3.2 1.78
Ito et al. (2004) 3.8±0.7
Lammertsma et al. (1983) 5.9±6.6 2.4±0.3
Sourbron et al. (2009) (measured) 2.6 1.3 82 23
Larsson et al. (2009) 6.4±1.8 3.9±1.1 71.7±16.4 30.6±7.6
Average±SD across references 4.6±1.5 2.3±0.8 69.8±7.1 28.3±6.2
Table 2.4.: Comparison between BV and BF values obtained from DSC and DCE MRI in brain(source: Zakariaee et al., 2018)
• λ: the brain/blood partition coefficient in mL/g (generally set to 0.9 mL/g)
• Scontrol: the signal intensity (usually averaged across repetitions) in the control
image
• Slabel: the signal intensity (usually averaged across repetitions) in the labeled image
• PLD: the Post-Label Delay
• T blood1 : the longitudinal relaxation time of blood in seconds (e.g., 1.480, 1.649 and
2.087 s at 1.5T, 3T and 7T (Zhang et al., 2013)), which depends on the subject’s
hematocrit concentration
• α: the labeling efficiency (generally set to 0.85 for PCASL)
• SP D: the signal intensity of a proton density-weighted image
• τ : the label duration
This model assumes that the entire labeled blood bolus is delivered to the target tissue,
that there is no outflow of labeled blood water and that the relaxation of labeled spins is
defined by blood T1 only.
Perfusion parameters quantified with single PLD/TI acquisition depend on the PLD/TI
value used. Using multiple PLD/TI acquisitions, the Arterial Transit Time (ATT), which is
2.4 Perfusion MRI 71
Figure 2.39.: Comparison of perfusion parameter maps obtained from PCASL and DSC MRI inacute ischemic stroke (source: Wang et al., 2013). PCASL data were acquired withmultiple PLDs. The arterial Cerebral Blood Volume (aCBV) was obtained accordingto aCBF = CBF ·ATT and Tmax is the time to the maximum value of the residualfunction.
the transport time from the labeling position to the tissue can be estimated and make the
BF estimation more precise. ATT can be a relevant parameter in steno-occlusive diseases.
However, multiple PLD/TI methods are more complex and require more measurements
and processing.
Figure 2.39 compares the absolute perfusion parameters quantification obtained
from PCASL to the corresponding parameters obtained with DSC MRI in acute ischemic
stroke. Although ASL performs relatively well to quantify absolute perfusion values, its
sensitivity is generally lower than DSC, especially in a clinical context where the number
of averaging cannot be extended. The low sensitivity of ASL comes from the fact that
only ∼1% of brain water is replaced by in-flowing blood water at every heartbeat (∼1s),
meaning that for a 2-second bolus of labeled blood, no more than 2% of a brain voxel
is disturbed in an ASL experiment (Alsop et al., 2015). Considering the longitudinal
relaxation and PLD, this brings the difference between the labeled and control image to
less than 1%. Physiological noise and patient motion therefore have a strong impact on
ASL measurements.
72 Chapter 2
To address that, a common strategy is to use background suppression to reduce as
much as possible the signal coming from the stationary tissue. Background suppression
strategies typically use initial selective saturation pulse and a carefully calculated inversion
pulse timing to ensure that the magnetization of stationary tissue is close to 0 at the time
of image acquisition (Maleki et al., 2012).
Regarding the readout, 3D segmented multi-echo RARE (Rapid Acquisition With
Relaxation Enhancement) (Hennig et al., 1986; Hennig, 1988) stack of spirals or 3D
segmented GRASE (GRadient- And Spine-Echo) (Feinberg et al., 1991) sequences are
recommended because of their SNR efficiency and good compatibility with background
suppression as they use only one excitation by TR, unlike 2D multi-slice strategies which
can be an alternative (single-shot EPI or spiral Fast Spin-Echo) (Alsop et al., 2015).
ASL could therefore be advantageous over DSC in the sense that it does not require
the injection of an exogenous CA, which is a non-negligible asset for patient low CA
clearance capacities or intolerant to CA. In addition, the acquisition time can be traded
for SNR through multiple averages, which cannot be with DSC. A longer scan time is
nonetheless required to reach the sensitivity of DSC. Another disadvantage of ASL, which
is particularly relevant at UHF with regards to SAR limits, is the high-energy deposition
of the pulse sequences and the high inversion efficiency required.
Intra-Voxel Incoherent Motion (IVIM)
Diffusion MRI Thermal agitation in any living body induces a random motion (or Brow-
nian motion) of the molecules. In particular, water molecules in human body (80%)
naturally moves in the tissue. This displacement is characterized by mean value of:
< r2 >=√
6D∆
where D is the coefficient of diffusion of H2O in the tissue. ∆ is the time of diffusion and
the factor 6 accounts for the degrees of freedom in 3D.
It is possible to make the MRI signal sensitive to the water molecule diffusion, yielding
Diffusion-Weighted Imaging (DWI). The most frequently used sequence to do so is the
spin-echo (Stejskal et al., 1965). Magnetic field gradients are added before and after
the 180° RF pulse. Figure 2.40 presents the theoretical cases of a voxel including two
proton spins staying at the same position (first row) and one proton spin staying still
2.4 Perfusion MRI 73
while the other changes of position (second row). In the first case, the two protons
being at a different location, their spins see a different magnetic field (because of the
gradient) and therefore precess at different frequencies. However, the 180° pulse changes
the direction of precession and spins come back in phase at TE. In the second case,
one of the two protons changes position (due to diffusion) and therefore experiences a
different magnetic field along the sequence, which changes in precession frequency. The
accumulated phase is different in absolute value before and after the 180° pulse. The two
protons do not come back in phase at TE and the signal is reduced proportionally to spin
diffusion.
b-value
b = γ 2G2δ 2(Δ −δ
3)
Figure 2.40.: DWI: sensitization of MRI signal to water diffusion (adapted from: White et al.(2014))
.
The b-value defines the diffusion weighting of the image and is a function of the
gyromagnetic ratio γ, the gradient amplitude G and the diffusion time Td = δ2(∆ − δ3)
where ∆ is the time between the two gradients and δ is the duration of each gradient:
b = γ2G2Td
The higher the b-value, the more sensitive the signal will be to slow diffusion. Inversely,
the lower the b-value, the more sensitive the signal will be to fast diffusion. Note that the
diffusion gradients are applied in a well-defined direction. When no diffusion gradients
74 Chapter 2
are applied, the obtained image is called b=0. The effect of Gaussian diffusion on MRI
signal is modeled according to:
S = Sb=0e−b · D
with Sb=0 the signal obtained with b = 0. The acquisition of the signal with no diffusion
gradients is therefore necessary to estimate the tissue diffusion coefficient D.
As the diffusion of water molecules is affected by their environment, diffusion MRI is
useful technique to assess the tissue microstructure in-vivo (Bihan, 1995). For example,
in spinal cord white matter where axonal fibers are mainly distributed along the inferior-
superior direction, diffusion is largely fostered along those fibers and restricted in their
transverse plane. The diffusion in spinal cord white matter is said anisotropic. In contrast,
the CSF has an isotropic diffusion. Consequently, diffusion coefficient depends on the
direction. To fully characterize the tissue microstructure, several diffusion-encoding
directions have to be acquired. A diffusion coefficient is estimated from each of them and
a diffusion tensor (Basser et al., 1994) can be computed:
Figure 2.41.: Calculation of the diffusion tensor for DTI (adapted from: Jellison et al. (2004)).
This is called Diffusion Tensor Imaging (DTI). At least 6 directions are necessary
to estimate the diffusion tensor. Diffusion indices such as the Fractional Anisotropy
(FA), Mean Diffusivity (MD) or Radial Diffusivity (RD) can then be derived and used as
biomarkers.
Typical b-values for DTI are 1000 s/mm2 in brain and 700-800 s/mm2 in spinal cord.
2.4 Perfusion MRI 75
In clinics, DWI is mandatory is case of suspected ischemia. DTI is largely used to
describe white matter impairment in degenerative pathologies and traumas (Sidaros
et al., 2008; Nir et al., 2013).
Intra-Voxel Incoherent Motion (IVIM) Intra-Voxel Incoherent Motion (IVIM) is a DWI-
based technique that includes the signal dephasing induced by the motion of blood water
molecules with perfusion (Le Bihan et al., 1988). As explained above, it is possible to
control the diffusion weighting with the b-value in order to sensitize the signal to different
diffusion speeds.
IVIM models the microvasculature as a randomly-oriented capillary network (Fig-
ure 2.42). Within a voxel, the motion of blood water molecules due to perfusion can then
be modeled as an incoherent random motion similar to the Brownian motion induced by
thermal agitation but with faster diffusion. Two Gaussian diffusion processes occurring
in the voxel are represented: the diffusion related to the Brownian motion and the
pseudo-diffusion induced by perfusion in the capillary network. The most frequently used
signal representation is:
S = Sb=0e−bD(fIV IM e−bD∗
+ 1 − fIV IM )
where D is the pure diffusion coefficient of water in tissue, D∗ is the perfusion-related
diffusion coefficient or pseudo-diffusion coefficient of blood water and fIV IM is the mi-
crovascular volume fraction.
Note that in this representation the diffusion coefficient of blood is assumed to be the
same as the diffusion coefficient D of all tissues within the voxel. This is a reasonable
assumption compared to the difference with the pseudo-diffusion coefficient D∗. Indeed,
D∗ is expected to be more than 10 times higher than D which enables the two processes
(diffusion and perfusion) to be tiered apart from each other (Le Bihan et al., 1988).
Moreover, it is important to note that the diffusion coefficient D estimated with IVIM
model is different from the coefficient of diffusion D estimated with DTI. The latter
should be higher.
While DTI requires the acquisition of only one b-value (in addition to b=0), IVIM
requires the acquisition of at least 2 non-null b-values (Le Bihan et al., 1988). However,
in practice, a large range of b-values (∼10) are acquired to mitigate the effects of noise
Figure 2.42.: Intra-Voxel Incoherent Motion (IVIM) model and signal representation (adaptedfrom Nicholas Theodore, M.D.)
.
Indeed, the bi-exponential representation has been showed to be very sensitive to noise
(Novikov et al., 2018) and people have been suspicious about the feasability to quantify
IVIM indices in the central nervous system. In 1992, King et al. (1992) investigated the
reliability of IVIM least-square fit in a rat brain and concluded that IVIM indices could
not be quantified reliably because of the difficulty to fit biexponential representation. In
2019, Milani et al. (2019) showed with simulations for kidney perfusion quantification
that fIV IM estimation reliability strongly decreased with the ratio D ∗ /D. Given that
perfusion velocity changes during cardiac cycle (e.g., up to a factor 2 in the anterior
cerebral artery (Federau et al., 2013), it would therefore be recommended to acquire data
at the peak of perfusion velocity. They confirmed this result in-vivo with maps showing
less inconsistent values and more consistent anatomical details when acquired at the
peak of perfusion velocity. Phase-contrast imaging sequence of the renal artery was used
to determine this time.
Healthy values and pathological applications IVIM values reported in literature for
healthy brain GM and WM are collected in Table 2.5. Large SD across studies can be
observed for fIV IM and D∗, attesting of the instability of the biexponential fit or of the
strong dependence on acquisition parameters. Estimation of D is more robust.
Healthy IVIM values in brain have also shown large variability depending on the b-
value distribution (Hu et al., 2020) and the fitting method (two-step or one-step approach).
2.4 Perfusion MRI 77
Table 2.5.: IVIM values reported in literature for healthy brain gray and white matter.
Reference fIV IM (%) D∗ (10−3 mm2/s) D (10
−3 mm2/s)
GM WM GM WM GM WM
Bisdas et al. (2013) 6.5±3.7 7.3±6.1 0.62±0.21
Bisdas et al. (2015) 15±3 12±2 4.85 3.74 0.67 0.62
Bertleff et al. (2017) 10.0 5.0 8.0 6.0 1.1 1.0
Wang et al. (2017a) 24.7 13.2 0.712 0.603
Wirestam et al. (2001) 20±9 16±8.7 14±53 21±60
Rydhög et al. (2014) 5.3±1.6 3.0±0.3 86±14 84±11 0.83±0.06 0.84±0.03
Wu et al. (2015) 14±2 7±1 8.2±0.9 7.9±0.9 0.84±0.05 0.77±0.04
Federau et al. (2015) 4.7±3.0 4.5±1.6 17.0±11.3 15.1±20.8 0.72±0.05 0.71±0.05
Stieb et al. (2016) 12.5 9.0 9.95 9.79 0.75 0.71
Grech-Sollars et al. (2015) 10.0 8.0 0.75 0.65
Ahlgren et al. (2016) 2.4±0.8 1.6±0.7 1.20±0.22 0.98±0.13
Wong et al. (2017) 2.40±0.04 2.21±0.3 0.73±0.03 0.72±0.05
Finkenstaedt et al. (2017) 10±3 6.22±0.48 0.91±0.09
Average±SD across references 10.9±6.6 7.3±3.0 19.3±25.5 19.4±25.0 0.84±0.16 0.75±0.13
Wu et al. (2019) also demonstrated the dependency of IVIM estimation on the diffusion
time Td. Briefly, D∗ and fIV IM generally increased the Td.
IVIM was therefore proposed as another endogenous alternative than ASL to DSC MRI
for perfusion assessment. In brain, several studies have looked at the relation between
IVIM and ASL or DSC (Wu et al., 2015; Wirestam et al., 2001; Stieb et al., 2016). Unlike
ASL and DSC, IVIM parameters quantification is not based on a bolus (of labeled blood
water or contrast agent). They are related to the microvascular blood volume and flow in
average in the capillary network during the acquisition. Therefore, correlations of IVIM
either with ASL or DSC were not higher than 0.6 in white matter and 0.9 in putamen for
ASL (Stieb et al., 2016) and 0.5 in gray matter for DSC (Wu et al., 2015).
Main applications of IVIM in the brain are tumor detection and grading. IVIM has also
been applied to other organs such as the lungs (Yuan et al., 2016), prostate (Shinmoto
et al., 2012), breast (Sigmund et al., 2011), liver (Luciani et al., 2008) or cervical
(Payabvash, 2018) cancer. Cerebral and myocardial infarction are fields of interest. More
particularly concerning ischemia evaluation, Gao et al. (2017) have shown a decrease in
78 Chapter 2
fIV IM , D∗ and D in the ischemic stroke hemisphere compared to contralateral side in a
canine stroke model. Diagnosis performance of IVIM imaging in acute stroke was assessed
in a clinical setting (Federau et al., 2014). fIV IM was found to be significantly reduced
in the visible infarct (2.6% vs. 5.6% in the contralateral side) but with a large variation
of the values across subjects (standard-deviation of 1.9% and 2.5% in contralateral side),
in agreement with the large range of values observed in the literature (Table 2.5).
2.4.4 State of the art in spinal cord
Measuring perfusion in spinal cord tissue has elicited the interest of researchers and
neurosurgeons seeking techniques to assess spinal cord tissue integrity and viability after
traumatic injury, chronic compression or for surgical planning.
Interesting work has first been done in mice using PASL at 11.75T. Duhamel et al.
(2008) were able to reveal the higher BF of gray matter compared to white matter at C3
and C6 vertebral level with 50 averages and acquisition time of 34 minutes per level for a
spatial resolution of 133×133 µm2 (Figure 2.43). BF was estimated at 226 mL/100g/min
in GM cortex, around 330 mL/100g/min in spinal cord GM, and 146 mL/100g/min in
spinal cord WM, yielding a GM/WM ratio of 2.3. However, even with long acquisition
time, the SNR of an 11.75T magnet, the large GM/WM volume ratio of the mouse spinal
cord (compared to human) and anesthetized subjects, BF measurements within GM and
WM showed up to 30% and 77% of in-ROI variations, and up to 16% and 40% of group
variations, respectively. Those variations in a well controlled set-up attest to the challenge
to measure perfusion in human spinal cord with MRI. Furthermore, a lower perfusion was
measured in average at L1 vertebral level, compared to C3 (285 vs. 310 mL/100g/min in
GM and 100 vs. 121 ml/100g/min in WM) (Duhamel et al., 2009).
Up to one year ago, clinical work has not gotten past the barrier of conference
proceedings.
Nair et al. (2010) evaluated a PASL technique in human at 3T. They were able to show
sensitivity to perfusion in cord ROI using multiple inversion times but BF mapping was
not reliable with an average of 26±11 mL/100g/min in cord (Figure 2.44a). Girard et al.
(2013) upgraded the PASL technique in human spinal cord at 1.5T with an additional
preparation dedicated to suppress signal from inflowing CSF using a global inversion
pulse and labeling at the CSF nulling point. They also compared it to PCASL which
showed a better sensitivity. Additional interesting features were the electrocardiogram
2.4 Perfusion MRI 79
Figure 2.43.: Brain and spinal cord BF maps measured in the mouse using ASL (Duhamel et al.,2008). (a) and (b) are the anatomic image and BF map obtained in the brain,respectively. (c) and (e) are the anatomic image and BF map obtained at C3, while(d) and (f) are at C6.
triggering, an HASTE (Half-fourier Acquisition Single-Shot Spin-Echo) readout (Semelka
et al., 1996) and 30 averages. However, although sensitivity to perfusion was highlighted
with multiple PLD/TI (0.9% versus 2% in brain), BF mapping was poorly reproducible
across subjects (Figure 2.44b). Despite registration, residual cord motion due to CSF
puslations were suspected and the labeling strategy and efficiency were questioned given
the complex spinal cord vascular network. Moreover, the use of HASTE introduced
blurring in the image due to T2 decay along the readout. Those studies attest to the
challenge of mapping the low perfusion of human spinal cord and to the high sensitivity
required for that.
By the same time, cardiac-gated IVIM at 3T was investigated (Callot et al., 2011).
Although evidence of microvascular volume appeared, no significant difference between
white and gray matter was found. However in mice, one year later, Callot et al. (2012)
were able to show a good correlation between the pseudo-diffusion coefficient D∗ and BF
measured with PASL. Slightly higher fIV IM and D∗ values were found in GM compared
80 Chapter 2
(a) ASL at 3T (b) ASL at 1.5T with CSF suppression strategy
Figure 2.44.: BF maps obtained in the human spinal cord with ASL at 3T (a) (Nair et al., 2010)and 1.5T (b) (Girard et al., 2013). Both studies acquired multiple inversion times(TI).
to WM at the group scale (N=5) but those parameters showed little sensitivity to post-
traumatic perfusion evolution compared to PASL within a single subject.
Finally, in 2017 and 2018, Wang et al. (2017b) applied Dynamic Susceptibility Contrast
(DSC) to post-operative and pre-operative Cervical Spondylotic Myelopathy patients’
spinal cord. Although neither assessment of the technique sensitivity nor BV values were
reported, they found a correlation between BV and post-operative recovery (as assessed by
mJOA) (Wang et al., 2017b) and a low correlation between BF and physical impairment
(attributable to condition needing decompression surgery) (Wang et al., 2018).
The first article reporting data of perfusion-related indices in the human spinal cord
came up in 2018 (Vargas et al., 2018). However, it only consisted of an example
of permeability index maps obtained in a patient with spinal cord glioblastoma (tumor
which involves much higher perfusion levels than healthy values) using Dynamic Contrast-
Enhanced (DCE). It is only in 2019 that BV-related indices in the spinal cord were first
explored in a research full paper. Using a multi-echo spin-and-gradient echo (SAGE)
EPI sequence for DSC MRI, Ellingson et al. (2019) investigated the correlations between
rBV, R′
2 (= 1T ′
2
), relative Oxygen Extraction Fraction (rOEF =R′
2
rBV ), anteroposterior
spinal cord diameter and functional status (mJOA score) in patients with cervical stenosis
(with or without myelopathy). Results suggested that BV was reduced with increased
compression and functional impairment. However, from an engineering point of view,
seeking to map perfusion in spinal cord, the perfusion was not quantified by voxel, or
even by slice. The perfusion was average across all the voxels in cord and across multiple
2.4 Perfusion MRI 81
slices (∼9), preventing any local assessment of the potential ischemia induced by cervical
stenosis.
Furthermore, a preliminary study applied VASO MRI to estimate the absolute value
of BV in spinal cord Lu et al. (2008). Interestingly, the results, averaged within a 3×3
voxels ROIin the center of the cord, were reproducible across subjects and field strengths:
4.3±0.7 mL/100mL tissue at 1.5T (N=6) and 4.4±0.7 mL/100mL tissue at 3T (N=4).
BV map generation was attempted but gray and white matter were barely differentiated
(Figure 2.45).
Figure 2.45.: Spinal cord BV map within one subject and one slice obtained with VASO MRI byLu et al. (2008). The gray scale of the BV map (e) goes from 0 to 10 mL blood/100mL tissue.
.
Finally, despite recent advances in Magnetic Resonance Angiography (see Appendix A.1),
the reference technique in clinics to assess the spinal cord vascular system impairment
82 Chapter 2
or infarction remains catheter Digital Subtraction Angiography, which is an invasive,
time-consuming, challenging and risky procedure. This technique enables the major
spinal vascular system from cervical to sacral levels to be depicted. Small arteries such as
the ASA and PSA can even be observed (Figure 2.46).
Figure 2.46.: Identification of the Anterior Spinal Artery (upper thin black arrow) and artery ofAdamkiewicz (two lower thin black arrows) using Digital Subtraction Angiography(Bowen et al., 1996). In-plane resolution of DSA was around 0.2×0.2mm2
.
Some MRA studies can be found in the literature, mostly focusing on thoracolumbar
imaging and the depiction of the famous Adamkiewicz artery (Vargas et al., 2010), but
Sheehy et al. (2005) showed the feasibility of ASA depiction in the cervical region at
2.4 Perfusion MRI 83
1.5T with three-dimensional contrast-enhanced MRA, a voxel size of 1mm3, maximum
intensity projection image and multi-plan reconstruction (Figure 2.47). In a group of 50
patients, ASA was visualized in 96% of the cases and identified with certainty in 74% of
the cases. Radiculomedullary feeders were identified in 48% of the cases.
Although such techniques do not provide perfusion measurements at the level of the
spinal cord tissue, it could be very useful to detect vascular abnormalities or impairments.
Figure 2.47.: Identification of the Anterior Spinal Artery (ASA) in cervical region (arrow) usingcontrast-enhanced Magnetic Resonance Angiography at 1.5T (Sheehy et al., 2005).According to the authors, the origin of the ASA can also be identified from the leftvertebral (arrowhead).
Vargas et al. (2015) highlighted the clinical relevance of imaging spinal cord ischemia,
proposed practical imaging tips for the clinics and identified the pitfalls and perspectives.
One important challenge for MRA in the spinal cord is the distinction between the ASA
and the anterior median vein, which have similar courses. Vertebral artery and vertebral
veins also have similar courses but have much larger diameters, making their distinction
easier.
To the best of my knowledge, there exist no published results so far on non-contrast
MRA application in the spinal cord.
84 Chapter 2
Altogether, those works attest to the remaining challenges to achieve a reliable
characterization of the spinal cord vascularization and perfusion in humans, which could
be beneficial in the context of Degenerative Cervical Myelopathy (DCM).
2.5 Degenerative Cervical Myelopathy
After traumatic spinal cord injury, Degenerative Cervical Myelopathy (DCM) is proba-
bly an area where spinal cord perfusion MR imaging would be greatly beneficial.
2.5.1 Pathogenesis
Anatomical degenerations
The name Degenerative Cervical Myelopathy (DCM) has been introduced recently by
Nouri et al. (2015) to refer to any degeneration of the cervical spine with alteration over
time, resulting in cervical canal stenosis and eventually symptoms such as pain, motor
and/or sensory disability, diagnosed as cervical myelopathy. This general term was intro-
duced with the objective to pool the different origins of cervical degenerations leading to
myelopathy, which can occur concomitantly but have been diagnosed or identified indi-
vidually as different conditions. The lack of dedicated term and international guidelines
has given rise to ambiguity in exploration and diagnosis of such condition, which can
indeed involve several processes. This lack of consensus might also be responsible for the
sparsity of epidemiological data regarding this pathology.
According to the conceptual classification from Nouri et al. (2015) Figure 2.48,
excluding congenital origins, the two main types of conditions are those induced by
ostheoartritic degenerations (e.g., osteophyte), most common from middle age onward
— Cervical Sondylothic Myelopathy (CSM) is one example —, and the conditions in-
volving non-osteoarthritic processes such as ligament hypertrophy or ossification — e.g.,
Ossification of the Posterior Longitudinal Ligament (OPLL). Those processes often occur
concomitantly.
Such classification is very helpful to further characterize the pathology and its patho-
genesis. The main anatomical degenerations that can be found in DCM patients are
depicted in Figure 2.49. The main degenerating anatomical entities are the vertebrae
2.5 Degenerative Cervical Myelopathy 85
Figure 2.48.: Conceptual classification of the pathological processes encountered in DegenerativeCervical Myelopathy (DCM) by Nouri et al. (2015). CSS: congenital spinal stenosis,KFS: Klippel-Feil syndrome, DS: Down syndrome, OPLL: ossification of posteriorlongitudinal ligament, OLF: ossification of ligamentum flavum.
.
(osteophyte, reshaping, loss of height, hypermobility), intervertebral disk (loss of height,
migration of disc material into spinal canal) and ligaments (hypertrophy, ossification).
These degenerations result in spinal canal stenosis, cord compression, spinal misalign-
ment and/or repeated dynamic injury to the cord due to vertebral hypermobility which
causes chronic repetitive microtrauma. Eventually, myelopathy appears with symptoms
such as sensory and motor loss, starting from tingling in upper limbs to dysfunction,
spasticity, gait disturbance and severe disability.
Potential causes for anatomical degenerations
The cervical column and its intervertebral disks have to support important loads such
as the head and to absorb the shocks and micro-trauma of everyday life activities. The
degenerations originate from the deterioration of these structures as a function of use
intensity over time, making the pathology more frequent in elderly population. The
use intensity also depends on the type of everyday life activities, including sport and
occupation. For instance, front-line rugby players were shown to present earlier cervical
spine degenerations than healthy controls of the same age, hypothesized to be related to
86 Chapter 2
Figure 2.49.: Illustration of the different anatomical degenerations found in Degenerative Cer-vical Myelopathy (DCM) (source: Nouri et al., 2015). PLL indicates posteriorlongitudinal ligament.
repetitive cervical traumas along their career (Berge et al., 1999). Those degenerations
were also correlated with age.
Congenital factors such as congenital spinal stenosis may also predispose for the develop-
ment of DCM. Potential genetic causes are also suspected for degenerative disk disease
and OPLL (Nouri et al., 2015).
Pathobiological effects of static chronic spinal cord compression
Effects of spinal cord compression have been investigated in animal models and
DCM patients. Multiple evidence of ischemia have been reported in DCM patients by
histology in GM and medial WM tracts (Breig et al., 1966; Hughes, 1978). Animal models
supported those findings using microangiography (Hoff et al., 1977), autoradiography
(Gooding et al., 1976) and hydrogen clearance (Al-Mefty et al., 1993). In particular,
Karadimas et al. (2013) demonstrated the different pathobiological processes induced
by static and chronic cord compression in a DCM rat model. Kalsi-Ryan et al. (2012)
2.5 Degenerative Cervical Myelopathy 87
summarized the hypothesized cascade of events deduced from the different studies as
presented in Figure 2.50.
Figure 2.50.: Pathobiological effects of static and chronic cervical cord compression accordingto Kalsi-Ryan et al. (2012). FasL is an inflammatory Fas ligand (transmembraneprotein belonging to the tumor necrosis factor family) whose signaling is suspectedto cause neurons and oligodendrocytes apoptosis.
Cord compression would both alter the vascular supply to the tissue, clamping the
supplying arteries and compromise the tissue microvasculature. Those processes would
result in a reduced blood flow within the tissue, triggering a neuroinflammatory reaction.
However, although ischemia is supposed to be the main driver in tissue degeneration,
mechanical effects of compression play also a significant role. Canine model of spinal cord
compression with ligation of segmental arteries (Gooding et al., 1975) or obstruction
of the arterial plexus (Shimomura et al., 1968) demonstrated the combined effects
of the two processes. The mechanical effects of compression might also play a role
in the initiation of the neuroinflammatory response. The activation of macroglia and
macrophage at the compression site is a well known component of the neuroinflammatory
response. Two distinct mechanisms are nourishing this phenomenon. On the one hand,
the chronic hypoxia caused by ischemia is accompanied by an increase in the extracellular
level of glutamate (major excitatory neurotransmitter), which is a well-identified process
in neuronal and oligodendroglial apoptosis. On the other hand, ischemia and compromise
of the microvascular network causes endothelial cell dysfunction disrupting the vascular
88 Chapter 2
basement membrane and the Blood-Spinal Cord Barrier (BSCB). Disruption of the BSCB
has been reported both in the early and late stages of the compression in DCM (Karadimas
et al., 2013). The infiltration of immune cell through the impaired BSCB exacerbates the
neuroinflammation. A vicious circle is established with inflammation potentiating the
endothelial cell loss and BSCB impairment, which in turn, lets immune cells extravasate
in the tissue environment nourishing the inflammation. Eventually, tumor necrosis
factors (Fas ligands, tumor necrosis factor-α) coming with the neuroinflammation to
regulate the immune system response are though to be responsible for additional neuronal
and oligodendrocytes death. Oligodendrocytes death results in demyelination, axonal
degeneration and axonal loss. Neuronal apoptosis induces an abnormal increase in
the number of astrocytes (astrogliosis), which inhibits axon regeneration, giving way to
myelopathy (Kalsi-Ryan et al., 2012; Nouri et al., 2015).
The inflammatory response in the central nervous system is originally dedicated to
heal the tissue (healing effect). However, as previously mention, it is also responsible for
the exacerbation of the initiated neuronal, oligodendroglial and endothelial cell death
(injurious effect). If at first the inflammatory profile of DCM was thought to be similar to
spinal traumatic injury, it is now becoming apparent that DCM inflammatory profile is slow,
driven by the chronic progressive compression and including compensatory mechanisms
along the compression course (Karadimas et al., 2015). Moreover, compared to spinal
cord injury, DCM does not show hemorrhagic necrosis (tissue death caused by bleeding)
and no evidence of bleeding were reported. However, more insights into the nature of the
inflammatory response to chronic spinal cord compression is needed to understand which
mechanisms are beneficial and which mechanisms are detrimental to the neuronal tissue
degeneration in DCM patients. The temporal profile of the mechanisms also remains
poorly described.
Dynamic injury mechanisms
In addition to static compression, it is recognized that spinal cord is injured by
repetitive dynamic effects with neck motion or vertebral segments hypermobility or
misalignment during everyday life activities. Hayashi et al. (2014) reported that, in a
group of symptomatic patients, anatomical MRI in neutral position showed spinal cord
compression for 5.3% of cases but that MRI examination in extension and flexion position
revealed a missed compression in 8.6% and 1.6% of cases, respectively. Furthermore,
Matsunaga et al. (2002) showed that for patients with spinal canal diameter between 6
2.5 Degenerative Cervical Myelopathy 89
and 14 mm, myelopathy preferentially developed in those with increased range of motion,
supposedly because of the dynamic factors.
In light of those results, myelopathy development in DCM cannot be considered solely
due to static chronic spinal cord compression.
Spatial distribution of tissue degenerations
A large proportion of DCM patients shows degenerations at multiple levels at the
same time. The type of degenerations can also be different across levels. According
to Northover et al. (2012), around 80% of patients show a multi-level disease. The
vertebral level the most frequently affected in DCM is C5-C6 (Northover et al., 2012;
Edwards et al., 1983). It could be explained by the higher mobility of the segment in
addition to the small anteroposterior spinal canal diameter at that level (one of the two
segments with the smallest spinal canal diameter) compared to others (Ogino et al.,
1983). Unfortunately, C5 to C7 is also the region with the most vulnerable vascular supply
(Baron et al., 2007; Firooznia et al., 1985; Yue et al., 2001). Nevertheless, the most
frequently affected level is likely to depend on the type of degeneration. For instance,
degenerative spondylolisthesis (translational displacement of one vertebral body over
another) has shown a higher frequency at C3-C4 (46%) and C4-C5 (49%) (Jiang et al.,
2011).
According to Breig et al. (1966), the anterior white matter columns are globally
preserved during anteroposterior compression. As the anterior artery, which directly
supplies those regions, has a zigzag course, the spinal cord inferior-superior stretching
with compression might not distort it significantly, allowing those regions to be irrigated.
In contrast, the infarction of central gray matter observed in DCM patients (Fehlings et al.,
1998; Ogino et al., 1983) could be explained by the obstruction of the central sulcal artery
running along the anteroposterior axis during compression and which is the main supply
to central gray matter. Similarly, corticospinal tracts and posterolateral white matter
seem to be the first and mains region affected by demyelination (Ogino et al., 1983; Breig
et al., 1966). Given that lateral white matter is mainly irrigated by radiculo-medullary
arteries running on the subpial surface with an anteroposterior course when arriving to
lateral white matter, a similar explanation as for gray matter and central sulcal artery can
be made: those arteries are likely to be more vulnerable to anteroposterior compression
(Gooding et al., 1975).
90 Chapter 2
Compensatory mechanisms in the chronically compressed spinal cord
Unlike in traumatic spinal cord injuries, compensatory mechanisms to adapt to the
slow and progressive chronic spinal cord compression occuring in DCM are largely sus-
pected. Several studies have investigated the potential repair and plasticity mechanisms
taking place and that can be used as treatment. Among them, the neurotrophic factors
(proteins involved in neuronal regulation, axonal growth and synaptic plasticity), which
have been used to foster axonal regeneration in injured central nervous system, and their
receptors have shown a higher expression rostrally and caudally to the compression sites
in mouse model compared to uncompresssed sites (Uchida et al., 2003). These results
are consistent with the higher number of neurons and oligodendrocytes reported rostrally
and caudally to the compression sites (Yu et al., 2009). Similarly, the degree of expression
of the growth-associated protein 43 (protein involved in neuronal development and
axonal regeneration) has been related to the degree of injury in a rat model of acute
compression (Li et al., 1996). Those findings are also consistent with correlation between
the increase in immunoreactivity of this protein and the degree and period of compression
reported by in mice (Uchida et al., 2002). Those results suggest that neuronal and axonal
regeneration may occur in the cervical human spinal cord to adapt and compensate for
the slow progression of the compression. Whether these compensatory mechanisms might
be too low or too slow compared to the degeneration, or whether they may end past a
given compression threshold, those are still pending questions.
2.5.2 Diagnosis
Clinical, neurological and radiological presentation
DCM is diagnosed based on clinical symptoms, neurological signs of spinal cord
dysfunction and radiological presentation. Clinical symptoms and neurological signs
must be accompanied with an MRI showing cord compression for DCM to be diagnosed.
Most commonly, the first symptom of DCM would be spastic gait (Gorter, 1976; Lunsford,
1980), followed temporally by upper extremity numbness and loss of fine motor control
of the hands. However, great variations of symptomatic presentation exist across patients,
hence the difficulty to detect DCM in the early stages (Tetreault et al., 2015). Naturally,
patients seek for medical examination when symptoms already appeared. Consequently,
little is known on the relation between the duration of cord compression before the
2.5 Degenerative Cervical Myelopathy 91
apparition of symptoms. Symptoms can even appear without static cord compression
visible during radiological examination in neutral position, due to the dynamic injury
component of DCM as previously mentioned.
The main clinical symptoms are (Kalsi-Ryan et al., 2012):
• Numb hands
• Bilateral arm parasthesia
• Spastic Ataxic gait
• L’Hermitte’s phenomenon
• Weakness
The main neurological signs are:
• Corticospinal tract signs
• Hyperreflexia
• Positive Hoffman sign
• Ataxia
• Atrophy of hand muscles
• Spasticity/clonus
And the MRI indicators are:
• Full effacement of CSF and deformation of cord
• Signal change on T1-weighted or T2-weighted image
• Vertebral segment-related signal change on T2-weighted image
• Reduction in cord cross-sectional area
92 Chapter 2
Grading scales
The main tools to quantify the extent of disability are Nurick’s classification (Nurick,
1972) and the Japanese Orthopaedic Association scale, which is the most frequently used
and which has two modified versions by Benzel et al. (1991) and Chiles et al. (1999)
adapted to Western societies (modified Japanese Orthopaedic Association, mJOA). Those
two grading systems are detailed in Appendix A.3. The mJOA scores the extent of motor
disability for upper and lower limbs, of sensory loss at upper and lower extremities, and
at trunk level and finally the alteration of bladder function.
In clinical practice, the radiological presentation is diagnosed with an evaluation of
spinal canal stenosis similar to the following grading system, as illustrated in Figure 2.51
(Baucher, 2019):
Grade 0: Spinal canal with normal anteroposterior width, no sign of subarachnoid spaces
reduction
Grade 1: Partial obliteration of anterior or posterior subarachnoid spaces, or both
Grade 2: Complete obliteration of anterior or posterior subarachnoid spaces, or both
Grade 3: Effects of anterior or posterior spinal cord impingement, or both (global pinch of
spinal cord)
Figure 2.51.: Example of clinical grading scale for spinal canal stenosis (from Baucher (2019))
2.5 Degenerative Cervical Myelopathy 93
2.5.3 Treatment
Treatment of DCM depends on the severity of the disease which can be evaluated with
several clinical grading scales such as those mentioned earlier. Usually, a decompressive
surgery is prescribed for moderate to severe DCM cases in order to reduce or even
eliminate the spinal canal stenosis and release the cord from the constraints that apply.
Such surgery is done either from anterior or posterior way. The anterior approach,
preferred for single-level presentations, typically consists of either a discectomy (removal
of the intervertebral disk) or a corpectomy (removal of part of the vertebral body)
(Tannous et al., 2014). The two successive vertebrae are then merged together. In the
posterior approach, most commonly prescribed for multi-level presentations, the vertebral
posterior part is removed (laminectomy) at the different levels involved (Kiely et al.,
2015).
For mild DCM presentations, as the evolution speed of degenerations is relatively
unknown and might vary across individuals, conservative management is preferred
although the number of surgery for mild cases has increased (Fehlings et al., 2017). In
that case, several neuroprotective drugs can potentially regulate inflammation and/or
preserve the tissue neuronal and axonal degeneration. Among them, the riluzole, which
is the only Food and Drug Administration approved pharmacotherapy for amyotrophic
lateral sclerosis, has been used to block glutamate receptors and increase glutamate
transporter activity with the objective to reduce glutamate excitotoxicity induced by
ischemia. It has shown promising results in animal models (Karadimas et al., 2012). Its
neuroprotective benefits to neurological recovery post-surgery are currently appraised in
a clinical trial (Fehlings et al. (2013), https://clinicaltrials.gov/ct2/show/study/
NCT01257828).
2.5.4 Epidemiology
Incidence and prevalence
Degenerative Cervical Myelopathy is the most common progressive non-traumatic
disorder of the spinal cord in the elderly population. However, as previously explained,
its global epidemiology is difficult to estimate because this pathology includes different
degenerative mechanisms which have generally been diagnosed independently. Besides,
most epidemiological studies were carried out in the local country. A comprehensive
sensitivity and 53.3% specificity while mJOA and conventional T1- and T2-weighted
MRI yielded 25.3% and 18.2% sensitivity and 100% and 81.3% specificity, respectively.
Grabher et al. (2016) were able to show regional atrophy and microstructural damage in
DCM patients far above the stenosis at a level not directly affected by the compression,
using CSA and DTI. Regarding metabolism alteration, Holly et al. (2009) measured a
significantly reduced ratio of N-acetylaspartate (NAA)/Creatine (Cr) concentration in
DCM patients compared to healthy controls using Magnetic Resonance Spectroscopy
(MRS), but this ratio was not correlated with the severity of the myelopathy. Interest-
ingly, Ellingson et al. (2015) combined Diffusion Tensor Imaging and MRS to define a
biomarker based on DTI fiber density, mean diffusivity and concentration ratio Choline
(Cho)/NAA, which showed a significant prediction of the mJOA (R2=0.8) in 27 DCM
2.5 Degenerative Cervical Myelopathy 97
patients. Functional MRI (fMRI) in brain has also been applied to DCM, in particular
to study the outcome of decompression surgery and functional recovery of the patient.
Differences in volume of activation were found pre-decompression surgery with respect
to healthy controls, post-decompression surgery with respect to controls and pre- and
post-surgery, suggesting a reorganization of the cortex in DCM patients (Duggal et al.,
2010). An alteration of the resting-state spontaneous activity of cortical neurons within
the sensorimotor network was also reported with resting-state fMRI, both before and
after decompression surgery (Tan et al., 2015).
In addition to prognosis issues, important questions regarding pathogenesis of DCM
still remain. In particular, the chain of processes from the spinal cord mechanical
compression leading to the myelopathy (resulting symptoms) and the timings of each
of those processes still needs to be understood and characterized. The relation between
the degree of compression and the resulting damage seems highly variable, with a broad
range of hardly predictable symptoms as per the current knowledge. New insights on
those questions would greatly benefit to the management and prognosis of patients.
2.6 Biomechanical modeling of spinal cord compression
To study the in-vivo mechanics of human pathologies or injuries (“bio-mechanics”),
three approaches are possible. 1) In-vitro mechanical models can be designed with either
synthetic materials or biologic samples harvested from cadavers with the objective to
reproduce the observed mechanisms and measure the effects. 2) The pathology or injury
can be reproduced in animal models and results are then extrapolated to human. Or
finally, 3) numerical models of human can be designed to simulate the pathology or
injury and estimate the effects with numerical calculations. The last approach, referred
as finite element modeling, is the most appropriate to study pathologies which deeply
involve in-vivo processes and anatomical dependencies such as Degenerative Cervical
Myelopathy (DCM).
98 Chapter 2
2.6.1 Finite element modeling
The finite element method
The finite element method is a numerical technique for solving problems which
involve continuous field systems under external influence and which are described
by comprehensive mathematical equations. The problems can be static or dynamic.
They can be exclusively structural (stress analysis), thermal (analysis of temperature
propagation), electromagnetic (analysis of electromagnetic fields propagation) or fluid-
mechanical, or they can combine those disciplines. The equations can include variable
such as displacement or temperature and physical properties such as density, stiffness,
permeability or conductivity.
The finite element method consists in dividing the geometrical model of the object
under study into an assembly of small parts called finite elements. Those elements are
interconnected by nodes and the action of the variable through or over each of them are
governed according to predefined functions (e.g., constant, linear, quadratic). Thanks
to the recent development of numerical calculations, it is possible to assemble those
equations into a global system and solve the problem with proper boundaries conditions.
The main steps of a finite element analysis are the following:
1. Geometrical design of the model. In the context of biomechanics, this step is often
perform based on anatomical images (e.g, CT scan, MRI, electron microscopy
images) of the body part to be studied. A reconstruction in 3D is usually involved.
2. Model discretization or meshing. The geometrical model domain is divided into
discrete or finite elements, making up the mesh. The resolution, number and
types of elements is a critical step. A too coarse mesh can result in an inadequate
parametric distribution whereas a too fine resolution can increase the computing
time needlessly and can even prevent the problem to solve. As more than millions of
elements are to be created, this step can hardly be done manually. Specific software
with automatic meshing methods are used. The description of the mesh is stored in
a big array containing the nodes coordinates and the element connectivities. The
element types (e.g, tetrahedral, hexahedral) are defined during this step too.
3. Definition of the interpolation functions within the elements. Interpolation functions
are necessary to interpolate the field variation over the element. Polynomial
2.6 Biomechanical modeling of spinal cord compression 99
functions are often used, with the degree depending on the number of nodes of the
element.
4. Definition of the element properties. The matrix equation defining how the variable
(e.g., displacement in structural analysis, temperature in thermal analysis) acts
through or over each element has to be established. Such matrix equation relates
the nodal values of the field to the element parameters such as the stiffness and the
density. Different formulations exist. The most popular are the Galerkin method, for
physical problems described by differential equations, and the variational formula-
tion for physical problems well described by a function minimization.
5. Assembly of the individual element equations into a global equation system. For
the example of a linear static analysis, the global equation system takes the form
K.δ = F where K is a the global stiffness matrix (square matrix), δ is the vector of
unknown nodal displacement (or temperature for thermal analysis) and F is the
vector of applied nodal forces (or heat flux in thermal analysis).
6. Definition of loading and boundary conditions. As the problem is to predict the field
variation in the system under external influence, the external influence referred
as loading, needs to be defined (e.g., displacement of an impinger along time).
Moreover, for the equation system to be solved, boundary conditions (e.g., null
displacement (δ = 0) at extremity nodes) need to be set.
7. Global equation system solving. To solve quasi-static problems, two methods exist:
the implicit method, better designed for static problems, and the explicit method
(more effective for dynamic problems) with energy relaxation as used in this PhD
thesis. With the implicit method, we seek to invert the system in order to obtain
the unknown nodal displacement δ = K−1.F according to the same example of
linear static analysis introduced earlier. However, due to the very large number of
equations, the system requires large memory storage and cannot be easily inverted.
Fortunately, the system is sparse, symmetric and positive definite. Direct and
iterative techniques have been developed to take advantage of those features to
store and solve the system efficiently. With the explicit method, the equation
includes acceleration and velocity such as M · δ + C · δ + Kδ = F , with M and C
generally being diagonal matrices easy to invert. For each node, the acceleration
is calculated at time step n as the difference between external and internal nodal
forces over the mass: δn = fext(tn)−fint(tn)m . Then, the velocity for time step n + 1
2
and displacement for time step n + 1 are derived according to: δn+ 1
2
= δn−1
2
+ δn∆t
100 Chapter 2
and δn+1 = δn + δn+ 1
2
∆t, with ∆t the time step duration. Internal nodal forces at
time step n + 1, fint(tn+1), are deduced from strain ǫn+1 (knowing δn and δn+1)
and stress σn+1 (= E · ǫn+1) calculation, looping over elements. Small time steps
(at least smaller than the time for a sound wave to travel across an element) are
required for the good stability of the calculations. To account for the quasi-static
behavior of the problem, all velocities are set to 0 each time the kinetic energy
reaches a maximum value (kinetic energy relaxation).
8. Calculation of additional results. The system solution provides the variable value
(e.g., displacement in structural analysis, temperature in thermal analysis) for
each node. Additional results of interest are then deduced from this solution. For
instance in structural analysis, strain and then stresses are usually calculated from
the nodal displacement using the appropriate Hooke’s law (relating displacement
to force via the stiffness) and strain-stress relations.
Specific considerations for structural analysis
In this thesis, we will mainly deal with structural finite element analysis of DCM
although considerations to integrate fluid-structure interactions to model perfusion
effects will be discussed.
In structural analysis, the results that are sought after are usually pressure, strain and
stresses. Stresses can be normal stresses or shear stresses, which in 3D results in 6 terms
often arranged in a symmetric 3 × 3 matrix (Figure 2.52):
σ11 σ12 σ13
σ21 σ22 σ23
σ31 σ32 σ33
Strains are defined similarly:
ǫ11 ǫ12 ǫ13
ǫ21 ǫ22 ǫ23
ǫ31 ǫ32 ǫ33
2.6 Biomechanical modeling of spinal cord compression 101
(a) Classical definition of 3D stresses on a cube (b) Schematic representation of shearstress
Figure 2.52.: (a) Classical definition of 3D stresses on a cube (source: Bergström,2015). The first subscript of the stress quantity is the normal direc-tion of the cube face and the second subscript is the direction of thestress. Strains are defined similarly. (b) Schematic representation of shearstress σzx = σ31 (source: https://www.shutterstock.com/image-vector/
The slope of the linear region is the elastic modulus E
σ
ϵ
Figure 2.53.: Typical stress-strain curve derived from measurement during a tensile experiment.A similar curve can be obtained with other types of experiments such as compressivetesting.
Note that the von Mises stress is not a true stress but is a theoretical metric to compare
the three dimensional stress with the yield limit of the material in a uniaxial tension test
which is experimentally easy to perform.
2.6.2 Finite element modeling of spinal cord compressions
Biomechanics of the spine
Challenges for the determination of spinal cord mechanical properties Challenges to
accurately measure the mechanical properties of the central nervous system tissue, and
in particular, of the spinal cord tissue, arise from the fast deterioration of the tissue
(dehydration, loss of the perfusion, etc.) from the moment it is harvested. The me-
chanical properties quickly change from in-vivo condition. Moreover, it is technically
more challenging to measure the mechanical properties of such a soft and fragile tissue.
Finally, spinal cord transverse area is extremely small, making the isolation and individual
measurements of gray and white matter mechanical properties even more complicated.
Nano-indentation is a promising tool for such thorough operations but remain an emerg-
ing technology. As a result, most of literature data come from uniaxial tensile testing
(traction testing) performed on the entire spinal cord.
2.6 Biomechanical modeling of spinal cord compression 103
Spinal cord tissue The majority of studies investigated the spinal cord properties in
tension. Seven studies from 1978 to 2006 reported modulus values for dog, cat, puppy,
human, rat and cow spinal cord, with different sample sizes, strain rate and under
different conditions Fiford et al., 2005; Hung et al., 1981a; Hung et al., 1981c; Hung
et al., 1981b; Oakland et al., 2006; Bilston et al., 1995; Tunturi, 1978. Those values
ranged from 0.0119 to 1.98 MPa. Most of the studies reported a “J-shaped” stress-strain
relationship. Tunturi (1978), one of the first study of spinal cord mechanical properties, a
modulus from 12 to 17 kPa was measured in the dog in-vivo with a quasi-static strain rate
(5 g increment). The most relevant of those studies is the work of Bilston et al. (1995) who
found an average elastic modulus value of 1.02, 1.17 and 1.37 MPa with strain rates of
0.048, 0.120 and 0.225 s-1, in 13 specimens obtained from 9 human cervical spinal cord.
A quasilinear viscoelastic model was found to fit the data adequately. The elastic modulus
of spinal cord therefore depends on the strain rate. For the study of DCM compressions,
we are interested in the lowest strain rate as the DCM compression mechanisms are quasi-
static. It can be considered that strain rates below 0.01 s-1 correspond to quasi-static
tensile tests.
Figure 2.54.: Strain-stress curves measured in the main studies for spinal cord under tensileloading (source: Bilston, 2011). Note that strain rates are higher than typicalquasi-static strain rates.
Fewer studies looked at the spinal cord behavior under compression. One of the first
(Hung et al., 1982) interestingly found a similar “J-shaped” stress-strain relation during
posterior quasi-static compression at T10 in the cat spinal cord. For displacement up to
∼0.5 mm, a linear relation was observed with Young’s modulus around 5 kPa. Moreover,
no strain-rate dependence was found in the tested range (≤0.0084 s-1). Later, Sparrey
et al. (2011) measured a peak stress around 0.8 kPa in compression with strain rate
104 Chapter 2
0.005 s-1 in porcine spinal white matter while Jannesar et al. (2018) measured a peak
stress of 7 kPa with strain rate 0.3 s-1 in non-human primate spinal white matter. In
human, the results from Hung et al. (1982) were supported 35 years later by Karimi et al.
(2017) in 24 male cadavers’ spinal cord at cervical level. A global nonlinear hyperelastic
behavior was observed (“J-shaped” stress-strain relation) and constants for Yeoh, Ogden
and Mooney-Rivlin laws were estimated. The linear model was also approximated and
yielded a mean elastic modulus of 40.12 kPa and peak stress of 62.26 kPa for a strain rate
of 1 s-1.
The literature therefore shows a great variability of the values, partly due to the
different loading types (tension, compression), strain rates and species. Nevertheless, it
seems that a hyperelastic model for the spinal cord tissue is adapted both in tension and
compression.
White versus gray matter Because of their difference in composition between white and
gray matter, different mechanical properties are expected between those two tissue types.
So far, four groups looked at those differences in different species. With tensile testing
in the cow, GM was found stiffer than WM with elastic modulus from 64 to 166 kPa
for strain rates from 3 × 10−4 to 5 × 10−2 s-1 in GM compared to 30 to 94 kPa for WM
(Ichihara et al., 2001; Ichihara et al., 2003). In the rabbit, GM was also found stiffer than
WM (3.3 vs. 3.2 kPa) during tensile testing but with a different methodology (pipette
aspiration method) (Ozawa et al., 2001). However the difference was not significant. In
the mouse, this time through indentation testing, Koser et al. (2015) supported those
findings reporting an elastic modulus of 0.127 kPa for GM and 0.067 kPa for WM, with
a strain rate of 2 × 10−2 s-1. Finally, according to the results of Nishida et al. (2020) in
compression, the gray matter would show less plasticity, suggesting a stiffer material than
white matter. The cell population in anterior gray matter horns was shown to decrease
under compression loading starting from a reduction in cord CSA of 30%, and reaching a
plateau from a CSA of 50% (Baba et al., 1996; Baba et al., 1997).
If all those studies agree with a higher modulus and stiffness of GM compared to WM,
the values substantially vary across studies, even for similar strain rates.
Interestingly, Ozawa et al. (2001) (in rabbit with pipette aspiration method) and
Koser et al. (2015) (with indentation method) measured the elastic modulus of the two
tissue types in the different orientation (axial, transversal and sagittal) to estimate the
anisotropy. It appeared that gray matter would behaves like an isotropic material whereas
white matter would be more anisotropic. However, one study found a higher elasstic
2.6 Biomechanical modeling of spinal cord compression 105
modulus of WM in axial and transversal directions (Ozawa et al., 2001) and the other
in the transversal and sagittal directions (Koser et al., 2015), which would be more
consistent with the longitudinal organization of white matter fibers.
Pia and dura mater Mazuchowski et al. (2003) showed the important mechanical role
of the pia mater during axial tensile testing, reducing the elastic modulus of the cord from
1.40 to 0.089 MPa when incising the pia mater. Indeed, the pia mater was shown to have
an elastic modulus of 2300 kPa, which is about 460 times higher than the spinal cord
tissue alone (Ozawa et al., 2004). By covering the spinal cord tissue (or parenchyma),
the pia mater triples the elastic modulus of the spinal cord and has an important function
for the spinal cord to recover its shape after injury. The dura mater, made of collagen
fibers mainly oriented in the longitudinal direction, plays a similar role in protection and
shape support with a stronger tensile strength and stiffness in the longitudinal than in
the circumferential direction (Runza et al., 1999).
Nerve roots In vitro, mouse nerve roots showed an elastic modulus of 1300 kPa under
tensile loading with quasi-static stretch rate (0.01 mm/s) (Singh et al., 2006). In pigs,
elastic modulus was around 2100 kPa (Nishida et al., 2015b). Therefore, nerve roots are
expected to be much stiffer (∼100 times) than spinal cord.
Ligaments The various ligaments of cervical spine showed different mechanical proper-
ties. Yoganandan et al. (2000) fitted a bilinear model to the cervical ligaments stress-strain
measurements, with a first linear region with elastic modulus E1 from strain 0 to ǫ12,
followed by a second linear region with elastic modulus E2. Obtained values were
summarized in Table 2.6.
Those results show that ligaments stiffness is of a very different order of magnitude
(∼1000 higher) compared to spinal cord tissue.
Intervertebral disks The interverbral discs, which play a role of shock absorber and
enables movements between adjacent vertebrae, are made of a fibrous outer layer called
the anulus fibrosus and a gelatinous and highly hydrated (∼85% water) center called
the nucleus pulposus (Figure 2.55). The nucleus pulposus takes 30 to 50% of the disc
transverse area and largely accounts for the elasticity of the disk. Intervertebral disc
106 Chapter 2
Table 2.6.: Elastic modulus values of cervical spine ligaments from Yoganandan et al. (2000).
and ligamentum flavum. Geometry was based on a CT scan acquired with 1-mm slice
thickness from C2 to C7 of a 21-year old man. In this study, different inferior-superior
profiles of compression and different transverse types were simulated in the context of
OPLL (compression at the level of the vertebral body only) (Figure 2.56). However, the
transverse types were not mixed through a multi-level compression, as can be observed
in real DCM cases. The different von Mises stress distribution obtained was observed
for different occupation ratio of the ossification into the spinal canal and different cord
CSA. Supporting the results of Nishida et al. (2012), the “central” type resulted in higher
maximum stress. The authors also points out a reduction of the cord CSA of 30% as a
critical compression threshold inducing significantly high stress. Finally, a higher effect of
the inferior-superior profile (compared to the transverse profile) is reported.
Still with the same model of cord (including WM, GM and pia mater), Nishida et al.
(2015a) studied the effects of dynamic effects of OPLL during motion of the vertebral
body with neck flexion. They found that both static and dynamic effects increased stress
in cord. In the case of combined static and dynamic compression, stress increased in the
entire spinal cord for a range of motion greater than 10°, even at a static compression
of 10% of the antero-posterior cord diameter, suggesting that dynamic effects occurring
during neck flexion are non-negligible.
Finally, given the variations in spinal cord shape and gray/white matter geometry
across cervical levels, the differences in stress distributions induced by posterior compres-
sion were simulated for compression levels of 10 to 40 % of the antero-posterior cord
diameter (Nishida et al., 2016). For compression levels of 10, 20 and 30 %, locations of
high stress values changed depending on the cervical levels, but they were similar for a
compression level of 40 %.
Accounting for perfusion All the previously cited studies focused on the potential patho-
logical effects of the constraints applying in the spinal cord parenchyma due to typical
2.6 Biomechanical modeling of spinal cord compression 111
(a) Different inferior-superior types of compression
(b) Different transverse types of compression
Figure 2.56.: Multi-level compression designs (a) with different transverse profiles (b) for simu-lations of ossification of the posterior longitudinal ligament by Khuyagbaatar et al.(2015).
DCM compression. However, as described in section Pathogenesis, there are strong
evidence that the pathogenesis of DCM and resulting tissue degeneration mainly originate
from ischemia. If the stress relaxation of gray and white matter allows a sufficient blood
flow to be maintained in the spinal cord parenchyma (Carlson et al., 1997; Carlson
et al., 2000), the perfusion impairment might come from supplying arteries. In a view
to investigate this hypothesis, Alshareef et al. (2014) proposed a spinal cord model
with fluid-structure interaction, including CSF, dura mater, the Anterior Spinal Artery
(ASA) and five arterial branches (Figure 2.57). The effects of anterior, posterior and
anteroposterior compressions on the arterial blood flow were investigated. The three
different types of loading showed significantly different ischemic potentials, with the
posterior compression being the most threatening as it induced a concomitant reduction
in blood flow in all arteries. In contrast, anterior compression would mainly impair the
ASA blood flow while other branches would be less affected and could allow the perfusion
of the spinal cord tissue to be maintained. Such approach could be of great interest to
112 Chapter 2
elucidate the pathological mechanisms of DCM. The inclusion of the microvasculature in
the model would have been relevant as perfusion has been shown to increase gray matter
stiffness (Hetzer et al., 2018). However, according to the authors, this was too complex.
Figure 2.57.: Finite element model of the spinal cord including anterior spinal arteries and fivebranches from Alshareef et al. (2014))
Furthermore, a finite element model of capillaries in extracellular matrix was em-
ployed to study the impacts of global compressive and shear strain on the capillary blood
pressure in the context of pressure ulcers formation with aging and spinal cord injury
(Shilo et al., 2012). Results in different capillary configurations showed that the critical
global compressive strain leading to capillary collapse increases with the capillary blood
pressure, meaning that capillary collapse is more likely to occur at low capillary blood
pressure.
2.6.3 The Spine Model for Safety and Surgery (SM2S)
Compared to all finite element models used to simulate DCM compressions as pre-
sented in the previous section, the Spine Model for Safety and Surgery (SM2S) is the
most complete spine models in terms of represented anatomical entities.
The SM2S model is the result of a fruitful collaboration between biomechanics
(Department of Mechanical Engineering, École de Technologie Supérieure, Montreal,
2.6 Biomechanical modeling of spinal cord compression 113
Quebec, Canada & Department of Mechanical Engineering, École Polytechnique, Mon-
treal, Quebec, Canada & Laboratoire de biomécanique appliquée, Aix-Marseille Université,
Marseille, France) and MRI (Centre de Résonance Magnétique en Biologie et Médecine,
Aix-Marseille Université, Marseille, France) research laboratories, as well as hospital
research centers (Department of Medical Engineering, Research Center, Hôpital du
Sacré-Cœur de Montréal, Montreal, Quebec, Canada & Research Center, Sainte-Justine
University Hospital Center, Montreal, Quebec, Canada), associated within an interna-
tional research laboratory (International Laboratory for Imaging and Biomechanics of the
Spine, iLab-Spine).
In constant development, the first version of the SM2S was published in 2009 (El-Rich
et al., 2009) (Figure 2.58a). Built out of the CT scan (with 0.6 mm-slice thicknesss) of
a 32-year old healthy male subject (Caucasian, 75.5 kg, 1.75 m), it included vertebrae,
intervertebral discs and ligaments of the lumbar spine segments L2 to L3. It was then
extended from T12 to L5 (Wagnac et al., 2012) (Figure 2.58b) and from T1 to L5
(Figure 2.58c) based on the same CT data (Wagnac, 2011). The spinal cord, with
distinction between white and gray matter based on histological cadaveric data (single
specimen) from literature (Kameyama et al., 1996), was then added along with pia mater,
dura mater, CSF, nerve roots and dentate ligaments (Fradet, 2013) (Figure 2.58d). The
model was then extended to the cervical region (Figure 2.58e) using the same methods
as for thoracic and lumbar regions (Sun, 2013). The anatomical CT data used were
acquired on a different subject but with similar characteristics and compatible geometrical
dimensions.
To refine the white and gray matter depiction — which was so far based on histological
data from a single subject, likely to be affected by tissue shrinkage due to harvesting — a
high-resolution T2*-weighted MRI template made out of transverse acquisitions at the
cervical level of 20 young healthy volunteers (Taso et al., 2015b) was used for white
and gray matter geometry at the cervical level (Taso, 2016) (Figure 2.58f). Finally, the
spinal cord was manually divided into 6 main functional regions based on the Gray’s
Anatomy atlas (Standring, 2008) and the unique spinal cord MRI atlas derived from it
(Lévy et al., 2015): anterior and posterior gray matter, and anterior, lateral and posterior
white matter (Taso, 2016; Rasoanandrianina, 2019) (Figure 2.58g).
Today, the SM2S is one of the most realistic model of the spine, with a detailed
anatomy from the sacrum to the highest cervical segment. It has been used in various
studies from crash simulation of traffic accident to ligament lesions.
114 Chapter 2
The SM2S (cervical segment from C4 to C6) has been first applied to DCM study by
Taso et al. (2015a). Intervertebral disc bulging, similar to the compressive mechanisms
occurring in DCM, was simulated by a global disc dislocation by 2 to 9 mm (with a velocity
of 0.05 mm/s) towards the cord which got compressed at various degrees. The degree of
compression was quantified by the ratio of antero-posterior cord diameter at compression
level over the initial diameter. The maximal compression obtained was 42% at C4-C5
and 61% at C5-C6. Results showed different von Mises and shear stresses distributions
between the two levels, due to morphological differences.
Interesting pioneering work was also conducted to combine multi-parametric MRI
maps acquired within Degenerative Cervical Myelopathy (DCM) patients to the biome-
chanical stresses obtained from spinal cord compression simulations (Taso et al., 2016).
Finally, important work has been carried out to refine the SM2S and apply it to different
traumatic spinal cord injuries (Beauséjour et al., 2020; Bailly et al., 2020).
2.6 Biomechanical modeling of spinal cord compression 115
(a) First version of the SM2S (L2-L3) (El-Richet al., 2009)
(b) SM2S extension from T12 to L5 (Wagnacet al., 2012)
imaging was performed in patients with cervical stenosis to
relate average SC perfusion measurements within a global
region to neurological scores and compression degree,11-13
but neither mapping of SC perfusion nor distinction between
SC regions were performed. Technical feasibility of dynamic
contrast-enhanced imaging for perfusion of intradural spi-
nal lesions at cervical level was also assessed at 1.5T and
3T,14 but again quantification was performed globally for the
whole lesion region, which involved high perfusion levels
with respect to healthy tissue.
Given the increasing concerns regarding gadolinium
deposition in bone and brain, even in patients with normal
renal function and intact blood–brain barriers,15,16 motivation
for endogenous contrast mechanisms has risen. Moreover,
with endogenous methods, acquisition duration can be traded
for signal-to-noise ratio (SNR), which cannot be done with
exogenous techniques where acquisition time and SNR are
inherently limited by contrast agent first-pass duration and re-
laxivity. Leveraging SNR is crucial in SC imaging to achieve
sufficient resolution.
Arterial spin labeling (ASL) is a common endogenous
method, which has been extensively applied in human brain
investigations.17 The technique also demonstrated potential
in the mouse SC where preclinical scanners enable global
tagging strategies.8,18 Yet, this technique is hardly applica-
ble to humans, given that such tagging strategies are lim-
ited by hardware capabilities given the human body size.
Furthermore, unlike in the brain, the multiple sources of per-
fusion of the SC tissue and the complexity and interindivid-
ual variability of the vascular network render local tagging
strategies nontrivial. Indeed, 2 groups attempted to map SC
perfusion at 1.5T19 and 3T20 with such techniques, but expe-
rienced poor reliability and reproducibility in their results,
and no further study was published since then.
7T MRI appears as a promising clinical avenue to increase
SNR and improve sensitivity. However, ASL remains prob-
lematic at this field strength given that labeling pulses re-
quire high energy and thus may encounter specific absorption
rate limits and suffer from B1 inhomogeneity issues. Indeed,
the limited efficacy and transmit (Tx) field homogene-
ity of the currently available Tx/receive coils for cervical
spine imaging at 7T jeopardizes the efficient initiation of a
labeling plane for continuous and pseudo-continuous ASL.
Parallel transmission and dielectric pads can alleviate this
constraint,21 but remain emerging technologies.
Given the major progress in SC diffusion MRI at 7T,22,23
intravoxel incoherent motion (IVIM) imaging emerges as a
promising technique for SC perfusion imaging. This tech-
nique aims at quantifying the signal decrease at low b-values
induced by blood water circulation through capillaries mim-
icking a Brownian motion random-walk at larger scale.24
Sensitivity to perfusion is therefore achieved through diffu-
sion gradients, which does not bring additional challenges at
ultrahigh field, unlike ASL relying on efficacy of the inver-
sion pulse. It also does not rely on in-flow blood labeling or
arterial input function to the tissue, which is an asset given
the multiple sources of perfusion of the SC. Furthermore,
IVIM has already been extensively applied in humans to
several organs (e.g., brain,25-30 kidneys,31 liver,10,32,33 heart,34
or pancreas35-37), but remains unexplored in SC.
In this study, we present a comprehensive protocol for
IVIM mapping of the human SC, exploiting increased SNR
from ultrahigh field strength. An optimization of data acqui-
sition, processing, and parameter fitting is proposed, carefully
considering estimation errors on derived IVIM parameters.
This work finally showcases, to the best of our knowledge,
the first perfusion-related in-vivo maps of the human SC and
quantifies the IVIM parameters within SC regions.
| 3LÉVY ET AL.
2 | METHODS
2.1 | Simulations
Two standard fitting approaches to estimate IVIM pa-
rameters were considered: the “two-step segmented”33,38
approach and the “one-step”38 approach. Their implemen-
tations are sketched in Figure 1. Both fitting pipelines were
implemented in Python (2.7), building upon the LMFIT
module (lmfit.github.io/lmfit-py), which facilitates distri-
bution and validation of implementation as it is all open
source.
F I G U R E 1 Implementation of the 2 “standard” fitting approaches encountered in literature: “Two-step segmented” (left side) and “One-step”
(right side) fitting. Each frame represents a fitting process and includes fit details (e.g., parameters initialization) whereas outbound arrows point
to parameter estimates resulting from this fitting process. Step A used the Conjugate Gradient optimization method because of its computational
speed whereas steps B and C used the Differential Evolution method to escape local optima. For both approaches, a first estimation of D is
performed based on high b-values signal (step A). This first estimate is definitive for the two-step segmented approach, but is only used as initial
value for the one-step approach along with intercept (S0(1 – fIVIM)init). After step B, all parameters are fitted; step C consists in a fine-tuning of the
fit, constraining parameter estimation to [95%; 105%] of the value obtained at the previous step. Parameter constraints at step B were defined based
on extreme values found in published IVIM studies within the brain WM and GM25-28,39-42 and typical SC radial and axial diffusivities23,43
4 | LÉVY ET AL.
Software and implementations can have a significant
impact on accuracy and precision of parameter estima-
tions25,28,39 regardless of computational speed. Therefore,
inspired by the work of Pekar et al,38 we performed Monte-
Carlo simulations to assess their performance under different
physiological and SNR conditions. Ranges of possible values
for IVIM parameters were defined according to ranges of val-
ues found in brain literature25-28,39-42 and typical SC radial
and axial diffusivities23,43:
• Visible microvascular volume fraction fIVIM (%): 1 to 30.
• Pseudo-diffusion coefficient D* (mm2/s): 3.0 × 10−3 to
35.0 × 10−3.
• Pure diffusion coefficient D (mm2/s): 0.3 × 10−3
(D⊥, diffusivity in the SC transverse plane) and 1.5 × 10−3
(D||, diffusivity along the SC axis).
The IVIM representation of the signal24 is given by
(Equation 1):
To assess performance of fitting algorithm, synthetic data were
generated using (Equation 1) and ranging a large number of
b-values inspired by IVIM protocols in brain25,26,40,44 and dif-
fusion tensor imaging (DTI) practice in SC45,46: 5, 10, 15, 20,
Submitted on July 24, 2020 to Magnetic Resonance in Medicine
Abstract
Purpose: To explore the feasibility of Dy-
namic Susceptibility Contrast (DSC) MRI at
7T for human spinal cord (SC) perfusion
mapping and fill the gap between brain and
SC cord perfusion mapping techniques.
Methods: Acquisition protocols for high-
resolution single-shot EPI in the SC were
optimized for both spin-echo and gradient-
echo preparations, including cardiac gat-
ing, acquisition times and breathing cycle
recording. Breathing-induced MRI signal
fluctuations were investigated in healthy
volunteers. A specific image and signal pro-
cessing pipeline was implemented to ad-
dress them.
The DSC technique was then evaluated in
3 healthy volunteers and 5 cervical spondy-
lotic myelopathy patients. Bolus depiction
on slice-wise signal within cord was investi-
gated and maps of relative perfusion indices
were computed.
Results: Signal fluctuations were divided
by 1.9 and 2.3 in apnea compared to free
breathing with spin-echo and gradient-echo,
144 Chapter 5
respectively. The ratio between signal fluc-
tuations and bolus peak in healthy volun-
teers was 5.0 % for spin-echo and 3.8 % for
gradient-echo, allowing a clear depiction of
the bolus on every slice and yielding rela-
tive blood flow and volume maps exhibiting
the expected higher perfusion of gray mat-
ter.
However, in patients, signal fluctuations
were increased by 4 in average using spin-
echo, compromising the depiction of the
bolus on slice-wise signal. Moreover, 3/18
slices had to be discarded because of fat
aliasing artifacts.
Conclusion: DSC MRI at 7T showed great
potential for SC perfusion mapping with
results never achieved so far for single-
subject and single-slice measurements. Sig-
nal stability needs to be improved in acquisi-
tion conditions associated with patients, but
guidelines to achieve that were identified
and proposed.
Keywords: spinal cord, dynamic suscepti-
bility contrast, DSC MRI, 7T MRI, perfusion,
ultrahigh field MRI
Introduction
Blood perfusion is frequently involved in
spinal cord (SC) injuries (Schubert, 2017;
Gilmor et al., 1998). Indeed, a prolonged
SC compression such as in traumas may
result in a local reduction of tissue perfu-
sion and progressive ischemia, leading to
metabolism alteration and potentially irre-
versible tissue necrosis (Beattie et al., 2000).
In such case, perfusion recovery is condi-
tional to clinical presentation improvement.
Similarly, in non-traumatic disorders such
as Cervical Spondylotic Myelopathy (CSM),
chronic SC compression may progressively
induce ischemia (Kalsi-Ryan et al., 2012).
Unfortunately today, there is a critical lack
of technique to confidently assess SC perfu-
sion status.
By contrast, in the brain, several tech-
niques such as Arterial Spin Labeling (ASL)
(Alsop et al., 2015), Intra-Voxel Incoherent
Motion (IVIM) (Le Bihan et al., 1988) or
the reference technique in clinics, Dynamic
Susceptibility Contrast (DSC) MRI, can now
provide reliable blood volume and blood
flow maps of patients with white (WM) and
gray (GM) matter distinction. Such maps
are an important tool for clinicians to assess
the extent of ischemic stroke for instance
(Aracki-Trenkic et al., 2020). From a clini-
cal point of view, SC perfusion maps would
be valuable to assess the extent and pro-
gression of perfusion deficit and identify
the specific functional area at stake. From
a technical point of view, regional mapping
of SC perfusion with high resolution would
also be a way to assess the reliability of the
measurements. Indeed, a similar GM/WM
perfusion difference in brain and SC is ex-
pected (based on microangiography (Turn-
bull, 1973), histology (Tator et al., 1997)
and ASL in mice (Duhamel et al., 2008)).
However, the transfer of the techniques
5.2 Manuscript 145
used in brain to SC is not trivial. Indeed,
its location in the vicinity of lungs, directly
surrounded by pulsatile Cerebrospinal Fluid
(CSF), is source of multiple biases and arti-
facts. In particular, breathing-induced field
fluctuations have shown a significant effect
on MRI signal, even at the cervical level
(Verma et al., 2014; Vannesjo et al., 2018).
Moreover, its size (∼8×13 mm2 in trans-
verse section) requires high resolution to
allow GM depiction. An additional chal-
lenge, similar to the brain (Duhamel et al.,
2008; Lu et al., 2008), is the low perfu-
sion level compared to other organs (e.g.
kidneys, liver, heart), with GM being more
perfused than WM (Duhamel et al., 2008;
Parkes Laura M. et al., 2004).
Among endogenous methods, ASL has
been experimented at 1.5T (Girard et al.,
2013) and 3T (Nair et al., 2010) for SC per-
fusion mapping. However, only poor sensi-
tivity and reliability were obtained. IVIM
was evaluated at 7T, but sensitivity at single-
subject and single-slice scale was limited
and averaging across multiple subjects (≥6)
was necessary to map the perfusion differ-
ence between GM and WM (Lévy et al.,
2020).
Using gadolinium injection, Vascular-
Space-Occupancy (VASO) MRI has been
used to map the absolute SC blood vol-
ume (BV) in healthy subjects (Lu et al.,
2008). A mean value of 4.3 mL/100 mL tis-
sue was obtained with a good reproducibil-
ity across field strengths (1.5 and 3T). How-
ever, this technique does not provide blood
flow-relative metrics. In addition, inflow-
ing fresh blood (Donahue et al., 2009) and
CSF volume changes (Scouten et al., 2008)
were shown to affect VASO MRI measure-
ments. Later, DSC was employed in CSM pa-
tients where ischemia is expected (Fehlings
et al., 1998), and showed promising sen-
sitivity at 3T. Indeed, relative SC BV was
negatively correlated to cord compression
and decreased with symptoms severity as
assessed by clinical tests (Ellingson et al.,
2019). However, those results were ob-
tained at the group level through multiple
voxel- and slice-averaged perfusion mea-
surements, with coarse resolution, which
helped sensitivity but excluded individual
and regional perfusion mapping, limiting
the clinical impact. In this exploratory study,
we aimed to assess the potential of DSC MRI
for regional perfusion-related indices map-
ping at the individual scale.
To cope with the high-resolution neces-
sary to GM and WM imaging in SC, the
investigations were performed at 7T, which
is now becoming a clinical tool (Staff News
Brief, 2017; Polimeni et al., 2018; Kraff
et al., 2017). Higher field strength theo-
retically provides higher SNR but also in-
creases susceptibility effects, which is ex-
pected to provide an increased sensitiv-
ity to gadolinium-based contrast agent bo-
lus in DSC imaging (Rohrer et al., 2005;
Noebauer-Huhmann et al., 2008). How-
ever, higher field strength also comes with
new challenges. Sensitivity to susceptibil-
ity variations and resulting B0 inhomogene-
146 Chapter 5
ity/fluctuations is increased. B1 transmis-
sion (B1+) and reception (B1-) are more
limited and heterogeneous. Such features
have significant consequences in the SC
physiological environment. The feasibility
and sensitivity of DSC MRI at 7T for hu-
man spinal cord perfusion mapping were
therefore investigated.
Materials and Methods
All acquisitions were performed on a 7T
whole-body research system (Magnetom,
Siemens Healthcare, Erlangen, Germany)
using a commercial 8-channel cervical-spine
transceiver surface coil (Rapid Biomedical
GmbH, Rimpar, Germany) with the 8 Tx-
channels hardware-combined into a single
transmit system.
Acquisition parameters
Acquisitions were cardiac gated (pulse
oximeter) to mitigate cord motion with CSF
pulsations. A single-shot two-dimensional
EPI readout was employed given the high
temporal resolution required, determined
by the cardiac beat. Physiological Moni-
toring Unit (PMU) was activated in the se-
quence code to allow acquisition time stamp
recordings, further used for post-processing
normalization by effective TR. A respiratory
belt was placed either on the subject’s ab-
domen or chest (depending on her/his main
mode of breathing) to record breathing cy-
cles during acquisition.
DSC can be performed using either
gradient-echo sequence based on the
change ∆R2∗ in R2
∗ relaxation rate, or spin-
echo sequence looking at the change ∆R2
in R2 relaxation rate. Both types of se-
quences were investigated.
An in-plane resolution of 0.7×0.7mm2
was aimed for, which was obtained with
truncated FOV coming with aliasing at the
edges but far from the cord. Acquisitions
were also performed with a coarser reso-
lution (1.0×1.0mm2) allowing the FOV to
include the whole neck cross-section. Fat
saturation was used without outer volume
suppression. Slice thickness was set to 5mm.
An acceleration factor of 2 (GRAPPA) was
used. Automatic calibration scans, partial
Fourier and TE were single-shot EPI, 6/8
and 42ms for the spin-echo sequence, and
gradient-echo FLASH, 5/8 and 22ms for the
gradient-echo sequence, respectively.
Acquisitions so far were limited to 3
slices (one by vertebral level, see Figure 5.1)
because of the Specific-Absorption-Rate
(SAR) restrictions associated with spin-echo
and TR around 800-1100 ms (cardiac cy-
cle). To optimize SNR with regards to the
subject’s cardiac cycle (effective TR), when
allowed by SAR limits, excitation flip angle
was set to the corresponding Ernst angle
(or 180 – Ernst angle for spin-echo), with
TR being the mean cardiac cycle duration
and T1 the mean longitudinal relaxation in
healthy SC tissue at 7T (∼1251 ms (Massire
et al., 2016)).
5.2 Manuscript 147
C3
C5
C4
Age / SexBody Mass
Index
Mean ± SD
cardiac period
Mean ± SD
breathing periodSAR restrictions
Shortest
cord<>coil
distance
Maximum inter-
slice frequency
difference
HC 1 37 y.o. / Female 18.93 kg/m2 903 ± 67 ms 4.1 ± 0.66 s 3.70 % 4.23 cm 63.8 Hz
HC 2 32 y.o. / Male 24.77 kg/m2 1064 ± 56 ms 2.9 ± 0.49 s 15.31 % 5.32 cm 17.4 Hz
HC 3 33 y.o. / Male 24.57 kg/m2 900 ± 54 ms 4.0 ± 0.52 s 2.45 % 4.44 cm 63.9 Hz
PATIENT 1 56 y.o. / Male 25.80 kg/m2 865 ± 38 ms 3.5 ± 0.48 s 61.41 % 5.34 cm 47.8 Hz
PATIENT 2 68 y.o. / Male 26.51 kg/m2 989 ± 28 ms 4.7 ± 1.37 s 50.63 % 5.64 cm 39.8 Hz
PATIENT 3 58 y.o. / Female 24.61 kg/m2 900 ± 34 ms 4.8 ± 0.71 s 10.63 % 4.34 cm 32.3 Hz
PATIENT 4 43 y.o. / Male 24.68 kg/m2 1178 ± 69 ms 3.5 ± 0.42 s 18.90 % 5.11 cm 38.6 Hz
PATIENT 5
(pre-surgery)54 y.o. / Male 24.11 kg/m2 901 ± 31 ms 4.4 ± 1.43 s 55.42 % 5.40 cm 10.4 Hz
PATIENT 5
(post-surgery)55 y.o. / Male 27.44 kg/m2 952 ± 68 ms 5.0 ± 2.04 s 18.25 % 4.35 cm 7.6 Hz
C2
C3
C4
C2
C3
C4
C3
C5
C4
C2C3
C4
C2
C3
C4
C2
C4
C3
C2
C4
C3C2
C3
C4
HC 1 HC 2 HC 3
PATIENT 1 PATIENT 2 PATIENT 3 PATIENT 4
PATIENT 5 PATIENT 5
(pre-surgery) (post-surgery)
Figure 5.1.: Acquisition characteristics for each participant, healthy volunteers (HC) and patients.Red arrows indicate spinal cord compressions. SAR restrictions were calculated basedon the reference voltage (required vs. set value) and the flip angle (Ernst anglevs. set value) within cord at the slice position of DSC acquisitions (SAR restrictions≤10 % implied that both the required reference voltage and optimal flip angle couldbe used). B0 inhomogeneities were assessed by measuring the maximum inter-slicefrequency difference within cord. Favorable and disadvantageous characteristicsfor SAR restrictions and B0 inhomogeneities were highlighted in green and red,respectively.
Figure 5.2.: Signal processing pipeline illustrated on a dataset with gadolinium injection (leftcolumn) and without (right column). A case with multiple missed triggers has beenspecially chosen here for illustration purposes but only a few triggers were generallymissed in the other datasets. The effect of those missed triggers can be visualized onthe first line (left column) which plots the signal in a conservative region of interestwithin the cord (all slices averaged), along time: the steady-state loss yields largesignal changes which are only partially corrected by the effective TR normalization(second line). Therefore, they need to be discarded (third line). The filtering ofbreathing frequencies (fourth line) removes most signal oscillations while keepingthe bolus profile and peak, as does the final smoothing (last line) which filters outthe remaining signal oscillations.
phase correctionSpin-echo single-shot EPI acquisitions in phantom
(0.7×0.7mm2, 5-mm thick slices)
Large distortionsFat aliasingNyquist N/2 ghosting
Single-shot EPI
with centered phase
correction
Multi-shot EPI
with centered phase
correction
Single-shot EPI
with local phase
correction
(A)
(B)
(C)
C5 C4 C3
Figure 5.3.: Image quality (A), frequent artifacts (B) and effects of GRAPPA calibration and EPIphase correction (C) in spin-echo and gradient-echo high-resolution EPI. (A) Onerepetition of spin-echo and gradient-echo EPI within the same healthy volunteer (23-year-old man, example subject of Figure 5.4). Comparison with the high-resolutiontransversal anatomical multi-echo gradient-echo FLASH image (first echo here)enables the EPI-related image distortions to be evaluated. (B): Frequent artifactsobtained with high-resolution single-shot EPI of the SC in different participants.(C): Example of effects on image quality that can be obtained with single-shot vs.multi-shot EPI for GRAPPA calibration scans and with local vs. centered phasecorrection algorithm.
To-Peak (TTP) as the time between
bolus arrival and bolus peak.
Depending on the study case, this rou-
tine and the preceding signal processing
pipeline were performed either on mean
152 Chapter 5
signal in cord across the three slices, slice-
wise or voxel-wise.
Results
Single-shot EPI image quality
Figure 5.3 compares the image quality
of spin-echo and gradient-echo EPI within
a healthy volunteer. Large signal dropout
at the periphery of the SC can be observed
with gradient-echo. Based on the anatom-
ical gradient-echo FLASH image, gradient-
echo EPI showed larger image distortions
compared to spin-echo. Figure 5.3 also
shows typical artifacts of high-resolution
single-shot EPI. Nyquist N/2 ghosting ar-
tifacts could usually be addressed with a
better shimming if achievable (not trivial).
Among all datasets, 3/27 slices in total had
to be discarded because of fat aliasing ar-
tifacts. The effects of the GRAPPA calibra-
tion scan mode and phase correction algo-
rithms used can be observed in the last row
of Figure 5.3 for acquisition in phantoms.
Although it is the default option in most
product sequences, single-shot EPI GRAPPA
calibration does not seem optimal to avoid
Nyquist N/2 ghosting. A “local” phase cor-
rection, as often referenced by MRI man-
ufacturers (estimation of a k-space phase
line-dependent shift in addition to a global
term), is therefore advised.
Effect of breathing
Figure 5.4 compares the signal stability
between apnea and free breathing condi-
tions, along with the free breathing signal
after motion correction and breathing fre-
quencies filtering, both with spin-echo and
gradient-echo preparation. Signal oscilla-
tions during free breathing are clearly miti-
gated during apnea. The mean tSD in cord
(all slices) increased from 0.64 s−1 in ap-
nea to 1.22 s−1 in free breathing with spin-
echo, and from 0.75 s−1 to 1.75 s−1 with
gradient-echo. Rigid motion correction and
breathing filtering enabled a tSD of 0.65 s−1
and 0.90 s−1 to be recovered, respectively.
Breathing-induced signal fluctuations were
higher with gradient-echo, which was ex-
pected given the higher sensitivity to sus-
ceptibility variations of the T2∗-weighted
signal. No clear slice-dependent effect of
breathing stood out, either at the individual
or group (3 subjects) level (Figure 5.4, right
column).
In-vivo DSC results
Figure 5.5 presents the DSC results ob-
tained with gadolinium injection in healthy
volunteers. The contrast agent bolus was
clearly visible in every subject. As expected,
the bolus peak obtained with spin-echo
(2.0 s−1) was lower than with gradient-echo
(10.3 s−1 in average across the subjects).
However, signal stability was better with
5.2 Manuscript 153
Apnea
Free breathing
Free breathing after filtering
Sp
in-E
ch
o E
PI
Apnea
Free breathing
Free breathing after filtering
Gra
die
nt-
Ech
o E
PI
Slice-wise fluctuations in cord within a healthy subject
with spin-echo and gradient-echo EPI
Slice-wise temporal
SD for every subject
Figure 5.4.: Breathing-induced signal fluctuations in spin-echo and gradient-echo high-resolutionsingle-shot EPI. The plots show the evolution of the signal in a conservative region ofinterest in the spinal cord slice-by-slice, along time for spin-echo and gradient-echoacquisitions in the same healthy participant in apnea and free breathing. Graphs onthe right-hand side show the temporal SD (tSD) by slice for each of the three subjectsfor inferior, middle and superior slices (represented in orange, brown and purple, re-spectively). Each marker represents a single subject; the data plotted in the left plotscorresponds to subject represented with the circle marker on the right side. For a faircomparison, only rigid motion correction and breathing frequencies (as measuredwith the respiratory belt) were applied to free breathing data (leading to the row“Free breathing after filtering”). Also, note that y-axes of the plots were adjustedindependently for spin-echo and gradient-echo data to allow the breathing-inducedfluctuations to be visualized despite the different amplitudes.
spin-echo (tSD of 0.10 s−1 vs 0.39 s−1),
in agreement with results in Figure 5.4,
yielding a ratio tSD/peak of 5.0 % with
spin-echo and 3.8 % with gradient-echo.
Regarding mapping potential, the tech-
nique provided clear rBF maps, exhibiting
the expected higher perfusion values of
GM compared to WM. Comparing spin-
echo to gradient-echo for high-resolution
(0.7×0.7 mm2) maps, less distortions were
154 Chapter 5
obtained with spin-echo. The bolus peak
observed in the high-resolution gradient-
echo acquisition was higher than with the
low-resolution (1.0×1.0 mm2) acquisition
(11.7 s−1 vs 8.8 s−1). Interpretations about
the effect of the resolution or about poten-
tial variations in perfusion values along the
inferior-superior axis are nonetheless too
preliminary at this stage.
Results in patients are presented in Fig-
ure 5.6. All patients’ data were acquired
with the spin-echo sequence. Individual
slice-wise plots showed generally more sig-
nal fluctuations in baseline with patients
than with healthy volunteers. In particular,
for PATIENT 2, signal fluctuations were on
the same order of magnitude as the bo-
lus. However, the bolus was still visible
in most cases but with different profiles:
for instance, the boluses seem shared be-
tween two peaks in PATIENTS 2, 3 and
4. The hypothesis that this difference in
bolus profile was due to the patients’ cord
compression and reflected a pathological
perfusion condition needs to be verified but
cannot be discarded. PATIENT 5, who had
received decompression surgery, moved
right after the injection (hence the multiple
missed triggers); nevertheless, the bolus
showed a more standard profile. Motion
was probably the reason why signal did
not come back to baseline after injection.
Last row of Figure 5.6 compares the signal
profiles in whole cord (all slices averaged)
between all patients and HC1 (green line).
In average across patients (discarding PA-
TIENT 5 who had surgery), the mean bolus
peak had the same amplitude as in HC1
(2.0 s−1), although timings and profile gen-
erally differed. However, the tSD in baseline
was more than 4 times higher (0.44 s−1 vs.
0.1 s−1 in HC1), yielding a tSD of the order
of gradient-echo EPI in healthy volunteers
and a ratio tSD/peak of 22 %.
Finally, to illustrate the potential of DSC
in the human SC, Figure 5.7 shows maps of
different perfusion-related indices obtained
in healthy volunteer HC1 and two patients
(with different in-plane resolutions). rBF
and rBV maps depicted the higher perfu-
sion values of GM compared to WM. Less
difference could be observed between the
two tissues with timing indices, BAT and
TTP, which showed relatively homogeneous
values in the cord. The GM/WM ratios
obtained in average in all three healthy
volunteers (HC1, HC2, HC3) were 2.2, 1.6,
1.4 and 1.0 for rBF, rBV, BAT and TTP re-
spectively (with regions of interest defined
on rBF and rBV maps, discarding voxels
corrupted by partial voluming at the edge
of the cord). They were respectively 2.2,
2.1, 0.4 and 1.0 in average across PATIENTS
1, 3 and 4 (only including slices were GM
could be depicted on rBF and rBV maps, i.e.
4/9).
5.2 Manuscript 155
DSC at 7T in healthy volunteersS
pin
-ech
o E
PI
Gra
die
nt-
ech
o E
PI
0 6
Relative Blood Flow
0 1
Relative Blood Flow
0.7×0.7mm2
C4(inferior)
C3(middle)
C2(superior)
HC 1
HC 2
HC 3
1.0×1.0mm2
0.7×0.7mm2
Figure 5.5.: DSC results in 3 healthy volunteers at 7T. On the left side, the mean signal in cord isplotted by slice along time. On the right side, the relative Blood Flow (rBF) mapsresulting from a voxel-wise processing are presented. Spin-echo EPI was tested inone healthy volunteer with high in-plane resolution (0.7×0.7 mm2) while gradient-echo EPI was tested in two healthy volunteers, with high and lower (1.0×1.0 mm2)resolution.
Discussion
This exploratory study investigated the
feasibility and sensitivity of DSC MRI at
7T for perfusion mapping in the human
SC, both in healthy volunteers and pa-
tients. Both spin-echo and gradient-echo
sequences were considered. Effects of phys-
iology on signal stability were characterized
and specific protocol and pipeline were de-
veloped to address them. The depiction of
the bolus was verified slice-wise in the cord
and maps of rBF, rBV, BAT and TTP indices
were produced.
Challenges and resulting
guidelines
Static B0 inhomogeneities
Several challenges of DSC at 7T are as-
sociated with single-shot EPI of the SC. In-
deed, this readout technique is extremely
sensitive to B0 inhomogeneities. The latter
can result in large distortions (Figure 5.3)
due to accumulated phase errors along the
readout. Spin-echo EPI is less sensitive
than gradient-echo as the effects of those
inhomogeneities are refocused. B0 inhomo-
geneities also affect the correction of the
shift between odd and even phase lines,
156 Chapter 5
PATIENT 1
PATIENT 2
PATIENT 3
PATIENT 4
PATIENT 5
(post-surgery)
PATIENTS
+
HC 1
0.7×0.7mm2
0.7×0.7mm2
0.7×0.7mm2
1.0×1.0mm2
1.0×1.0mm2
Figure 5.6.: DSC results in 5 patients at 7T. The last row plots the signal in cord (all slicesaveraged) along time, for every patient in blue, and for the healthy volunteer (HC1)in green. Other rows are individual slice-by-slice plots of patients. All data ac-quired in patients were spin-echo EPI. The in-plane resolution is indicated on thetop right-hand corner of each plot.
which can vary across the FOV. A “local”
phase correction (as generally referenced
by MRI manufacturers) – i.e., estimation
of an individual shift per line in addition
to a global shift for all lines – is therefore
advised. GRAPPA calibration can also be
affected by distortions. For that, multi-shot
EPI (also referenced as FLEET (Polimeni et
al., 2016)) or gradient-echo FLASH (Tala-
gala et al., 2016) based calibration should
be preferred when available. Otherwise,
in general, important efforts need to be
spent on shimming (shim box adjustments,
reiterated shim currents calculation, and
even manual shim currents adjustments if
needed) prior to imaging to achieve good
high-resolution single-shot EPI quality at 7T
in the SC.
Dynamic B0 fluctuations and signal
instability
This study clearly showed that DSC in
the SC at 7T is also challenged by signal
fluctuations in time. Breathing-induced B0
5.2 Manuscript 157
0
0.9 40 25 35
0 0 0
Figure 5.7.: Examples of perfusion index maps that can be obtained from DSC in spinal cordat 7T: relative Blood Flow (rBF), relative Blood Volume (rBV), Bolus Arrival Time(BAT) and Time-To-Peak (TTP). Presented maps correspond to the middle slice ofspin-echo DSC acquisitions with 0.7×0.7mm2 in-plane resolution (HC 1, PATIENT 1)and with 1.0×1.0 mm2 in-plane resolution (PATIENT 4). For each perfusion index,colormaps were set to the same range for an easier comparison across subjects.
Table 6.1.: Compression indices compared between SM2S model at t=0 (row 1, dark gray back-ground), DCM patients group (rows 2, 3) and literature (row 5 and below). Row 4reports the equivalent percentage compression of SM2S model if the mean compres-sion measured in patients is applied to the model. The compression indices foundin literature were reported in percentage with regards to controls when data wereavailable (italic format within table). For easier visualization, background of spinalcanal-based indices was colored in light gray. Agreement of cord-based indices arounda value of 70% compression (with regards to uncompressed value) was highlighted ingreen. Compression indices are defined in Figure 6.1.
A-P: anteroposterior; R-L: Right-Left; CSA: Cross-Sectional Area; SD: standard-deviation; N: DCM patients sample size; at max. comp: at
level of maximal compression.
174 Chapter 6
Figure 6.1.: Definition of the compression indices measured on anatomical MRI data. Diagramsrepresent a simplified transversal view of the cord (black outline) and spinal canal(blue outline). A-P: anterior-posterior, R-L: right-left, CSA: Cross-Sectional Area.
chosen for its conformity to the human
anatomy and the number of anatomical
features included. It is a 3D finite element
model of the spine made from the CT scan
of a 32-year old healthy man. It includes
vertebrae, ligaments, IVDs, SC gray and
white matter (GM, WM), spinal roots, dura
and pia matter, dentate ligaments and gan-
glion. GM and WM were modeled accord-
ing to an elastic law with tangent moduli of
1.67×10-1 and 0.9× 10-1 MPa respectively
(Ichihara et al., 2001). Their geometry was
defined based on a high-resolution MRI
atlas (Taso et al., 2014). Anterior and pos-
terior GM regions, WM dorsal column, WM
lateral motor, WM lateral sensory and WM
anterior regions were defined according
to histological and MRI atlases (Standring,
2008; Lévy et al., 2015). Those regions
were modelled as a continuous mesh. SC
was meshed with tetrahedral elements, as
were the IVD, made of a nucleus and an
annulus (Wagnac et al., 2012). To comply
with the finite element modeling require-
ments stated in Viceconti et al. (Viceconti
et al., 2005), Table 6.2 lists all model pa-
rameters and associated methodological
references dedicated to model validation.
For clarity purposes, in the subsequent text,
the posterior>anterior axis was defined
along ~x , the right>left axis along ~y and
the inferior>superior axis along ~z (see Fig-
ure 6.2). Since literature review and MRI
data both showed that C5-C6 was the most
frequently affected level in DCM, the cervi-
cal segment from C4 to C6 was extracted to
focus on single-level compressions.
General simulation features Simulations
were designed with HyperMesh v17 and
performed with RADIOSS v17 (Altair Engi-
neering Inc., MI, USA).
C4 and C6 vertebrae were fixed. C5-C6
IVD and C5-C6 ligamentum flavum were
used to impose the SC loading with a given
6.2 Manuscript 175
Table 6.2.: Model parameters used for simulations with associated references. ρ: density(g·mm−3), E: Young’s Modulus (MPa), ν: Poisson’s ratio, M: mass (g), K: stiffness (N),Et: tangent modulus (MPa), (µ1, µ2): ground shear hyperelastic modulus (MPa), (a1,a2): material exponent parameters (MPa).
ρ: density (g.mm-3), E: Young’s Modulus (MPa), n: Poisson’s ratio, M: mass (g), K: stiffness (N), E : tangent modulus
6.2 Manuscript 177
Figure 6.2.: Main compression types observed in the DCM group. First row shows anatomicaltransversal MRIs (T2*-weighted scans). Red arrows indicate the compression pro-cesses occurring as pointed out by the clinician. Second and third rows show thetransversal and sagittal views for the corresponding simulations (constraint maps arethe Von Mises stress). Anatomical markers are indicated on each image (A: anterior,P: posterior, L: left, R: right).
kinematic condition (see below). Con-
straints on those entities were therefore not
considered. To account for the quasi-static
behavior of the degenerative process, the
kinetic energy relaxation was forced at each
computing step.
Median diffuse type All nodes of C5-C6
IVD were translated along −~x by 9.9 mm
to reach a 30 % reduction in CSA at the
compression site.
Median focal type C5-C6 IVD was divided
into two groups of nodes. The central line
(∼6.5 mm thickness out of 20 mm in diam-
eter) was translated by 9.8mm along −~x
while the remaining nodes were translated
by 7.9 mm to reach a 30 % reduction in CSA
and avoid rupture of too many elements.
178 Chapter 6
Lateral type C5-C6 IVD was divided into
four groups of nodes. The most left part of
the disk (7.4 mm thick), a central-left line
(2.5 mm thick), the central line (1.9 mm
thick) and the remaining right part of the
disk (7.6 mm thick) were translated along
−~x by 11.2 mm, 10.5 mm, 8.5 mm and
8.1 mm respectively. This design helped to
create asymmetry in the compression while
reaching a 30 % reduction in CSA.
Circumferential type All nodes of C5-
C6 IVD were translated along −~x by
4.4 mm while all nodes of C5-C6 ligamen-
tum flavum were translated along +~x by
4.4 mm.
Quantification
Stresses along X, Y, Z, shear stresses in
XY, YZ, ZX and Von Mises stress were ex-
tracted with HyperView v2017 and Com-
pose v2019.2 (Altair Engineering Inc., MI,
USA). Data were processed with Python
v3.6.
Analysis along inferior-superior axis To
mitigate outliers effect, the 95th percentile
of each constraint absolute value within SC
was extracted at each millimeter for each
compression type and plotted along the I-S
axis. The absolute value made this metric in-
dependent from the direction of constraints.
Analysis along compression development
For each simulation step, the 95th percentile
of each constraint absolute value within SC
was extracted for each compression type.
Analysis across spinal cord regions The
95th percentile of each constraint absolute
value within each of the 6 SC regions (an-
terior and posterior GM, WM dorsal col-
umn, WM lateral motor, WM lateral sensory,
WM anterior pathways) was extracted for
each compression type and pictured on a
transversal unwrapped SC map. Note that
left and right regions were quantified to-
gether to get rid of bias caused by potential
asymmetry in compression types (e.g., lat-
eral type).
Results
Table 6.1 compares compression indices
derived from patients’ MRI data to litera-
ture. Those measurements were normal-
ized to initial SM2S model dimensions (1st
row) to determine the equivalent compres-
sion in the model. Compression indices
based on spinal canal dimensions showed
poor agreement between patients’ average
value, SM2S model and available literature
data. However, cord-based indices, and
in particular, A-P cord diameter and cord
CSA showed a rough agreement around a
30 % compression value between the mea-
surements performed on the DCM cohort
with respect to initial SM2S dimensions
6.2 Manuscript 179
and literature data with respect to controls
(equivalent to an index value of 70 % with
respect to uncompressed state).
Figure 6.2 shows the similarity obtained
between the designed simulations and
observed DCM compression patterns on
transversal MRIs. The median diffuse com-
pression is mainly caused by the migration
of a large portion of the disk into the canal
in addition to osteophyte development. In
the median focal type, the compression is
more local, predominantly caused by os-
teophyte developments and/or herniated
disk; this was modelled by a more promi-
nent migration of the central R-L line of
the disk. The lateral compression is caused
by an asymmetric degeneration of the disk
and/or osteophyte development; it was
simulated by a more prominent migration
of the left side of the disk. Finally, the
circumferential type involves an additional
process: hypertrophy and bulking of the
ligament flavum induce a posterior stenosis
of the spinal canal while disk migration
and/or osteophyte development constrict
the cord anteriorly.
A sole observation of constraint maps
(as in Figure 6.2 ) does not enable to detect
differences between compression types. For
all types, GM appears as the structure with
the most constraints, which is attributable
to its highest rigidity compared to WM.
Profiles along I-S axis look similar and so
far, history of the compression development
process is missing.
The quantitative constraints profile
along I-S axis in whole SC is presented
in Figure 6.3. Two profiles can be iden-
tified. Median diffuse and circumferential
types show a peak of the constraints at the
level of compression whereas median fo-
cal and lateral types show low stress values
but extending over a larger height of the
SC, spreading from upper C5 level down to
lower C6. Such features would not have
been detectable with a sole qualitative ob-
servation of constraint maps (Figure 6.2),
hence the value of the quantitative analysis.
Median diffuse appears as the type inducing
the highest constraint to the SC tissue with
a peak of the Von Mises stress at 0.15 MPa
and σX (stress along ~x) at 0.14 MPa. For all
types, the highest directional stress is σX
while the highest shear stress is in the ZX
plane (τZX).
Figure 6.4 presents the evolution of
constraints within cord along the develop-
ment of the pathology until compression
threshold is reached. A linear rise of the
constraints can be observed with the devel-
opment of the compression but at different
pace according to compression types. Con-
straints in SC start to increase earlier for
median focal and lateral types but at a
slower pace than other types. Median dif-
fuse shows the latest rise of the constraints
and fastest pace. Nevertheless, care must
180 Chapter 6
be taken when comparing those results as
time scale and respective individual timings
of degenerative changes are unknown and
may highly vary across population. Again,
for all types, the constraints are dominated
by σX and τZX .
Figure 6.5 presents constraints analysis
by SC sub-regions. Spinal pathways were af-
fected differently according to compression
type. Globally, highest constraint values
were found for Von Mises and directional
stresses. τXY and τY Z showed the lowest
values.
The median diffuse type showed the highest
stress values. Interestingly, this compres-
sion type also showed the highest shear
stress value (τZX in GM posterior horns).
This type also showed the highest σZ (in
anterior WM).
The median focal type also showed low-
est stress values but a similar distribution
across regions, except in GM posterior horns
apparently less affected.
The lateral type showed a very similar pro-
file as the median focal type but with lower
stress values (σX , Von Mises). Of note,
although the compression pattern is asym-
metric, the lateral pathways were not the
most affected.
Finally, the circumferential type almost
showed no shear stress and constraints were
mainly found in σX (and consequently in
Von Mises stress). Interestingly, σX was
similarly distributed between anterior and
posterior regions. This compression type
was the type showing the highest σX in pos-
terior GM horns and dorsal columns.
6.2 Manuscript 181
Figure 6.3.: Constraints value (95th percentile of the absolute value by millimeter) along theinferior-superior axis for each compression type. The extent of each vertebral level isindicated below. σX ,σY , σZ : stresses along X, Y, Z; τXY , τY Z , τZX : shear stresses inplane XY, YZ, ZX.
Discussion
In this work, the effect of DCM compres-
sion pattern on constraints applying in SC
was investigated. To design the most real-
istic simulations possible, compression fea-
tures were defined based on MRI measure-
ments in 20 patients and DCM data avail-
able in literature. A compression threshold
inducing myelopathy was defined based on
the SC CSA and four compression patterns
were simulated with a comprehensive finite
element spine model. Differences in terms
of I-S profile, constraint evolution along de-
generations development and distribution
across SC sub-regions were examined.
Main findings
Regardless of compression type, the
main constraints standing out were along
the A-P axis, as well as along I-S axis in an-
terior regions. In addition to the obvious
A-P compression, the anatomy (alignment
between the disk and the opposite vertebrae
posterior part) might also be responsible for
a sliding of the disk in the I-S direction, in-
ducing constraints along this axis as well.
Moreover, GM is globally the most affected
structure, which is attributable to its higher
rigidity compared to WM. This result is in
agreement with histopathologic and clinico-
pathologic studies reporting most severely
affected central GM, anterior cell loss and
182 Chapter 6
Figure 6.4.: Constraints value (95th percentile of the absolute value in whole cord at each sim-ulation step) along the development of the compression until threshold, for eachtype. The x-axis corresponds to the simulation steps until compression thresholdis reached. The time sale of degenerative spine changes leading to DCM, whichextends over several years, and the respective timings of individual processes, areunknown. Therefore, care should be taken when interpreting those results in termsof dynamics. σX , σY , σZ : stresses along X, Y, Z; τXY , τY Z ,τZX : shear stresses inplane XY, YZ, ZX.
GM infarction in DCM patients (Fehlings et
al., 1998; Penning, 1978).
Interestingly, ischemia and compression
are thought to be additive causes to tis-
sue necrosis. Experimental studies in dogs
demonstrated the combined effects of those
two processes, by anterior SC compression
and ligation of segmental arteries (Good-
ing et al., 1975), and by cervical compres-
sion and obstruction of the arterial plexus
(Shimomura et al., 1968). Ischemia clearly
exacerbated the pathologic effects of com-
pression and made corticospinal tracts more
vulnerable to injury. This observation con-
curs with clinicopathologic studies report-
ing that corticospinal tracts demyelination
as one of the first pathological changes in
DCM (Ogino et al., 1983). Considering
those findings, our results suggest that lat-
eral WM tracts damage occurring in DCM
cannot be explained by applying constraints
only, but that ischemia would be a necessary
component to this process.
In agreement with previous biomechani-
cal studies on DCM compressions (Nishida
et al., 2012; Khuyagbaatar et al., 2015), the
6.2 Manuscript 183
Figure 6.5.: Spinal cord regions analysis at compression threshold. Each constraint value (95th
percentile of the absolute value by region) were quantified and plotted by region onan unwrapped transversal map. Region labels are indicated on the bottom left-handcorner. Note that left and right regions were quantified together to get rid of biascaused by potential asymmetry in compression types (e.g., lateral type). Color scalewas defined according to minimum and maximum values across all constraints andregions. σX , σY , σZ : stresses along X, Y, Z; τXY , τY Z ,τZX : shear stresses in planeXY, YZ, ZX.
median diffuse type would induce the high- est stress. Median focal and lateral types
The reference technique for perfusion imaging in brain, DSC, was therefore inves-
tigated. This technique makes use of gadolinium-based contrast agent injected intra-
venously during acquisition. This injection is not innocuous, especially when using
linear agents compared to macrocyclic agents that were demonstrated to be more stable
(Cowling et al., 2019). First, gadolinium depositions have been observed in brain and
bone, even in subjects with intact blood-brain barrier (supposed to stop the contrast agent
leakage in the extravascular space) and healthy renal functions (supposed to eliminate the
contrast agent) (Kanda et al., 2015; Ramalho et al., 2016). Those depositions have been
shown to trigger nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis
which are potential cause of deaths (Grobner et al., 2007). If the risk of gadolinium
deposition is widely recognized, the clinical significance remains unknown. According
to an international survey, the clinical significance of gadolinium accumulation in brain
might be largely underestimated as 58 % of radiologists declared that they would not
report that finding, the main reason being the risk of provoking unnecessary patient
anxiety (Fitzgerald et al., 2019). Fortunately, this increasing concern leads to a change
in the practice (for 28 % of respondents). The risk/benefit balance has therefore to be
evaluated. In addition to this risk, injection involves additional technical procedures for
catheter insertion and do not allow room for error. Indeed, data cannot be acquired
again in case of patient motion or artifacts. This brings also important challenges for the
sequence or protocol developmental stage. Extensive tests with injection are not possible.
Besides, data in healthy subjects are very rare, making difficult to build control groups in
studies.
Nevertheless, DSC offered the most reliable map of spinal cord perfusion in all slices
for healthy volunteers but also in 5/18 slices acquired in patients. Despite the image
distortions, a clear depiction of the spinal cord gray matter blood volume and blood
flow could be obtained with an in-plane resolution of 0.74×0.74 mm2 (and a 5-mm slice
thickness). The effects of breathing on the signal were well-characterized and filtered out.
A slightly lower gray matter/white matter perfusion ratio was measured (∼2) compared
to the brain. No effect of the vertebral levels between C2 and C4 was observed. However,
the sensitivity to contrast agent passage was reduced in DCM patients. In particular,
image quality was low. Nyquist N/2 ghost artifacts were visible and varied in time. They
could be due to a poor B0 shimming or to eddy currents induced by the demanding EPI
readout in the coil or in the patients themselves. Indeed, the echo spacing was set to the
minimum possible value to get the lowest possible TE and highest signal, increasing the
gradients switching rate while the readout gradient amplitude was high due to the high
resolution.
7.1 Assessing perfusion status of the human spinal cord 197
A lower resolution (1.04×1.04 mm2 in-plane, slice thickness of 5 mm) was also tested
and indeed resulted in lower ∆R2 variations in the baseline, however the bolus passage
was still hardly detectable. This lower sensitivity in patients might be explained by more
irregular breathing cycles in patients compromising the breathing filtering, more SAR
restrictions on flip angle resulting in a higher proportion of physiological noise in the
acquired signal, or simply more discomfort. Nevertheless, the hypothesis of an altered
perfusion due to spinal cord compression to explain this lower sensitivity to the bolus
cannot be discarded. More acquisitions in patients with GRE-EPI and/or following the
identified and proposed guidelines, will bring more insights.
Finally, Arterial Input Function (AIF) extraction potentials were also investigated (data
not shown, see Lévy et al. (2019)). Anterior and posterior spinal arteries and/or veins
can be identified with high-resolution (0.3×0.3 mm2 in-plane) multi-echo gradient echo
image. If the arterial phase would be discriminated from the venous phase with the bolus
timings, EPI-related distortions in DSC data render the spatial correspondence with the
multi-echo gradient echo image difficult. In addition, the lower spatial resolution, the
limited signal steadiness obtained within the spinal cord tissue and the touchy location
of anterior and posterior spinal arteries at the border between spinal cord and pulsing
CSF, make the AIF extremely challenging to estimate reliably. Relative blood volume and
blood flow thus seem the most accessible perfusion metrics in the short term.
Even though a lot of progress is still needed, this thesis paved the way of perfusion
MRI mapping in the spinal cord. The IVIM path was extensively explored. Even though
optimizations are still possible, this technique is presently poorly reliable and sensitive to
multiple biases in the spinal cord. DSC appeared more promising with the drawback that
it requires contrast agent injection. More experience and data will undoubtedly enable the
technique to be improved in the spinal cord. Multiple avenues for improvement (which
will be described later) can be envisioned. More importantly, this thesis allowed the
main hurdles and critical points for spinal cord perfusion MRI to be identified. Promising
development avenues resulting from this 3-year project will also be described.
198 Chapter 7
7.1.2 Major hurdles
Vascular network
The complexity of the spinal cord vascular network is a major difficulty for perfusion
MRI in the cord. First, looking at the spinal cord cross-section, the tissue is supplied
from different arteries. The major arteries are the Anterior Spinal Artery (ASA), which is
estimated to supply two thirds of the cross-section and in particular the gray matter and
anterior white matter, and the Posterior Spinal Arteries (PSA), which would supply the
remaining third (postero-lateral white matter). Direct branches of radiculo-medullary
arteries also supply the peripheral lateral white matter. In addition to the aforementioned
AIF issues, this implies that two AIF would be necessary depending on the tissue side
(anterior or posterior) to obtain an accurate absolute quantification of perfusion. Looking
at the spinal cord longitudinally, given the limited number of radicular branches, it is
very likely that some portions of the ASA and PSA have an ascending flow while others
would have a descending flow, meaning that one AIF by slice would be necessary. It is
consequently also a challenge for efficient blood labeling in Arterial Spin Labeling (ASL).
The independence of IVIM from an AIF is therefore a non-negligible advantage for the
spinal cord. In addition to this complexity, a relatively large interindividual variability of
the vascular network has been reported, especially regarding the number and position of
radicular branches along the inferior-superior axis. Little is known about the significance
of this variability. Being able to measure perfusion in spinal cord would potentially
provide more insights on the inter-individual variability of the vascular architecture,
another interest of this thesis project.
Impacts of spinal cord MRI-specific issues for perfusion imaging
Difficulties specific to spinal cord Magnetic Resonance Imaging add to these challenges.
The CSF pulses with cardiac beat which causes complex motion of the cord can be
mitigated with cardiac gating and acquisition of data during the quiescent phase. If
this strategy is theoretically working, its application in practice is not trivial for several
reasons. It requires perfect detection of cardiac beat, either using electrocardiogram
or pulse oximeter. At 7T, the electrocardiogram is not reliable because it is distorted
due to the increased electric conduction of blood when it is pumped at high speed
through the aortic arch (Keltner et al., 1990; Krug et al., 2013). The pulse oximeter
positioned on a finger extremity is an alternative, although the signal can be disturbed
7.1 Assessing perfusion status of the human spinal cord 199
if the patient’s finger moves during acquisition. Moreover, the quiescent phase targeted
for acquisition might not be the phase for highest perfusion levels and the duration of
this phase certainly changes across subjects as heartbeat changes. For instance in brain,
Federau et al. (2013) reported a significant increase of D∗ and fIV IM · D∗ during systole
compared to diastole, while Milani et al. (2019) showed through simulations and in-vivo
measurements in kidney that acquiring data at the time of maximum blood velocity
significantly reduced errors in IVIM parameter estimation (root-mean-square relative
error on the fit reduced from 2.7 to 1.7% with acquisition at the time of maximum blood
velocity). Even though the time of maximum blood velocity in the spinal cord tissue
might be extremely challenging to measure, considering that systole and diastole instants
in the cardiac cycle scales with the duration of this cycle, it might be judicious to adapt
the acquisition delay after trigger according to the subject’s cardiac cycle duration. Cord
and CSF quiescent phases were also determined as a percentage of the cardiac cycle
duration (Figley et al., 2007; Figley et al., 2008).
The vicinity of lungs, which has shown effects on signal steadiness with breathing, is
also a difficulty specific to spinal cord MRI which is increased at 7T. High B0 shimming
performance are therefore required. Respiratory belt signal can be used to apply correc-
tion such as breathing frequency filtering as proposed in this thesis for DSC or with a
time-dependent phase demodulation of k-space as proposed by Vannesjo et al. (2019).
But, if breathing-induced phase shifts can be corrected, increased signal decay due to
altered B0 homogeneity cannot be recovered with this technique. What is lost is lost.
Processes affecting T2* with the same temporal frequency cannot be detected either with
such techniques. A better approach, although more technically challenging and not yet
widely available, is real-time shimming. The efficacy of the technique for EPI has been
demonstrated at 3T for thoracic spine (Topfer et al., 2018). A 7T cervical spine coil array
featuring such technique is currently being tested by the same research group (Lopez Rios
et al., 2019).
Last but not least, the spinal cord cross-section is very small. The high resolution
required to depict gray matter restricts SNR and increases echo train length, which
can have different consequences depending on the readout type but mainly results in
increased distortions in EPI and longer echo time.
Those challenges have a particular impact for perfusion MRI. With this in mind, the
most relevant optimizations to focus on have been identified all along the thesis and will
be summarized in the next section.
200 Chapter 7
7.1.3 Optimizations to focus on
From a general point of view, whatever technique is used, one main target to pursue
stood out.
Given the very low blood volume and blood flow in the spinal cord parenchyma and
the high resolution required to discriminate gray from white matter, the Signal-to-Noise
Ratio (SNR) has to be maximized. Now given the limited time, it is the SNR per time
unit which has to be maximized, referred as the SNR efficiency. Note that maximizing
the SNR efficiency maximizes the temporal SNR (tSNR) which refers to the mean signal
over the standard-deviation across the time series. However, once the thermal noise
(hardware-related) has been reduced, the noise in the time series becomes dominated by
the physiological noise and improvement in the SNR of a single repetition does not yield
significant improvements in tSNR anymore, as showed in Triantafyllou et al. (2011) (see
Figure 7.1).
Figure 7.1.: Temporal SNR as a function of the SNR of a single repetition (i.e., only accounting forthe thermal noise, «SNR0») for a 12-channel (red) and 32-channel (green) head coilarrays, different voxel sizes (markers in legend) and different GRAPPA accelerationfactors («R1» refers to non-accelerated acquisitions and the corresponding points forR=2, 3 and 4 can be found on the left side of that point in that respective order. Theblue line is the identity line tSNR=SNR0 and the black line is the fit of the in-vivodata to the noise model (source: Triantafyllou et al., 2011). Above a certain value ofSNR0, the time series is dominated by physiological noise and improvement in SNR0
does not yield a significant increase in tSNR anymore.
7.1 Assessing perfusion status of the human spinal cord 201
Therefore, once this point has been reached, the remaining available SNR increase can
be traded for higher acceleration factor to limit geometric distortions due to the long EPI
readout for instance. However, in the case of parallel imaging, the accurate estimation of
the thermal noise in a single repetition («SNR0») requires heavy calculations involving
Monte-Carlo simulations based on measurements of the coil array g-factor map and the
noise covariance matrix as well as access to the reconstruction routine, including the
parallel imaging reconstruction algorithm used as in Triantafyllou et al. (2011).
Increasing field strength linearly increases the SNR efficiency (as explained in sec-
tion 2.3.1) and for human, 7T MRI is the optimum in terms of clinically approved field
strength.
As averaging data increases the SNR by the square root of the number of averages,
one strategy is to acquire as many images as possible in the allocated time. This strategy
is possible for endogenous techniques. For exogenous techniques based on the passage
of the contrast agent in the tissue, acquisition time cannot be traded for SNR. However,
the same target (optimization of SNR efficiency or tSNR) holds. Common rapid imaging
strategies such as cited in section 2.2.2 are therefore generally employed whatever the
perfusion technique. EPI is the most frequently used readout because of its efficient
k-space coverage and low SAR, compared to turbo-flash or turbo-spin-echo readouts for
instance, although preparation and readout are sometimes intimated related such as for
turbo-spin-echo. For exogenous perfusion MRI, it is also important to have a fast readout
as a snapshot image because we are imaging a constantly changing mechanism. However,
EPI is poorly robust to B0 inhomogeneities.
In the two perfusion techniques investigated in this thesis, the sensitivity to perfusion is
obtained through T2 dephasing (direct or indirect): T2 dephasing induced by molecular
displacement in association with diffusion gradients for IVIM or T2/T2* dephasing
induced by susceptibility effects of the contrast agent for DSC. T1-weighted sequences
thus could not be used such as in DCE MRI which are less sensitive for blood flow
estimation. This consequently precludes the use of turbo-flash readouts which provide
great image quality even in the presence of B0 heterogeneity. The challenge here was
therefore to have a fast readout with a signal sensitive to transverse magnetization
dephasing and robust to B0 inhomogeneities. To cope with the high sensitivity of EPI to
B0 inhomogeneities, spin-echo EPI sequences were preferred at first over gradient-echo
EPI (sensitivity to T2 relaxation and mitigation to T2* relaxation). Nonetheless, other
solutions could be considered.
202 Chapter 7
In the case of IVIM, segmented EPI approach could be used (as time is not limited
by the bolus as in DSC). The long echo train length (coming with high resolution) in
single-shot EPI introduces SNR loss due to the T2*-weighted signal decay along readout.
If Nseg is the number of segments, the SNR gained with data averaging in single-shot EPI
(√
Nseg) has to be compared with the SNR gained when reducing the readout by Nseg.
In addition, the reduction of the readout length with segmented EPI offers a reduction
in image distortions, which can be a significant advantage at 7T in the spinal cord but
comes at the expense of longer acquisition times (limited in clinical routine) and a higher
probability of patient motion.
In the case of DSC where the time allocated for acquiring the whole image is limited
by the cardiac cycle (0.6 to 1.5 s), other readout techniques could theoretically be of
interest. Given its increased sensitivity to contrast bolus (T2* weighting) compared to
spin-echo,GRE-EPI is of course a solution of interest if post-processing methods could
be able to correct image distortions. But steady-state free precession sequences, such
as FISP/FFE/GRASS or trueFISP/balanced FFE/FIESTA (vendor-dependent acronyms)
or fast spin-echo sequences, such as RARE/FSE/TSE, could also be considered. Such
sequences use evenly spaced pulses with short TR to maintain a non-null transverse
magnetization or consecutive refocusing pulses to acquire more than one echo after each
90° excitation pulses. Those techniques could provide great image quality in the spinal
cord with very little or no distortions. However, the cardiac gating is challenging with
those sequences and they are limited by SAR at 7T because of their higher number of
pulses compared to EPI. Increasing the repetition time is therefore necessary at 7T which
deteriorates the temporal resolution.
This leads to the benefits and drawbacks of ultra-high field MRI.
7.1.4 Benefits and drawbacks of Ultra-High Field
Benefits and drawbacks of Ultrahigh Field (UHF) MRI have been listed in section 2.3.
Their consequences on our objective will be discussed here.
SNR was increased at 7T with a larger proportion of protons contributing to the signal
compared to 3T, but SNR efficiency was limited by SAR for some subject morphologies
which required more power to properly flip the magnetization in the spinal cord. SAR
restrictions are also proper to the coil design which is different between 3T and 7T.
For IVIM, SAR was less a limitation than for DSC because TR was not restricted. The
7.1 Assessing perfusion status of the human spinal cord 203
limitation was on the minimal TE (because of the diffusion gradients). Nevertheless,
despite the high in-plane resolution used (0.7×0.7 mm2), a tSNR around 11 was obtained
for IVIM (native value, without any processing or averaging), ranging from 9 to 14. It
was slightly lower for DSC due to SAR limitations for some subjects, leading to a tSNR
as low as 5. Excluding subjects with limited coil voltage, tSNR was around 11 for DSC
data, increased to 13 after motion correction and to 22 with an in-plane resolution of
1.04×1.04 mm2 (respectively, 28 after motion correction).
SAR limitations can be alleviated with more appropriate coil array design. The coil
array used in this work is a "first generation" prototype, now commercialized by Siemens
Healthcare with the Terra 7T system but which might benefit from future developments.
The inferior-superior extent of the "relatively optimal" B1 transmit field is currently
limited to 3-4 vertebral levels (depending on the subject’s morphology), and thus needs
to be improved. It is worth noting that parallel transmission (possible with this coil array
but not yet used) is more likely to efficiently improve the B1 transmit field homogeneity
for 7T MRI of the spinal cord. This emerging technology requires a specific expertise
in electromagnetic simulations to ensure that no local SAR hot spots are produced with
the new field distribution using the transmit channels independently. Dieletric pads
placed around the patient’s neck could also help B1 transmit homogeneity but currently
also require ethics approval as they modify the field distribution similarly to a new coil.
Dieletric pads can additionally help mitigating B0 homogeneity, which is also a major
the Cramer-Rao lower bounds have an analytical expression considerably speeding up the
calculations. Multi-computing on cluster grid would be necessary to solve the problem.
Nonetheless, this approach can provide the answer to the optimal IVIM distribution
question irrespective of which organ the application is dedicated to.
More simply, given the good robustness of D (as showed in DTI) and the poor
reliability of fIV IM and D∗ when estimated jointly in the spinal cord, one could focus the
repetitions on high-b-values (e.g., from 500 to 900 s/mm2) and on b=0. Such approach
might help to estimate fIV IM reliably (as the intercept of the regression line based on
high b-values with slope D in logarithmic scale). Estimation of the blood flow-related
metric would be dropped in that case but it seems to be the price for a reliable estimation
of the microvascular volume fraction in the spinal cord.
DSC parameter mapping
The main perspective for DSC at 7T would be to work on the quality of GRE-EPI in
order to maximize the sensitivity to contrast agent and obtain reliable results in every
patient. Accessing the state-of-the-art methods for EPI phase correction (e.g., local
estimation of phase errors) and GRAPPA calibration (e.g., FLEET or GRE automatic
calibration scans on Siemens systems) would probably help a lot to reduce Nyquist N/2
ghost artifacts. As mentioned earlier, dynamic signal fluctuations will also have to be
minimized . Once reliable relative Blood Volume and Blood Flow maps are obtained,
EPI-related distortions would need to be address. Depending on the coil configuration,
simultaneous multi-slice techniques could then be to consider in order to double or triple
the number of slices, provided that the patient’s spinal cord is straight enough to neglect
partial volume effects due to slices orientation deviation from the transverse plane of the
cord. Meanwhile, the comparison of pros and cons of 7T with respect to 3T should also
be evaluated carefully as mentioned at the end of the previous section since it is not fully
clear that 7T is beneficial yet.
Another approach to address the sensitivity to B0 fluctuations and to significantly
improve the image quality would be to use Gradient-echo with turbo-FLASH readout.
Such images would include a prominent T1 weighting because of the short TR so a
different signal representation will have to be applied (e.g., Dynamic Contrast-Enhanced
(DCE) model) but the images will show very few or almost no distortions and will be much
less sensitive to B0 inhomogeneities than the EPI readout. The sensitivity to contrast agent
might be reduced though. In the context of Degenerative Cervical Myelopathy where
7.1 Assessing perfusion status of the human spinal cord 209
a disruption of the blood-spinal cord barrier is another expected tissue degeneration
(Kalsi-Ryan et al., 2012), the DCE model might additionally be of interest to assess the
degree of contrast agent extravasation.
Finally, by way of comparison, a Vascular Occupancy (VASO) MRI protocol can be easily
included as it only requires a 1-minute acquisition before and after the DSC protocol
(including injection). In the perspectives of absolute quantification, high-resolution
(0.18×0.18 mm2 in plane) multi-echo GRE images could be also added to the protocol to
detect the Anterior Spinal Artery (ASA) and the Posterior Spinal Arteries (PSA). Images
from Massire et al. (2016) (see Figure 2.27c) indeed showed potential for depiction of the
anterior and posterior spinal arteries or the anterior and posterior median spinal veins.
Because of their proximity (see Figure 2.6), those arteries are difficult to discriminate
from those veins just based on anatomical images (even with a high-resolution). However,
timing of the bolus could enable this discrimination. The challenge then to extract an AIF
would be to locate those arteries on the EPI as a simple reslicing of the multi-echo GRE
image would not be sufficient, EPI distortions would need to be corrected and partial
volume effects (due to the different resolutions and slice thicknesses) managed. Magnetic
Resonance Angiography (MRA) could potentially be used to detect the ASA (Sheehy et al.,
2005).
Further perspectives
The main perfusion MRI technique that has not been investigated in this thesis is
Arterial Spin Labeling (ASL). However, given all the drawbacks of the dependence on
contrast agent injection (in part vis-à-vis the development stage, for which it is not easy
to recruit healthy subjects to be injected), I think it is important to keep developing at
least one contrast-free technique in parallel, all the more so as some patients cannot be
catheterized or can present contraindications. Moreover, ASL is at least as promising as
IVIM. Indeed, those two techniques were compared in the injured mice to follow the
perfusion changes induced by a traumatic injury (Callot et al., 2012). As can be observed
in Figure 7.2, the spinal cord blood flow as measured with Pulsed ASL enables healthy
white and gray matter perfusion to be discriminated more precisely than with fIV IM or
D∗. In addition, the perfusion loss right after injury and the recovery in the next days
shows a better defined trend with less noise for ASL. It should nonetheless be noted that
the ASL scheme used required large inversion volume, and that mouse physiology is
210 Chapter 7
different from human’s (blood flow approximately 5-fold higher, larger GM/WM ratio
potentially associated with a larger blood volume and a different blood supply).
Figure 7.2.: Comparison between IVIM and ASL in the monitoring of perfusion changes in theinjured mice (from Callot et al. (2012)). Graphs (a) and (b) show the evolution ofIVIM parameters post-injury, with a comparison to healthy values (N=5) while (c)shows the evolution of the spinal cord blood flow (SCBF) as measured by continuousASL.
As described in the first chapter (see subsection 2.4.4), two different attempts to apply
ASL to human spinal cord were reported in conference proceedings (Nair et al., 2010;
Girard et al., 2013) but the poor reliability of the results discouraged more developments.
However, at 3T (Nair et al., 2010), continuous ASL was used whereas the most efficient
tagging scheme as advised in the ASL consensus paper (Alsop et al., 2015) is pseudo-
continuous ASL. And indeed, this tagging scheme showed better sensitivity to perfusion
at 1.5T (Girard et al., 2013) as illustrated by the obtained signal difference between tag
and control images (Figure 7.3).
Figure 7.3.: Signal in human cord from control and tag images using PCASL at 1.5T (from: Girardet al. (2013))
In light of those results, PCASL would be worth further developments at 3T and even
7T. Indeed, if it appears technically challenging due to the SAR limits at 7T, ASL has been
successfully applied at 7T in brain (Ghariq et al., 2012; Wang et al., 2015; Gardener
et al., 2015; Pfeuffer et al., 2002). One advantage of ASL compared to DSC is that a
7.1 Assessing perfusion status of the human spinal cord 211
longer acquisition time can be traded for SNR and alleviation of SAR limits. However,
ASL requires the identification of the best arteries to tag with adequate transit time (prior
MRA could be beneficial for a patient-specific ASL protocol), and above all, more optimal
cervical coil design or parallel transmission to provide efficient labeling. Many challenges
for the future!
7.2 Biomechanical modeling of DCM-like spinal cord
compression
7.2.1 Achievements
Useful features of the study
The first important feature of the biomechanical study of degenerative compressions
performed in the context of this thesis lies in the definition of a quantitative value for
the compression threshold beyond which substantial tissue damage is likely to occur
and induce myelopathy. This compression threshold of 30% in Cross-Sectional Area
has been determined based on both previous morphological literature data and a DCM
patient cohort. It was actually consistent with several other finite element simulations
of chronic spinal cord compression which particularly reported a significant increase of
the constraints above this value (Kato et al., 2010; Kim et al., 2013; Khuyagbaatar et al.,
2015). It was additionally observed in mice under chronic compression that the number
of motoneurons in gray matter started to decrease above the same threshold value (30%
compression in CSA) (Baba et al., 1996; Baba et al., 1997), even though the connection
with human has to be made with caution since the gray matter/white matter ratio is
higher in the mouse (∼50% versus 20%). Nevertheless, this compression value really
stands out as a critical threshold.
The quantitative definition of a compression threshold is essential for the compar-
ison across different compression patterns. In most studies, simulations and analysis
were performed with an arbitrary compression degree or multiple degrees, which makes
the interpretation of the results and their validity with respect to observed symptoms
complicated. It is also possible that, in practice, the critical compression value changes
212 Chapter 7
depending on the compression type (median diffuse, median acute, lateral, circumferen-
tial). More data are necessary to define a myelopathic compression threshold for each
compression type.
The second interesting feature compared to previous studies looking at chronic de-
generative compression is the anatomic fidelity of the model. Indeed, given the large
variability in compression patterns as well as in the symptoms nature and severity ob-
served in DCM, the anatomy appears as a critical factor. For instance, the anatomy
of the vertebrae, and in particular the height between the lamina (which clamps the
cord on the posterior side) and the intervertebral disk compressing the cord against it,
induced normal stress along the inferior-superior axis and shear stress in those planes.
The anatomy of ligaments and intervertebral disk (position, size, shape) also played an
important role which simple artificial shapes (e.g., perfect parallelepiped, tetrahedron)
might not account for in previous studies.
The third important feature of the finite element analysis carried out in this thesis is
the automatic pipeline for a quantitative analysis of constraints along time steps, across
anatomic spinal cord Region-Of-Interest (ROI) and along any dimension. To the best of
my knowledge, none of the previous finite element study of chronic compression looked
at the induced constraints in such a quantitative manner. The most common approach
is to visually compare constraint maps. However, such approach intrinsically limits the
extent of the analysis and results to be tabulated. It will inevitably miss some aspects of
the constraint patterns. The quantitative set up has the power to reveal subtle differences.
In a view to relate mechanical constraints to tissue perfusion and to explore the time
scale of the events, such analysis is essential.
Important findings
Based on this biomechanical study and on its classification across compression types
(consistent with Nishida et al. (2012) and Khuyagbaatar et al. (2015)), the median
diffuse type would be more detrimental to the tissue, supporting the findings of Nishida
et al. (2012) and Khuyagbaatar et al. (2015). The magnitude of the induced stresses
was higher for this type. The predominant stress was normal or "directional" stress while
shear stress was marginal. Based on the simulated material properties, the main affected
region is by far the gray matter which is consistent with the motoneurons death observed
in compressed mouse spinal cord (Baba et al., 1996; Baba et al., 1997) and with the
reported gray matter infarction in DCM patients (Fehlings et al., 1998). The secondly
7.2 Biomechanical modeling of DCM-like spinal cord compression 213
affected regions would then be the anterior and posterior regions, which actually result
in a global injury pattern affecting all regions in the sagittal plane, even for the lateral
compression type. This is intuitively explained by the main anterior-posterior direction of
the applied loading. However, the observed resulting stresses could not directly explain
the corticospinal tracts demyelination reported in clinicopathologic studies of DCM
(Ogino et al., 1983). According to Fehlings et al. (1998) based on experimental studies in
dogs of Shimomura et al. (1968) Gooding et al. (1975), ischemia would exacerbate the
pathological effects of mechanical compression and make the corticospinal tracts more
vulnerable than others to injury. Consequently, mechanical stress only might not be able
to explain the tissue degeneration observed in corticospinal tracts of DCM patients, hence
the benefit of coupling biomechanical simulation to perfusion measurements.
7.2.2 Model validity
The final concern as in any biomechanical study is the validity of such simulations.
Model validation
Model validation in biomechanics applied to human is complex due to the in-vivo
nature of the problem and the legal/ethical/moral impossibility to perform experimental
measurements.
The Spine Model for Safety and Surgery (SM2S) benefits from the conjoint work of
several research groups associated within an international laboratory (the iLab-Spine). As
a consequence, the model benefits from the multiple validation studies which have been
carried out since 2009. Those mainly focused first on vertebrae and ligaments and later,
on integration of the spinal cord. Nevertheless, fewer validation studies investigated
the gray and white matter properties (Fournely et al., 2020). As a matter of fact, the
in-vivo characterization of spinal cord tissue properties is extremely challenging as they
immediately start to change once harvested. Very recently, ex-vivo measurements were
performed using nano-indentation within the iLab-Spine but results are not published
yet. This work will certainly help the validation and refinement of the model. In the
meantime, values derived from the literature for bovine tissue (Ichihara et al., 2001;
Ichihara et al., 2003) were used for the simulations. Sensitivity analysis — i.e. repeating
the study with varied parameters (e.g., different values of gray and white matter tangent
214 Chapter 7
modulus) — would evaluate the dependency of the obtained results in the gray and white
matter parameters. Such study would be interesting first because the gray and white
matter parameters of the human spinal cord are barely known and secondly because they
are likely to change with age, ischemia and tissue degeneration.
Similar analysis could also be performed on other simulation parameters which were
arbitrarily set: the duration of the simulation, the mesh resolution, the compression
velocity, the proportion of asymmetry for lateral and circumferential types, the impactor
sharpness for all types, ..., are many parameters that could affect the results. Morphology-
dependent parameters (vertebral body height, spinal cord occupation ratio in the spinal
canal, etc.) can be added to this list.
Relating constraints to symptoms
The list of influencing parameters can be very long. Multiplying the number of
simulation designs increases the number of simulation to perform by the number of
parameters and their respective values, quickly making the mission very tedious.
One approach to relate the mechanical stress from those simulations to patients’
symptoms would be to classify symptoms according to the compression types. However,
it requires (1) that patients can all be classified within a single type (e.g., multi-level
compression with different compression types across levels are possible), (2) that common
symptoms stand out within each compression type and (3) that differences in symptoms
across types emerge. Those differences then will have to be explored in light of the
biomechanical simulations.
Another approach is to design the simulation so as to best represent what is happening
to the patient, also referred as patient-specific simulations. This approach is more techni-
cally challenging. First the model will need to be warped to the dimensions of the patient
based on general anatomic details (vertebral body height, spinal canal diameter, cord
diameter). This step can be performed by means of 3D anatomical MRI of the patient
and anatomical landmarks manually defined by the user. For this step, care should be
taken to minimize the contribution of degenerations in the warping. In a second step, the
displacement of the degenerated anatomical entities (e.g., intervertebral disk, ligament)
will need to be measured on the MRI and set in the simulation. This procedure can be
made quasi-automatic to minimize manual user intervention, reducing the likelihood of
errors and saving time. Although more technically challenging, this approach will be
7.2 Biomechanical modeling of DCM-like spinal cord compression 215
much closer to the actual constraints that applies in the patient. This approach has the
potential to address the question of the contribution of the mechanical constraints to the
symptoms of DCM.
7.2.3 Perspectives
Direct perspective for this work would be to overcome the limitations of the study.
First, simulations were performed on a very limited length of the spine (C4 to C6)
and top and bottom vertebrae were fixed. Including more segments, or even the whole
spine (although not computationally efficient) would eliminate any potential bias on the
constraint distribution along the inferior-superior axis caused by this artificial crop. Also
in this respect, fixing all vertebrae is also advised as they are expected to be maintained
by the neck and back muscles. This will additionally help reach the compression threshold
faster for every type.
Secondly, although many parameters might have an effect on simulation results, it
would be interesting to identify a few (simulation duration, mesh, compression velocity)
and analyze the sensitivity of the results to those parameters by way of validation. The
initial spinal canal diameter has been reported as a critical underlying factor in the
eventual development of DCM (Burrows, 1963; Murone, 1974). Its effect should also be
considered but it requires a complex reshaping of the model.
Thirdly, given the long time scale which the compression process develops over, it is
speculated, based on cortical studies specific to DCM, that neural plasticity would allow
the tissue to adapt and compensate for compression (Tam et al., 2010; Holly et al., 2007).
This means that the tissue would have time to relax the constraints (or a part of it) during
chronic compression. Such process would also be relevant to model for a more realistic
and accurate analysis of the constraints along the compression process.
Last but not least, investigating the effect of mechanical properties change with tissue
degeneration along compression would provide more insights into the understanding
of the biomechanics of the pathology. Such investigations would imply to first estimate
how the tissue properties vary with neuronal loss, demyelination, inflammation and
blood-spinal cord barrier disruption which might not be trivial given the challenges
already faced in the estimation of healthy gray and white matter properties.
Next step would be to include compression at multiple levels as it is often observed.
The effect of the vertebral body height and distance between two compressed levels will
thus have a strong meaning as the effects of multiple compressions could meet in the same
216 Chapter 7
place. In that regard, multi-level versus single-level compressions might have significant
consequences on the patient’s symptoms, and a step forward towards patient-specific
simulations would be taken. Nonetheless, the experimental plan and analysis for such
study along with validation or sensitivity analysis is very complex given the number of
degrees of freedom (compression types, number of compressed levels, distance between
levels).
Furthermore, including strain in the study would refine the analysis. Indeed, Doppman
(1975) observed, inter alia, that flattening the cord (stretching it to left and right side)
using a balloon catheter in the monkey disrupted the perfusion in intramedullary arteries
running transversely because of the elongation and narrowing applied. This finding
suggests that the disruption of perfusion rather comes from the strain applied to the
vascular network than from the stress applied to the tissue. It also suggests that including
arteries and veins in the SM2S might be necessary to actually grasp the compression
mechanisms leading to ischemia. In the first place, arteries and veins can be modeled
very simply as straight tubes such as proposed in Alshareef et al. (2014). Magnetic
Resonance Angiography (MRA) images of the spinal cord could further be used to design
more sophisticated representations of the spinal cord vascular network if necessary. Such
feature would take a further step in addressing the question about whether the ischemia
is rather due to arterial supply interruption or to capillary network alteration within the
cord parenchyma.
7.3 Relating perfusion and mechanical constraints in
chronic spinal cord compression
As enunciated in introduction and objectives, this PhD is part of a global project
aiming to relate pathophysiological deficit measured with MRI to mechanical constraints
simulated with biomechanical models in the context of degenerative spinal cord compres-
sion to guide surgery and help identifying risk and prognosis factors. This PhD work was
particularly conducted with the perspective of establishing a quantitative relationship
between mechanical constraints and induced ischemia, which could allow neurosurgeons
to define threshold criteria and assist them in surgical decisions.
However, despite the multiple achievements resulting from this work, this objective
has not been reached yet. A promising method to map human spinal cord perfusion
7.3 Relating perfusion and mechanical constraints in chronic spinal cord
compression
217
(DSC) has been identified and its feasibility at 7T was investigated. But obtained per-
fusion map still lack reliability to confidently depict ischemia in DCM patients. On the
biomechanics side, realistic simulations of typical DCM compression patterns could be
designed and an analysis pipeline was set up to quantitatively investigate the constraints
distribution in spinal cord along compression process, along the spinal cord and across
spinal pathways. But given the large variability of DCM presentations (compression
patterns and symptoms), those simulations still need to get closer to the actual pattern of
compression to relate resulting constraints to symptoms. Reliability of the results also
requires verification for example through sensitivity analysis on the parameters likely to
vary.
Without method for mapping, one could imagine to quantify perfusion parameters in
the whole cord (or in a large ROI within the cord, at the compression site for instance) in
a cohort of patients, along with their respective anatomical MRIs. Then, those patients
would be classified into the four simulated compression types (median diffuse, median fo-
cal, lateral, circumferential). Provided that differences in perfusion across types emerges,
one would then try to explain them based on the results of the biomechanical simulations.
However, given the large number of parameters the simulations depend on, this might be
a highly biased method subject to much larger approximations than the subtle changes
likely to be caused by normal morphological variations.
Indeed, the observed compression pattern in DCM varies a lot (type of compression,
affected levels, number of affected levels, degree of compression). Distribution of
constraints and ischemia within cord is directly related to the compression pattern. For
these reasons and as mentioned earlier, I would advise instead to opt for an approach
focused on the individual case, that is patient-specific approach. Those are also the reason
why a mapping of perfusion indices (instead of a global index value for a large region) is
interesting. In the first place and as development stage, high-resolution 2D transverse
acquisitions were preferred so as to use the difference between gray and white matter
perfusion as a validation index for the obtained perfusion maps. Ideally such acquisitions
would include more slices (≥10) so as to sample and cover both compression area(s) and
healthy tissue rostro-caudally, hence giving a better picture of the effect of compression
on the perfusion distribution (combined with an assessment of microstructural alteration
of course). On the biomechanics side, it would be important to stick the simulation
design to the individual patient’s compression pattern especially in the inferior-superior
direction. Moreover, in order to address the question about the level in vascular network
of the perfusion disruption induced by compression (rather on arterial/vein vascular
218 Chapter 7
network or within capillary network), the main arteries and veins should be included in
the SM2S, even as simple straight tubes as in Alshareef et al. (2014).
In the context of degenerative spinal cord compression, mechanical constraints induced
by compression can be simulated, perfusion deficit could be measured, symptoms can
be assessed and all of them could possibly be related. But in this chain of events,
right in-between perfusion deficit and symptoms, microstructural damages secondary
or concomitant to ischemia should also be evaluated using advanced MRI techniques,
such as diffusion MRI, magnetization transfer-based techniques and/or relaxometry MRI
— as currently developed at the CRMBM (see Massire et al. (2016), Taso et al. (2016),
and the article under revision from Baucher et al. about T1 mapping for microstructural
assessment of the cervical spinal cord in the evaluation of patients with degenerative cervical
myelopathy) —, or using a combination of those techniques (multi-parametric MRI) as
proposed in Martin et al. (2018). Putting those techniques altogether is one of the
iLab-Spine’s challenges.
Finally, a completely different approach to relate ischemia and microstructural al-
terations to biomechanical tissue properties but still coupling biomechanics to MRI, is
Magnetic Resonance Elastography (MRE). As described in chapter 2 (section 2.6.2), this
technique enables the shear modulus of the tissue to be measured in-vivo. It was applied
in the cervical spinal cord at 1.5T in a preliminary study (Kruse et al., 2009). However,
with the proposed driver, displacements in the order of 200 µm were identified, which
could correspond to intrinsic bulk motion. In addition, if preliminary stiffness measure-
ments could be extracted, these showed large variations across the cord and could only
be valid for a global assessment. Once further improved, this technique could potentially
be a promising alternative to estimate the expected change of gray and white matter
mechanical properties with aging and tissue degeneration, with a view to investigate the
effects of such changes on finite element simulation results.
7.3 Relating perfusion and mechanical constraints in chronic spinal cord
compression
219
General conclusion 8Degenerative spinal cord compression involves mechanical constraints and perfusion
deficit in the spinal cord, which induce an inflammatory reaction resulting in neuronal
and oligodendroglial death and eventually myelopathy. Indeed, Degenerative Cervical
Myelopathy (DCM) is a common spinal cord disorder in elderly population. If the chain of
pathological events seems consistent with clinical observations and experimental findings,
little is known about the modality of action of each pathological process, their respective
contribution and interactions, as well as the timescale of the processes. As a consequence,
progression of the pathology is difficult to monitor and predict. Moderate/severe DCM are
treated with decompression surgery to limit neurological deterioration but management
of mild DCM is controversial: non-operative treatments (cervical collars or physiotherapy)
with periodic monitoring of symptoms are often preferred over surgery. This PhD work is
part of a global project aiming at exploring and characterizing the different processes
involved in degenerative spinal cord compression.
The first part of the thesis was dedicated to MR technique developments for measure-
ment of spinal cord perfusion, which could ultimately be used by clinicians to assess
the severity of the disease. Quantifying perfusion in the human spinal cord reliably is
extremely challenging as evidenced by previous attempts from different research groups.
Spinal cord is small, its perfusion is low (≤5% of tissue volume) and its vascular network
is complex. Tissue perfusion comes from multiple arteries, from bottom to top with a
limited number of branches running transversely (radicullomedullary arteries) feeding
the smaller arteries (Anterior Spinal Artery and Posterior Spinal Arteries) and at variable
levels. A high SNR is therefore essential to perform reliable measurements. The benefits
of 7T MRI, on the road to clinics, were engaged.
The first investigated technique was Intra-Voxel Incoherent Motion (IVIM). Although
interesting for its independence from Arterial Input Function and its additional estimation
of the diffusion coefficient for microstructural assessment, this technique showed poor
reliability in the spinal cord at the individual level despite a large number of averages. The
higher perfusion of the butterfly-shaped gray matter could only be clearly revealed after
an averaging across slices and subjects. The bi-exponential signal representation of IVIM
221
is indeed speculated to be too sensitive to physiological noise in the human spinal cord
at 7T at the individual level. The second investigated technique, Dynamic Susceptibility
Contrast (DSC), which requires injection of a gadolinium-based contrast agent, showed
more promising results. Known sources of physiological noise were addressed with
cardiac gating and identification of breathing-induced signal fluctuations. Well-defined
relative Blood Flow and Blood Volume maps were obtained in healthy subjects with
in-plane resolution of 0.74×0.74 mm2. Results were more mitigated in case of suspected
perfusion deficit as accounted for by DCM patients. The lack of sensitivity of the spin-
echo sequence to R2 change with contrast compared to gradient-echo sensitive to R∗
2 is
incriminated. The poor robustness of the current static/dynamic B0 shimming routine on
7T whole-body human systems seems also a major source of temporal instability. Benefits
of the currently available technology for spinal cord MRI at 7T needs to be evaluated
against the available technologies at 3T for such an application. Whatever technique or
field strength is used, SNR efficiency is the key.
The second part of the thesis explored the pathological processes of DCM from an
anatomical and biomechanical point of view. The detailed anatomy of the finite element
Spine Model for Safety and Surgery (SM2S) was employed to simulate the constraints
induced by typical DCM compressions. Despite the high variability of compression
patterns across patients, some standards were extracted from literature and from a cohort
of 20 patients. Hence, a 30% reduction in Cross-Sectional Area appeared as a consistent
critical threshold beyond which cell loss and myelopathy occur. The most frequently
affected is C5-C6 and four transverse compression types were selected for simulation
design: median diffuse, median focal, lateral and circumferential. An automatic pipeline
for quantitative analysis of the constraints across compression process, along spinal cord
length and across spinal pathways was set up. Based on induced stress, the median
diffuse compression type would be the most detrimental. Higher stress in gray matter
was in agreement with reported gray matter infarction in DCM patients and motoneuron
loss but demyelination of corticospinal tracts could not be explained by directly induced
stress only. However, sensitivity of those results to simulation parameters need to be
evaluated and strain should be included in the analysis.
In the perspective to investigate the relationship between simulated mechanical con-
straints and perfusion deficit, patient-specific simulation design and perfusion assessment
appeared necessary in front of the large inter-individual variability of compression pat-
terns and symptoms. Such achievements would provide the clinicians with more tools
to monitor the disease progression and optimally manage mild DCM. Furthermore, they
222 Chapter 8
would open the door to new knowledge on the acceptable and non-acceptable constraints
values for the spinal cord tissue integrity, with a large number of applications in the
scope.
223
Publications, communications
and international commitments
9
Journal articles
Published
• Lévy, Simon, Stanislas Rapacchi, Aurélien Massire, Thomas Troalen, Thorsten
Feiweier, Maxime Guye, and Virginie Callot. “Intravoxel Incoherent Motion at
7 Tesla to Quantify Human Spinal Cord Perfusion: Limitations and Promises.”
Magnetic Resonance in Medicine, February 14, 2020, mrm.28195. https://doi.
In order to get a better idea of the inside structure of the dyalizer and dimensions
of the synthetic fibers, the dialyzer was scanned with a micro-Computed Tomography
scanner (Figure A.4b) thanks to Laure Balasse at the European Research Center in Medical
Imaging (CERIMED, Marseille, France). The inside diameter of the hollow fibers was
roughly estimated around 50 µm.
Table A.1.: Flow rate in dyalizer as a function of pump speed indicator.
Pump speed indicatorFlow rate (mL/s)
At the dyal-izer input
At the dyal-izer output
Average
0.5 1.2 1.3 1.3
1.0 4.2 4.8 4.5
1.5 7.0 7.0 7.0
2.0 9.7 9.9 9.8
2.5 12.4 12.5 12.4
3.0 14.9 15.1 15.0
3.5 17.4 17.3 17.4
4.0 19.8 19.8 19.8
4.5 21.4 21.4 21.4
5.0 23.5 22.7 23.1
The flow rate resulting from different pump speeds was manually measured at the
input and output of the dyalizer (Table A.1). Then, the phantom was used to check the
sensitivity of the IVIM acquisition protocol to water flow at different speeds. Figure A.5
shows the obtained MRI signal decay in the dyalizer as a function of b-values and at
different pump speeds. The diffusion encoding was applied longitudinally to the dyalizer
which was positioned along the inferior-superior axis.
Note that the signal was normalized by the signal value at b=800 s/mm2 in order to
better visualize the deviation of the signal from the case with no flow (i.e. only thermal
diffusion with coefficient D) for the different pump speeds. We can first observe that
with the pump turned off, the signal decay is linear (in logarithmic scale), showing a
null microvascular fraction fIV IM of 0. By contrast, for non-null pump speeds, a positive
242 Appendix A
fIV IM is measured and the decay at low b-values gets faster (the pseudo-diffusion
coefficient D∗ increases). Secondly, it is interesting to notice that even at high b-values
(600 and even 700 s/mm2), the flow rate has an effect on the signal as evidenced by the
difference in the linear fit (based on high b-values only) across pump speeds.
To have a rough idea of the flow rate provided by the pump compare to in-vivo flow
rates, let us consider, on the one hand, a value of 60 mL/100g tissue/min in the healthy
gray matter. Given a gray matter density of 1.04 g/cm3, this corresponds to a blood flow of
58.0 mL/100cm3/min. On the other hand, the priming volume of the dyalizer is 116cm3
(according to the vendor). Therefore, a flow rate of 4.5 mL/s (pump speed indicator on
1) would correspond to a flow of 232.8 mL/100cm3/min inside the dyalizer. This is about
4 times higher than the gray matter blood flow, and still, we see flow effects on the high
b-values. This result supports that the one-step fit is more appropriate in case of low
perfusion levels. It also suggests that considering higher b-values (≥800 s/mm2), which
is possible thanks to the increased SNR at 7T, might improve the separation between
perfusion and pure diffusion effects in the phantom.
A.4 Conception of a perfusion phantom 243
(a) Dyalizer (left) and perfusion phantom without the tubes (right)
(b) Micro-Computed Tomography scans of the dyalizer (left: transversal view, right:sagittal view
Figure A.4.: Perfusion phantom made of a dialyzer, a pump and long tubes (a). The dyalizer wasscanned with a micro-Computed Tomography scanner (b) thanks to Laure Balasse(European Research Center in Medical Imaging (CERIMED), Marseille, France).
244 Appendix A
Figure A.5.: Logarithm of the mean MRI signal value within the dyalizer (normalized by thevalue at b=800 s/mm2) as a function of the b-value and the pump speed. Thethin straight lines represent the linear fit of b-values ≥600 s/mm2. The diffusionencoding was applied longitudinally to the dyalizer which was positioned along theinferior-superior axis.
A.4 Conception of a perfusion phantom 245
Bibliography
Ahlgren, André, Linda Knutsson, Ronnie Wirestam, et al. (May 2016). “Quantification of mi-crocirculatory parameters by joint analysis of flow-compensated and non-flow-compensatedintravoxel incoherent motion (IVIM) data: Joint Analysis of Flow-Compensated and Non-Flow-Compensated IVIM Data”. en. In: NMR in Biomedicine 29.5, pp. 640–649. DOI: 10.1002/nbm.
3505 (cit. on p. 78).
Ahn, C. B., J. H. Kim, and Z. H. Cho (Mar. 1986). “High-Speed Spiral-Scan Echo Planar NMRImaging-I”. In: IEEE Transactions on Medical Imaging 5.1, pp. 2–7. DOI: 10.1109/TMI.1986.
4307732 (cit. on pp. 35, 36).
Al-Mefty, Ossama, H. Louis Harkey, Isam Marawi, et al. (Oct. 1993). “Experimental chroniccompressive cervical myelopathy”. en. In: Journal of Neurosurgery 79.4, pp. 550–561. DOI:10.3171/jns.1993.79.4.0550 (cit. on p. 87).
Alshareef, Mohammed, Vibhor Krishna, Jahid Ferdous, et al. (Sept. 2014). “Effect of Spinal CordCompression on Local Vascular Blood Flow and Perfusion Capacity”. en. In: PLoS ONE 9.9.Ed. by Michael Fehlings, e108820. DOI: 10.1371/journal.pone.0108820 (cit. on pp. 112, 113,217, 219).
Alsop, David C., John A. Detre, Xavier Golay, et al. (Jan. 2015). “Recommended implementationof arterial spin-labeled perfusion MRI for clinical applications: A consensus of the ISMRMperfusion study group and the European consortium for ASL in dementia: RecommendedImplementation of ASL for Clinical Applications”. en. In: Magnetic Resonance in Medicine 73.1,pp. 102–116. DOI: 10.1002/mrm.25197 (cit. on pp. 69–73, 211).
Amato, Alexandre Campos Moraes and Noedir Antônio Groppo Stolf (Sept. 2015). “Anatomia dacirculação medular”. en. In: Jornal Vascular Brasileiro 14.3, pp. 248–252. DOI: 10.1590/1677-
5449.0004 (cit. on pp. 16, 19).
Andersson, Jesper L. R., Stefan Skare, and John Ashburner (Oct. 2003). “How to correct suscepti-bility distortions in spin-echo echo-planar images: application to diffusion tensor imaging”. In:NeuroImage 20.2, pp. 870–888. DOI: 10.1016/S1053-8119(03)00336-7 (cit. on p. 34).
Apruzzese, Alessio, Mauro Silvestrini, Roberto Floris, et al. (2001). “Cerebral Hemodynamicsin Asymptomatic Patients with Internal Carotid Artery Occlusion: A Dynamic SusceptibilityContrast MR and Transcranial Doppler Study”. en. In: p. 6 (cit. on p. 66).
Atkinson, Ian C., Laura Renteria, Holly Burd, Neil H. Pliskin, and Keith R. Thulborn (Nov. 2007).“Safety of human MRI at static fields above the FDA 8T guideline: Sodium imaging at 9.4T doesnot affect vital signs or cognitive ability”. en. In: Journal of Magnetic Resonance Imaging 26.5,pp. 1222–1227. DOI: 10.1002/jmri.21150 (cit. on p. 49).
Baba, Hisatoshi, Yasuhisa Maezawa, Shinichi Imura, et al. (Feb. 1996). “Quantitative analysis ofthe spinal cord motoneuron under chronic compression: an experimental observation in themouse”. en. In: Journal of Neurology 243.2, pp. 109–116. DOI: 10.1007/BF02443999 (cit. onpp. 105, 212, 213).
Baba, Hisatoshi, Yasuhisa Maezawa, Kenzo Uchida, et al. (Apr. 1997). “Three-dimensional to-pographic analysis of spinal accessory motoneurons under chronic mechanical compression:an experimental study in the mouse”. en. In: Journal of Neurology 244.4, pp. 222–229. DOI:10.1007/s004150050076 (cit. on pp. 105, 212, 213).
Bailly, Nicolas, Lucien Diotalevi, Marie-Hélène Beauséjour, et al. (Apr. 2020). “Numerical in-vestigation of the relative effect of disc bulging and ligamentum flavum hypertrophy onthe mechanism of central cord syndrome”. en. In: Clinical Biomechanics 74, pp. 58–65. DOI:10.1016/j.clinbiomech.2020.02.008 (cit. on p. 115).
Barker, Anthony T, Reza Jalinous, and Ian L Freeston (1985). “Non-invasive magnetic stimulationof human motor cortex”. In: The Lancet 325.8437. Publisher: Elsevier, pp. 1106–1107 (cit. onp. 97).
Baron, Eli M. and William F. Young (Jan. 2007). “Cervical Spondylotic Myelopathy: A briefreview of its pathophysiology, clinical course, and diagnosis”. en. In: Neurosurgery 60.suppl_1,S1–35–S1–41. DOI: 10.1227/01.NEU.0000215383.64386.82 (cit. on p. 90).
Barry, Robert L., Baxter P. Rogers, Benjamin N. Conrad, Seth A. Smith, and John C. Gore (June2016). “Reproducibility of resting state spinal cord networks in healthy volunteers at 7 Tesla”.en. In: NeuroImage 133, pp. 31–40. DOI: 10.1016/j.neuroimage.2016.02.058 (cit. on pp. 52,54).
Barry, Robert L, Seth A Smith, Adrienne N Dula, and John C Gore (Aug. 2014). “Resting statefunctional connectivity in the human spinal cord”. en. In: eLife 3, e02812. DOI: 10.7554/eLife.
02812 (cit. on p. 52).
Barry, Robert L., S. Johanna Vannesjo, Samantha By, John C. Gore, and Seth A. Smith (Mar. 2018).“Spinal cord MRI at 7T”. en. In: NeuroImage 168, pp. 437–451. DOI: 10.1016/j.neuroimage.
2017.07.003 (cit. on pp. 38, 46, 50).
Basser, P. J., J. Mattiello, and D. Lebihan (Mar. 1994). “Estimation of the Effective Self-DiffusionTensor from the NMR Spin Echo”. In: Journal of Magnetic Resonance, Series B 103.3, pp. 247–254. DOI: 10.1006/jmrb.1994.1037 (cit. on p. 75).
Baucher, Guillaume (2019). “Cartographie T1 de la moelle spinale cervicale dans l’évaluationdes patients atteints de myélopathie cervicale dégénérative”. French. Research master inneurosciences. Marseille: Aix-Marseille University (cit. on p. 93).
Beauséjour, Marie-Hélène, Yvan Petit, Jeremy Hagen, et al. (May 2020). “Contribution of injuredposterior ligamentous complex and intervertebral disc on post-traumatic instability at thecervical spine”. en. In: Computer Methods in Biomechanics and Biomedical Engineering, pp. 1–12.DOI: 10.1080/10255842.2020.1767776 (cit. on p. 115).
Benzel, EC, J Lancon, L Kesterson, and T Hadden (Sept. 1991). “Cervical laminectomy and dentateligament section for cervical spondylotic myelopathy”. eng. In: Journal of spinal disorders 4.3,pp. 286–295. DOI: 10.1097/00002517-199109000-00005 (cit. on pp. 93, 240).
Berge, Jérôme, Bertrand Marque, Jean-Marc Vital, Jacques Sénégas, and Jean-Marie Caillé (July1999). “Age-Related Changes in the Cervical Spines of Front-Line Rugby Players”. en. In: TheAmerican Journal of Sports Medicine 27.4, pp. 422–429. DOI: 10.1177/03635465990270040401
Bertleff, Marco, Sebastian Domsch, Sebastian Weingärtner, et al. (Dec. 2017). “Diffusion parametermapping with the combined intravoxel incoherent motion and kurtosis model using artificialneural networks at 3 T”. en. In: NMR in Biomedicine 30.12, e3833. DOI: 10.1002/nbm.3833
(cit. on p. 78).
Betts, J Gordon, Peter Desaix, Eddie Johnson, et al. (2018). Anatomy & Physiology. en (cit. onp. 107).
Bianciardi, Marta, Jonathan R. Polimeni, Kawin Setsompop, et al. (2014). “Evaluation of dynamicoff-resonance correction of respiratory instability in MRI signals for high-order sphericalharmonic basis set and multivariate modeling of respiratory sources”. In: Proc. Int. Soc. Magn.Reson. Med. 22. Milan, Italy, p. 1623 (cit. on p. 205).
Bihan, Denis Le (Nov. 1995). “Molecular diffusion, tissue microdynamics and microstructure”. en.In: NMR in Biomedicine 8.7, pp. 375–386. DOI: 10.1002/nbm.1940080711 (cit. on p. 75).
Bilston, Lynne E (2011). Neural tissue biomechanics. Vol. 3. Springer Science & Business Media(cit. on p. 104).
Bilston, Lynne E. and Lawrence E. Thibault (Sept. 1995). “The mechanical properties of thehuman cervical spinal cordIn Vitro”. en. In: Annals of Biomedical Engineering 24.S1, pp. 67–74.DOI: 10.1007/BF02770996 (cit. on p. 104).
Bisdas, Sotirios and Uwe Klose (Aug. 2015). “IVIM analysis of brain tumors: an investigation ofthe relaxation effects of CSF, blood, and tumor tissue on the estimated perfusion fraction”.en. In: Magnetic Resonance Materials in Physics, Biology and Medicine 28.4, pp. 377–383. DOI:10.1007/s10334-014-0474-z (cit. on p. 78).
Bisdas, Sotirios, Tong San Koh, Constantin Roder, et al. (Oct. 2013). “Intravoxel incoherent motiondiffusion-weighted MR imaging of gliomas: feasibility of the method and initial results”. en. In:Neuroradiology 55.10, pp. 1189–1196. DOI: 10.1007/s00234-013-1229-7 (cit. on p. 78).
Bloch, Felix (1946). “Nuclear Induction”. In: Physical Review 70, pp. 460–474 (cit. on p. 24).
Block, F, WW Hansen, and M Packard (1946). “The nuclear induction experiment”. In: PhysicalReview 70.7-8, pp. 474–485 (cit. on p. 24).
Bloembergen, N., E. M. Purcell, and R. V. Pound (Apr. 1948). “Relaxation Effects in NuclearMagnetic Resonance Absorption”. In: Physical Review 73.7. Publisher: American Physical Society,pp. 679–712. DOI: 10.1103/PhysRev.73.679 (cit. on p. 42).
Boer, Vincent O., Bart L. vd Bank, Gerard van Vliet, Peter R. Luijten, and Dennis W. J. Klomp (Feb.2012). “Direct B0 field monitoring and real-time B0 field updating in the human breast at 7tesla”. en. In: Magnetic Resonance in Medicine 67.2, pp. 586–591. DOI: 10.1002/mrm.23272
(cit. on p. 205).
Bowen, Brian C, Steven DePrima, Pradip M Pattany, et al. (1996). “MR Angiography of NormalIntradural Vessels of the Thoracolumbar Spine”. en. In: p. 12 (cit. on p. 83).
Brand, Michael, Stephan Ellmann, Matthias Sommer, et al. (Nov. 2015). “Influence of Cardiac MRImaging on DNA Double-Strand Breaks in Human Blood Lymphocytes”. en. In: Radiology 277.2,pp. 406–412. DOI: 10.1148/radiol.2015150555 (cit. on p. 50).
Breig, Alf, Ian Turnbull, and Ove Hassler (1966). “Effects of mechanical stresses on the spinalcord in cervical spondylosis: a study on fresh cadaver material”. In: Journal of neurosurgery25.1, pp. 45–56 (cit. on pp. 87, 90).
Bulte, Daniel, Peter Chiarelli, Richard Wise, and Peter Jezzard (Oct. 2007). “Measurement ofcerebral blood volume in humans using hyperoxic MRI contrast”. en. In: Journal of MagneticResonance Imaging 26.4, pp. 894–899. DOI: 10.1002/jmri.21096 (cit. on p. 68).
Burrows, Edmund H. (1963). “The sagittal diameter of the spinal canal in cervical spondylosis”. In:Clinical Radiology 14.1, pp. 77 –86. DOI: https://doi.org/10.1016/S0009-9260(63)80015-X
(cit. on p. 216).
Buxton, Richard B., Lawrence R. Frank, Eric C. Wong, et al. (Sept. 1998). “A general kinetic modelfor quantitative perfusion imaging with arterial spin labeling”. en. In: Magnetic Resonance inMedicine 40.3, pp. 383–396. DOI: 10.1002/mrm.1910400308 (cit. on p. 71).
Cadotte, D. W., A. Cadotte, J. Cohen-Adad, et al. (Apr. 2015). “Characterizing the Locationof Spinal and Vertebral Levels in the Human Cervical Spinal Cord”. In: American Journal ofNeuroradiology 36, pp. 803–810. DOI: 10.3174/ajnr.A4192 (cit. on p. 11).
Calamante, Fernando (2013). “Arterial input function in perfusion MRI: A comprehensive review”.en. In: Progress in Nuclear Magnetic Resonance Spectroscopy, p. 32 (cit. on pp. 61, 63).
Calamante, Fernando, David L. Thomas, Gaby S. Pell, Jonna Wiersma, and Robert Turner (July1999). “Measuring Cerebral Blood Flow Using Magnetic Resonance Imaging Techniques”. en.In: Journal of Cerebral Blood Flow & Metabolism 19.7, pp. 701–735. DOI: 10.1097/00004647-
Callot, V, G Duhamel, P Moulin, and P J Cozzone (2011). “Intra Voxel Incoherent Motion (IVIM)MRI of the human spinal cord: preliminary results and potentiality”. en. In: Proc. Intl. Soc. Mag.Reson. Med. 19, p. 1 (cit. on p. 80).
Callot, Virginie, Guillaume Duhamel, Jérôme Laurin, André Mauès de Paula, and Patrick J Cozzone(2012). “Intra Voxel Incoherent Motion (IVIM) MRI: an alternative method to get spinal cord(SC) vascular description. Preliminary results in healthy and injured mice.” en. In: Proc. Intl.Soc. Mag. Reson. Med. 20, p. 1037 (cit. on pp. 80, 210, 211).
Carlson, Gregory D, Carey D Gorden, Shigenobu Nakazowa, et al. (2000). “Perfusion-limitedrecovery of evoked potential function after spinal cord injury”. In: Spine 25.10, pp. 1218–1226(cit. on pp. 110, 112).
Carlson, Gregory D, Karen E Warden, James M Barbeau, et al. (1997). “Viscoelastic relaxationand regional blood flow response to spinal cord compression and decompression”. In: Spine22.12, pp. 1285–1291 (cit. on pp. 110, 112).
Chiles III, Bennie W., Michael A. Leonard, Haroon F. Choudhri, and Paul R. Cooper (Apr. 1999).“Cervical Spondylotic Myelopathy: Patterns of Neurological Deficit and Recovery after AnteriorCervical Decompression”. In: Neurosurgery 44.4, pp. 762–769. DOI: 10 . 1097 / 00006123 -
199904000-00041 (cit. on pp. 93, 240).
Chomiak, J., J. Dvorak, J. Antinnes, and A. Sandler (June 1995). “Motor evoked potentials:appropriate positioning of recording electrodes for diagnosis of spinal disorders”. en. In:European Spine Journal 4.3, pp. 180–185. DOI: 10.1007/BF00298243 (cit. on p. 97).
Christensen, Søren, Kim Mouridsen, Ona Wu, et al. (June 2009). “Comparison of 10 PerfusionMRI Parameters in 97 Sub-6-Hour Stroke Patients Using Voxel-Based Receiver OperatingCharacteristics Analysis”. en. In: Stroke 40.6, pp. 2055–2061. DOI: 10.1161/STROKEAHA.108.
546069 (cit. on p. 62).
Cohen-Adad, J. and C. Wheeler-Kingshott (2014). Quantitative MRI of the Spinal Cord. ElsevierScience (cit. on p. 38).
Collins, Christopher M. and Zhangwei Wang (May 2011). “Calculation of radiofrequency elec-tromagnetic fields and their effects in MRI of human subjects: RF Field Calculations in MRI”.en. In: Magnetic Resonance in Medicine 65.5, pp. 1470–1482. DOI: 10.1002/mrm.22845 (cit. onp. 48).
Cowling, Tara and Nina Frey (2019). “Macrocyclic and Linear Gadolinium Based Contrast Agentsfor Adults Undergoing Magnetic Resonance Imaging: A Review of Safety”. In: Canadian Agencyfor Drugs and Technologies in Health (cit. on pp. 196, 197).
Czyz, Marcin, Krzysztof Scigala, Wlodzimierz Jarmundowicz, and Romuald Bedzinski (2011).“Numerical model of the human cervical spinal cord-the development and validation.” In: Actaof Bioengineering & Biomechanics 13.4 (cit. on p. 109).
De Leener, Benjamin, Vladimir S. Fonov, D. Louis Collins, et al. (2018). “PAM50: Unbiasedmultimodal template of the brainstem and spinal cord aligned with the ICBM152 space”. In:NeuroImage 165, pp. 170 –179. DOI: 10.1016/j.neuroimage.2017.10.041 (cit. on p. 13).
Dietrich, Benjamin E., David O. Brunner, Bertram J. Wilm, et al. (Apr. 2016). “A field camera forMR sequence monitoring and system analysis: MR Sequence Monitoring and System AnalysisCamera”. en. In: Magnetic Resonance in Medicine 75.4, pp. 1831–1840. DOI: 10.1002/mrm.25770
(cit. on p. 36).
Dixon, W T (Oct. 1984). “Simple proton spectroscopic imaging.” In: Radiology 153.1. Publisher:Radiological Society of North America, pp. 189–194. DOI: 10.1148/radiology.153.1.6089263
(cit. on p. 234).
Donahue, Kathleen M, Hendrikus GJ Krouwer, Scott D Rand, et al. (2000). “Utility of simultane-ously acquired gradient-echo and spin-echo cerebral blood volume and morphology maps inbrain tumor patients”. In: Magnetic resonance in medicine 43.6. Publisher: Wiley Online Library,pp. 845–853 (cit. on p. 64).
Doppman, John L (1975). “The mechanism of ischemia in anteroposterior compression of thespinal cord.” In: Investigative radiology 10.6, pp. 543–551 (cit. on pp. 117, 217).
Dortch, Richard D., Adrienne N. Dula, K. Li, et al. (2012). “Quantitative magnetization transferimaging of human cervical spinal cord at 7 Tesla”. In: Proc. Int. Soc. Magn. Reson. Med. 20.Melbourne, Victoria, Australia, p. 0614 (cit. on p. 52).
Doyle, Mark, Edward G. Walsh, Gerald G. Blackwell, and Gerald M. Pohost (Feb. 1995). “BlockRegional Interpolation Scheme for k-Space (BRISK): A Rapid Cardiac Imaging Technique”. en.In: Magnetic Resonance in Medicine 33.2, pp. 163–170. DOI: 10.1002/mrm.1910330204 (cit. onp. 235).
Duerst, Yolanda, Bertram J. Wilm, Michael Wyss, et al. (Aug. 2016). “Utility of real-time fieldcontrol in T 2 *-Weighted head MRI at 7T: Utility of Real-Time Field Control”. en. In: MagneticResonance in Medicine 76.2, pp. 430–439. DOI: 10.1002/mrm.25838 (cit. on p. 45).
Duggal, N., D. Rabin, R. Bartha, et al. (Mar. 2010). “Brain reorganization in patients withspinal cord compression evaluated using fMRI”. en. In: Neurology 74.13, pp. 1048–1054. DOI:10.1212/WNL.0b013e3181d6b0ea (cit. on p. 98).
Duhamel, Guillaume, Virginie Callot, Patrick J. Cozzone, and Frank Kober (2008). “Spinal cordblood flow measurement by arterial spin labeling”. In: Magnetic Resonance in Medicine 59,pp. 846–854. DOI: 10.1002/mrm.21567 (cit. on pp. 7, 79, 80).
Duhamel, Guillaume, Virginie Callot, Patrick Decherchi, et al. (2009). “Mouse lumbar and cervicalspinal cord blood flow measurements by arterial spin labeling: Sensitivity optimization and firstapplication”. In: Magnetic Resonance in Medicine 62, pp. 430–439. DOI: 10.1002/mrm.22015
Dula, Adrienne N., Siddharama Pawate, Lindsey M. Dethrage, et al. (Sept. 2016). “Chemicalexchange saturation transfer of the cervical spinal cord at 7 T: Cest of the Cervical Spinal CordAT 7 T”. en. In: NMR in Biomedicine 29.9, pp. 1249–1257. DOI: 10.1002/nbm.3581 (cit. onp. 53).
Dvorak, Jiri, Martin Sutter, and Joerg Herdmann (2005). “Cervical myelopathy: clinical andneurophysiological evaluation”. In: The Aging Spine. Ed. by Max Aebi, Robert Gunzburg, andMarek Szpalski. Berlin, Heidelberg: Springer Berlin Heidelberg, pp. 99–105 (cit. on p. 96).
Edwards, WC and H LaRocca (1983). “The developmental segmental sagittal diameter of thecervical spinal canal in patients with cervical spondylosis”. eng. In: Spine 8.1, pp. 20–27 (cit. onp. 90).
El-Rich, Marwan, Pierre-Jean Arnoux, Eric Wagnac, Christian Brunet, and Carl-Eric Aubin (June2009). “Finite element investigation of the loading rate effect on the spinal load-sharingchanges under impact conditions”. In: Journal of Biomechanics 42.9, pp. 1252–1262. DOI:10.1016/j.jbiomech.2009.03.036 (cit. on pp. 114, 116).
Ellingson, Benjamin M., Noriko Salamon, Anthony J. Hardy, and Langston T. Holly (Oct. 2015).“Prediction of Neurological Impairment in Cervical Spondylotic Myelopathy using a Combinationof Diffusion MRI and Proton MR Spectroscopy”. en. In: PLOS ONE 10.10. Ed. by MohammedShamji, e0139451. DOI: 10.1371/journal.pone.0139451 (cit. on p. 97).
Ellingson, Benjamin M., Davis C. Woodworth, Kevin Leu, Noriko Salamon, and Langston T. Holly(Aug. 2019). “Spinal Cord Perfusion MR Imaging Implicates Both Ischemia and Hypoxia inthe Pathogenesis of Cervical Spondylosis”. en. In: World Neurosurgery 128, e773–e781. DOI:10.1016/j.wneu.2019.04.253 (cit. on p. 81).
European Parliament and Council (2013). “Directive 2013/35/EU of 26 June 2013 on theminimum health and safety requirements regarding the exposure of workers to the risks arisingfrom physical agents (electromagnetic fields)”. In: L 179/1.EU (Ed.) Pp. 1–21 (cit. on p. 50).
Federau, C., S. Sumer, F. Becce, et al. (Aug. 2014). “Intravoxel incoherent motion perfusionimaging in acute stroke: initial clinical experience”. en. In: Neuroradiology 56.8, pp. 629–635.DOI: 10.1007/s00234-014-1370-y (cit. on p. 79).
Federau, Christian, Patric Hagmann, Philippe Maeder, et al. (Aug. 2013). “Dependence of BrainIntravoxel Incoherent Motion Perfusion Parameters on the Cardiac Cycle”. en. In: PLOS ONE8.8. Ed. by Jeroen Hendrikse, e72856. DOI: 10.1371/journal.pone.0072856 (cit. on pp. 77,200).
Federau, Christian, Kieran O’Brien, Adrien Birbaumer, et al. (Feb. 2015). “Functional Mappingof the Human Visual Cortex with Intravoxel Incoherent Motion MRI”. en. In: PLOS ONE 10.2,e0117706. DOI: 10.1371/journal.pone.0117706 (cit. on p. 78).
Fehlings, M. G. and G. Skaf (Dec. 1998). “A review of the pathophysiology of cervical spondyloticmyelopathy with insights for potential novel mechanisms drawn from traumatic spinal cordinjury”. eng. In: Spine 23.24, pp. 2730–2737 (cit. on pp. 90, 213, 214).
Fehlings, Michael G., Lindsay A. Tetreault, K. Daniel Riew, et al. (Sept. 2017). “A Clinical PracticeGuideline for the Management of Patients With Degenerative Cervical Myelopathy: Recommen-dations for Patients With Mild, Moderate, and Severe Disease and Nonmyelopathic PatientsWith Evidence of Cord Compression”. en. In: Global Spine Journal 7.3_suppl, 70S–83S. DOI:10.1177/2192568217701914 (cit. on p. 94).
Fehlings, Michael G., Jefferson R. Wilson, Spyridon K. Karadimas, Paul M. Arnold, and BrankoKopjar (Oct. 2013). “Clinical Evaluation of a Neuroprotective Drug in Patients With CervicalSpondylotic Myelopathy Undergoing Surgical Treatment: Design and Rationale for the CSM-Protect Trial”. en. In: Spine 38, S68–S75. DOI: 10.1097/BRS.0b013e3182a7e9b0 (cit. onp. 94).
Feinberg, David A. and Koichi Oshio (1991). “GRASE (gradient-and spin-echo) MR imaging: anew fast clinical imaging technique”. In: Radiology 181, pp. 597–602 (cit. on p. 73).
Fiford, Rodney J. and Lynne E. Bilston (July 2005). “The mechanical properties of rat spinal cordin vitro”. en. In: Journal of Biomechanics 38.7, pp. 1509–1515. DOI: 10.1016/j.jbiomech.
2004.07.009 (cit. on p. 104).
Figley, C.R. and P.W. Stroman (July 2007). “Investigation of human cervical and upper thoracicspinal cord motion: Implications for imaging spinal cord structure and function”. en. In:Magnetic Resonance in Medicine 58.1, pp. 185–189. DOI: 10.1002/mrm.21260 (cit. on p. 200).
Figley, C.R., D. Yau, and P.W. Stroman (Sept. 2008). “Attenuation of Lower-Thoracic, Lumbar,and Sacral Spinal Cord Motion: Implications for Imaging Human Spinal Cord Structure andFunction”. en. In: American Journal of Neuroradiology 29.8, pp. 1450–1454. DOI: 10.3174/
ajnr.A1154 (cit. on p. 200).
Finkenstaedt, Tim, Markus Klarhoefer, Christian Eberhardt, et al. (May 2017). “The IVIM signalin the healthy cerebral gray matter: A play of spherical and non-spherical components”. In:NeuroImage 152, pp. 340–347. DOI: 10.1016/j.neuroimage.2017.03.004 (cit. on p. 78).
Finsterbusch, Jürgen, Christian Sprenger, and Christian Büchel (Oct. 2013). “Combined T2*-weighted measurements of the human brain and cervical spinal cord with a dynamic shimupdate”. en. In: NeuroImage 79, pp. 153–161. DOI: 10.1016/j.neuroimage.2013.04.021
(cit. on p. 47).
Firooznia, Hossein, Jung H. Ahn, Mahvash Rafii, and Kristian T. Ragnarsson (Feb. 1985). “Suddenquadriplegia after a minor trauma. The role of preexisting spinal stenosis”. en. In: SurgicalNeurology 23.2, pp. 165–168. DOI: 10.1016/0090-3019(85)90337-4 (cit. on p. 90).
Fitzgerald, Ryan T., Vikas Agarwal, Jenny K. Hoang, et al. (May 2019). “The Impact of GadoliniumDeposition on Radiology Practice: An International Survey of Radiologists”. en. In: CurrentProblems in Diagnostic Radiology 48.3, pp. 220–223. DOI: 10.1067/j.cpradiol.2018.02.003
Fournely, Marion, Yvan Petit, Eric Wagnac, Morgane Evin, and Pierre-Jean Arnoux (May 2020).“Effect of experimental, morphological and mechanical factors on the murine spinal cordsubjected to transverse contusion: A finite element study”. en. In: PLOS ONE 15.5. Ed. byAlexander Rabchevsky, e0232975. DOI: 10.1371/journal.pone.0232975 (cit. on p. 214).
Fradet, Léo (2013). “Biomechanical study of vertebromedullar traumas of the human spine”.French. PhD thesis. Marseille-Montreal: Aix-Marseille Université & École de TechnologieSupérieure de Montréal (cit. on pp. 114, 116).
Fraum, Tyler J., Daniel R. Ludwig, Mustafa R. Bashir, and Kathryn J. Fowler (Aug. 2017).“Gadolinium-based contrast agents: A comprehensive risk assessment: Gadolinium Risk Assess-ment”. en. In: Journal of Magnetic Resonance Imaging 46.2, pp. 338–353. DOI: 10.1002/jmri.
25625 (cit. on p. 196).
Gaddikeri, S., R.S. Gaddikeri, T. Tailor, and Y. Anzai (Apr. 2016). “Dynamic Contrast-EnhancedMR Imaging in Head and Neck Cancer: Techniques and Clinical Applications”. en. In: AmericanJournal of Neuroradiology 37.4, pp. 588–595. DOI: 10.3174/ajnr.A4458 (cit. on p. 67).
Gailloud, P., A. Ponti, L. Gregg, C. A. Pardo, and J. H. D. Fasel (June 2014). “Focal Compression ofthe Upper Left Thoracic Intersegmental Arteries as a Potential Cause of Spinal Cord Ischemia”.en. In: American Journal of Neuroradiology 35.6, pp. 1226–1231. DOI: 10.3174/ajnr.A3833
(cit. on p. 18).
Gao, Qian-Qian, Shan-Shan Lu, Xiao-Quan Xu, et al. (Aug. 2017). “Quantitative assessment ofhyperacute cerebral infarction with intravoxel incoherent motion MR imaging: Initial experiencein a canine stroke model: IVIM of Hyperacute Stroke”. en. In: Journal of Magnetic ResonanceImaging 46.2, pp. 550–556. DOI: 10.1002/jmri.25556 (cit. on p. 78).
Gardener, Alexander G. and Peter Jezzard (June 2015). “Investigating white matter perfusionusing optimal sampling strategy arterial spin labeling at 7 Tesla: Measurement of WhiteMatter Perfusion at 7 Tesla”. en. In: Magnetic Resonance in Medicine 73.6, pp. 2243–2248. DOI:10.1002/mrm.25333 (cit. on p. 211).
Gelderen, P. van, J.A. de Zwart, P. Starewicz, R.S. Hinks, and J.H. Duyn (Feb. 2007). “Real-timeshimming to compensate for respiration-induced B0 fluctuations”. en. In: Magnetic Resonancein Medicine 57.2, pp. 362–368. DOI: 10.1002/mrm.21136 (cit. on pp. 47, 205).
Ghariq, Eidrees, Wouter M. Teeuwisse, Andrew G. Webb, and Matthias J. P. van Osch (Apr.2012). “Feasibility of pseudocontinuous arterial spin labeling at 7 T with whole-brain coverage”.en. In: Magnetic Resonance Materials in Physics, Biology and Medicine 25.2, pp. 83–93. DOI:10.1007/s10334-011-0297-0 (cit. on p. 211).
Girard, Olivier M., Virginie Callot, Benjamin Robert, Patrick J. Cozzone, and Guillaume Duhamel(2013). “Perfusion MRI of the Human Cervical Spinal Cord using Arterial Spin Labeling”. In:Proceedings of the 21st annual meeting of the International Society for Magnetic Resonance inMedicine. Salt Lake City, Utah, USA, p. 0349 (cit. on pp. 7, 79, 81, 211).
Gong, He, Ming Zhang, Ling Qin, and Yajun Hou (Aug. 2007). “Regional Variations in the Apparentand Tissue-Level Mechanical Parameters of Vertebral Trabecular Bone with Aging Using Micro-Finite Element Analysis”. en. In: Annals of Biomedical Engineering 35.9, pp. 1622–1631. DOI:10.1007/s10439-007-9332-8 (cit. on p. 108).
Goo, Hyun Woo and Young-Shin Ra (2017). “Advanced MRI for Pediatric Brain Tumors withEmphasis on Clinical Benefits”. en. In: Korean Journal of Radiology 18.1, p. 194. DOI: 10.3348/
kjr.2017.18.1.194 (cit. on p. 60).
Gooding, Michael R, Charles B. Wilson, and Julian T Hoff (1975). “Experimental cervical myelopa-thy: effects of ischemia and compression of the canine cervical spinal cord”. en. In: J Neurosurg.43, pp. 9–17 (cit. on pp. 7, 88, 90, 214).
Gooding, MR, CB Wilson, and JT Hoff (1976). “Experimental cervical myelopathy: autoradio-graphic studies of spinal cord blood flow patterns.” In: Surgical neurology 5.4, pp. 233–239(cit. on p. 87).
Gorter, K. (Sept. 1976). “Influence of laminectomy on the course of cervical myelopathy”. en. In:Acta Neurochirurgica 33.3-4, pp. 265–281. DOI: 10.1007/BF01886675 (cit. on p. 91).
Graaf, Robin A. de, Peter B. Brown, Scott McIntyre, et al. (Aug. 2006). “High magnetic field waterand metabolite protonT1 andT2 relaxation in rat brain in vivo”. en. In: Magnetic Resonance inMedicine 56.2, pp. 386–394. DOI: 10.1002/mrm.20946 (cit. on p. 42).
Grabher, Patrick, Siawoosh Mohammadi, Aaron Trachsler, et al. (July 2016). “Voxel-based analysisof grey and white matter degeneration in cervical spondylotic myelopathy”. en. In: ScientificReports 6.1, p. 24636. DOI: 10.1038/srep24636 (cit. on p. 97).
Greaves, Carolyn Y., Mohamed S. Gadala, and Thomas R. Oxland (Mar. 2008). “A Three-Dimensional Finite Element Model of the Cervical Spine with Spinal Cord: An Investigation ofThree Injury Mechanisms”. en. In: Annals of Biomedical Engineering 36.3, pp. 396–405. DOI:10.1007/s10439-008-9440-0 (cit. on p. 109).
Grech-Sollars, Matthew, Patrick W. Hales, Keiko Miyazaki, et al. (Apr. 2015). “Multi-centrereproducibility of diffusion MRI parameters for clinical sequences in the brain: Multi-centrereproducibility of diffusion MRI using clinical sequences”. en. In: NMR in Biomedicine 28.4,pp. 468–485. DOI: 10.1002/nbm.3269 (cit. on p. 78).
Griepp, Eva B, Gabriele Di Luozzo, Deborah Schray, Angelina Stefanovic, and Sarah Geisbüsch(2012). “The anatomy of the spinal cord collateral circulation”. en. In: Annals of cardiothoracicsurgery, p. 8 (cit. on p. 15).
Grist, Thomas M., Charles A. Mistretta, Charles M. Strother, and Patrick A. Turski (Dec. 2012).“Time-resolved angiography: Past, present, and future”. en. In: Journal of Magnetic ResonanceImaging 36.6, pp. 1273–1286. DOI: 10.1002/jmri.23646 (cit. on p. 235).
Griswold, Mark A., Peter M. Jakob, Robin M. Heidemann, et al. (June 2002). “Generalizedautocalibrating partially parallel acquisitions (GRAPPA)”. en. In: Magnetic Resonance in Medicine47.6, pp. 1202–1210. DOI: 10.1002/mrm.10171 (cit. on p. 33).
Grobner, T. and F.C. Prischl (Aug. 2007). “Gadolinium and nephrogenic systemic fibrosis”. en. In:Kidney International 72.3, pp. 260–264. DOI: 10.1038/sj.ki.5002338 (cit. on pp. 68, 197).
Guérin, Bastien, Jorge F. Villena, Athanasios G. Polimeridis, et al. (Nov. 2017). “The ultimate signal-to-noise ratio in realistic body models: The Ultimate Signal-to-Noise Ratio in Realistic BodyModels”. en. In: Magnetic Resonance in Medicine 78.5, pp. 1969–1980. DOI: 10.1002/mrm.26564
(cit. on pp. 40, 41).
Haacke, E. Mark, R. W. Brown, M. R. Thompson, and R. Venkatesan (1999). “Magnetic resonanceimaging: physical principles and sequence design”. In: New York: A John Wiley and Sons (cit. onpp. 25, 28, 32, 35).
Haacke, E. Mark, Yingbiao Xu, Yu-Chung N. Cheng, and Jürgen R. Reichenbach (Sept. 2004).“Susceptibility weighted imaging (SWI)”. en. In: Magnetic Resonance in Medicine 52.3, pp. 612–618. DOI: 10.1002/mrm.20198 (cit. on p. 43).
Hahn, E. L. (Nov. 1950). “Spin Echoes”. In: Physical Review 80.4. Publisher: American PhysicalSociety, pp. 580–594. DOI: 10.1103/PhysRev.80.580 (cit. on p. 26).
Haroon, H A, T F Patankar, X P Zhu, et al. (Mar. 2007). “Comparison of cerebral blood volumemaps generated from T 2 * and T 1 weighted MRI data in intra-axial cerebral tumours”. en. In:The British Journal of Radiology 80.951, pp. 161–168. DOI: 10.1259/bjr/17112059 (cit. onp. 67).
Hayashi, Tetsuo, Jeffrey C Wang, Akinobu Suzuki, et al. (2014). “Risk factors for missed dynamiccanal stenosis in the cervical spine”. In: Spine 39.10. Publisher: LWW, pp. 812–819 (cit. onp. 89).
Heilmaier, Christina, Jens M. Theysohn, Stefan Maderwald, et al. (Dec. 2011). “A large-scalestudy on subjective perception of discomfort during 7 and 1.5 T MRI examinations”. en. In:Bioelectromagnetics 32.8, pp. 610–619. DOI: 10.1002/bem.20680 (cit. on p. 49).
Helenius, J., J. Perkiö, L. Soinne, et al. (Sept. 2003). “Cerebral hemodynamics in a healthypopulation measured by dynamic susceptibility contrast MR imaging”. en. In: Acta Radiologica44.5, pp. 538–546. DOI: 10.1080/j.1600-0455.2003.00104.x (cit. on p. 63).
Hennig, J (July 1988). “Multiecho imaging sequences with low refocusing flip angles”. en. In:Journal of Magnetic Resonance (1969) 78.3, pp. 397–407. DOI: 10.1016/0022-2364(88)90128-
X (cit. on p. 73).
Hennig, J., A. Nauerth, and H. Friedburg (Dec. 1986). “RARE imaging: A fast imaging methodfor clinical MR”. en. In: Magnetic Resonance in Medicine 3.6, pp. 823–833. DOI: 10.1002/mrm.
1910030602 (cit. on p. 73).
Henning, A., W. Koning, A. Fuchs, et al. (Sept. 2016). “1 H MRS in the human spinal cord at 7 Tusing a dielectric waveguide transmitter, RF shimming and a high density receive array: SpinalCord MRS 7 T”. en. In: NMR in Biomedicine 29.9, pp. 1231–1239. DOI: 10.1002/nbm.3541
Hetzer, Stefan, Patric Birr, Andreas Fehlner, et al. (Jan. 2018). “Perfusion alters stiffness of deepgray matter”. en. In: Journal of Cerebral Blood Flow & Metabolism 38.1, pp. 116–125. DOI:10.1177/0271678X17691530 (cit. on pp. 108, 113).
Hoff, Julian, Merry Nishimura, Lawrence Pitts, et al. (1977). “The role of ischemia in the patho-genesis of cervical spondylotic myelopathy: A review and new microangiographic evidence”. In:Spine 2.2. Publisher: LWW, pp. 100–108 (cit. on p. 87).
Holly, Langston T., Bonnie Freitas, David L. McArthur, and Noriko Salamon (Mar. 2009). “Protonmagnetic resonance spectroscopy to evaluate spinal cord axonal injury in cervical spondyloticmyelopathy: Laboratory investigation”. en. In: Journal of Neurosurgery: Spine 10.3, pp. 194–200.DOI: 10.3171/2008.12.SPINE08367 (cit. on p. 97).
Holly, Langston T and Jonathan Marehbian (2007). “Cortical reorganization in patients withcervical spondylotic myelopathy”. en. In: J. Neurosurg 6, p. 8 (cit. on p. 216).
Hoult, D. I. and Paul C. Lauterbur (1979). “The sensitivity of the zeugmatographic experimentinvolving human samples”. In: Journal of Magnetic Resonance (1969) 34.2, pp. 425 –433. DOI:https://doi.org/10.1016/0022-2364(79)90019-2 (cit. on p. 39).
Hu, L. S., J. M. Eschbacher, J. E. Heiserman, et al. (July 2012). “Reevaluating the imagingdefinition of tumor progression: perfusion MRI quantifies recurrent glioblastoma tumor fraction,pseudoprogression, and radiation necrosis to predict survival”. en. In: Neuro-Oncology 14.7,pp. 919–930. DOI: 10.1093/neuonc/nos112 (cit. on p. 65).
Hu, Xiaoping, Tuong Huu Le, Todd Parrish, and Peter Erhard (Aug. 1995). “Retrospective estima-tion and correction of physiological fluctuation in functional MRI”. en. In: Magnetic Resonancein Medicine 34.2, pp. 201–212. DOI: 10.1002/mrm.1910340211 (cit. on p. 45).
Hu, Yu-Chuan, Lin-Feng Yan, Yu Han, et al. (Dec. 2020). “Can the low and high b-value distributioninfluence the pseudodiffusion parameter derived from IVIM DWI in normal brain?” en. In: BMCMedical Imaging 20.1, p. 14. DOI: 10.1186/s12880-020-0419-0 (cit. on p. 77).
Hughes, JT (1978). “Disorders of the spine”. In: Pathology of the spinal cord. Vol. 6. London: WBSaunders, pp. 166–76 (cit. on p. 87).
Hung, Tin-Kan and Guan-Liang Chang (Feb. 1981a). “Biomechanical and Neurological Responseof the Spinal Cord of a Puppy to Uniaxial Tension”. en. In: Journal of Biomechanical Engineering103.1, pp. 43–47. DOI: 10.1115/1.3138244 (cit. on p. 104).
Hung, Tin-Kan, Guan-Liang Chang, Hsin-Sun Lin, Frank R. Walter, and Leon Bunegin (Jan.1981b). “Stress-strain relationship of the spinal cord of anesthetized cats”. en. In: Journal ofBiomechanics 14.4, pp. 269–276. DOI: 10.1016/0021-9290(81)90072-5 (cit. on p. 104).
Hung, Tin-Kan, Hsin-Sun Lin, Leonid Bunegin, and Maurice S. Albin (Mar. 1982). “Mechanicaland neurological response of cat spinal cord under static loading”. In: Surgical Neurology 17.3,pp. 213–217. DOI: 10.1016/0090-3019(82)90284-1 (cit. on pp. 104, 105).
Hung, TK, GL Chang, JL Chang, and MS Albin (June 1981c). “Stress-strain relationship andneurological sequelae of uniaxial elongation of the spinal cord of cats”. eng. In: Surgicalneurology 15.6, pp. 471–476. DOI: 10.1016/s0090-3019(81)80043-2 (cit. on p. 104).
Iatridis, James C, Mark Weidenbaum, Lori A Setton, and Van C Mow (1996). “Is the nucleuspulposus a solid or a fluid? Mechanical behaviors of the nucleus pulposus of the humanintervertebral disc”. In: Spine 21.10. Publisher: LWW, pp. 1174–1184 (cit. on p. 107).
Ichihara, Kazuhiko, Toshihiko Taguchi, Itsuo Sakuramoto, Shunichi Kawano, and Shinya Kawai(2003). “Mechanism of the spinal cord injury and the cervical spondylotic myelopathy: newapproach based on the mechanical features of the spinal cord white and gray matter”. In:Journal of Neurosurgery: Spine 99.3. Publisher: Journal of Neurosurgery Publishing Group(cit. on pp. 105, 109, 214).
Ichihara, Kazuhiko, Toshihiko Taguchi, Yoshinori Shimada, et al. (2001). “Gray matter of thebovine cervical spinal cord is mechanically more rigid and fragile than the white matter”. In:Journal of neurotrauma 18.3, pp. 361–367 (cit. on pp. 105, 109, 214).
International Electrotechnical Commission (2015). “Part 2-33: Particular requirements for thesafety of magnetic resonance diagnostic devices”. In: Medical electrical equipment. Edition 3.2.IEC (Ed.), pp. 60601–2–33 (cit. on p. 48).
Irwan, Roy, Daniël D. Lubbers, Pieter A. van der Vleuten, et al. (June 2007). “Parallel imaging forfirst-pass myocardial perfusion”. en. In: Magnetic Resonance Imaging 25.5, pp. 678–683. DOI:10.1016/j.mri.2006.10.012 (cit. on p. 206).
Ito, Hiroshi, Iwao Kanno, Chietsugu Kato, et al. (2004). “Database of normal human cerebralblood flow, cerebral blood volume, cerebral oxygen extraction fraction and cerebral metabolicrate of oxygen measured by positron emission tomography with 15 O-labelled carbon dioxideor water, carbon monoxide and oxygen: a multicentre study in Japan”. In: European journal ofnuclear medicine and molecular imaging 31.5. Publisher: Springer, pp. 635–643 (cit. on p. 68).
Jannesar, Shervin, Mark Allen, Sarah Mills, et al. (July 2018). “Compressive mechanical char-acterization of non-human primate spinal cord white matter”. en. In: Acta Biomaterialia 74,pp. 260–269. DOI: 10.1016/j.actbio.2018.05.002 (cit. on p. 105).
Jellison, Brian J., Aaron S. Field, Joshua Medow, et al. (Mar. 2004). “Diffusion Tensor Imaging ofCerebral White Matter: A Pictorial Review of Physics, Fiber Tract Anatomy, and Tumor ImagingPatterns”. en. In: American Journal of Neuroradiology 25.3, pp. 356–369 (cit. on p. 75).
Jiang, Sheng-Dan, Lei-Sheng Jiang, and Li-Yang Dai (June 2011). “Degenerative cervical spondy-lolisthesis: a systematic review”. en. In: International Orthopaedics 35.6, pp. 869–875. DOI:10.1007/s00264-010-1203-5 (cit. on p. 90).
Johnson, John Bertrand (1928). “Thermal agitation of electricity in conductors”. In: Physicalreview 32.1. Publisher: APS, p. 97 (cit. on p. 39).
Juchem, Christoph, Terence W. Nixon, Piotr Diduch, et al. (July 2010). “Dynamic shimming ofthe human brain at 7 T”. en. In: Concepts in Magnetic Resonance Part B: Magnetic ResonanceEngineering 37B.3, pp. 116–128. DOI: 10.1002/cmr.b.20169 (cit. on p. 47).
Juchem, Christoph, Terence W. Nixon, Scott McIntyre, et al. (Oct. 2011). “Dynamic multi-coilshimming of the human brain at 7T”. en. In: Journal of Magnetic Resonance 212.2, pp. 280–288.DOI: 10.1016/j.jmr.2011.07.005 (cit. on p. 47).
Kafali, Sevgi Gokce, Tolga Çukur, and Emine Ulku Saritas (Sept. 2018). “Phase-correcting non-local means filtering for diffusion-weighted imaging of the spinal cord”. In: Magnetic Resonancein Medicine 80.3. Publisher: John Wiley & Sons, Ltd, pp. 1020–1035. DOI: 10.1002/mrm.27105
(cit. on p. 207).
Kalavagunta, C and G J Metzger (2010). “A field comparison of r1 and r2* relaxivities of Gd-DTPAin aqueous solution and whole blood: 3T versus 7T”. en. In: Proc. Intl. Soc. Mag. Reson. Med.18. Stockholm, Sweden, p. 4990 (cit. on p. 60).
Kalavagunta, Chaitanya, Shalom Michaeli, and Gregory J. Metzger (Mar. 2014). “In vitro Gd-DTPArelaxometry studies in oxygenated venous human blood and aqueous solution at 3 and 7 T:IN VITRO 3-7 T Gd-DTPA RELAXOMETRY IN BLOOD AND WATER”. en. In: Contrast Media &Molecular Imaging 9.2, pp. 169–176. DOI: 10.1002/cmmi.1568 (cit. on pp. 58, 60).
Kalsi-Ryan, Sukhvinder, Spyridon K. Karadimas, and Michael G. Fehlings (Nov. 2012). “CervicalSpondylotic Myelopathy: The Clinical Phenomenon and the Current Pathobiology of an In-creasingly Prevalent and Devastating Disorder”. In: The Neuroscientist 19.4. Publisher: SAGEPublications Inc STM, pp. 409–421. DOI: 10.1177/1073858412467377 (cit. on pp. 87–89, 92,210).
Kameyama, Takashi, Yoshio Hashizume, and Gen Sobue (1996). “Morphologic features of thenormal human cadaveric spinal cord”. In: Spine 21.11. Publisher: LWW, pp. 1285–1290 (cit. onp. 114).
Kanda, Tomonori, Toshio Fukusato, Megumi Matsuda, et al. (July 2015). “Gadolinium-basedContrast Agent Accumulates in the Brain Even in Subjects without Severe Renal Dysfunction:Evaluation of Autopsy Brain Specimens with Inductively Coupled Plasma Mass Spectroscopy”.en. In: Radiology 276.1, pp. 228–232. DOI: 10.1148/radiol.2015142690 (cit. on p. 197).
Karadimas, Spyridon, Eun Su Moon, and Michael G Fehlings (2012). “The Sodium Channel/Gluata-mate Blocker Riluzole is Complementary to Decompression in a Preclinical Experimental Modelof Cervical Spondylotic Myelopathy (CSM) Implications for Translational Clinical Application”.In: Neurosurgery 71.2. Publisher: Oxford University Press, E543–E543 (cit. on p. 94).
Karadimas, Spyridon K., Georgios Gatzounis, and Michael G. Fehlings (Apr. 2015). “Pathobiologyof cervical spondylotic myelopathy”. en. In: European Spine Journal 24.S2, pp. 132–138. DOI:10.1007/s00586-014-3264-4 (cit. on p. 89).
Karadimas, Spyridon K., Eun Su Moon, Wen-Ru Yu, et al. (June 2013). “A novel experimentalmodel of cervical spondylotic myelopathy (CSM) to facilitate translational research”. en. In:Neurobiology of Disease 54, pp. 43–58. DOI: 10.1016/j.nbd.2013.02.013 (cit. on pp. 87, 89).
Karimi, Alireza, Ahmad Shojaei, and Pedram Tehrani (Dec. 2017). “Mechanical properties of thehuman spinal cord under the compressive loading”. en. In: Journal of Chemical Neuroanatomy86, pp. 15–18. DOI: 10.1016/j.jchemneu.2017.07.004 (cit. on p. 105).
Kato, Yoshihiko, Tsukasa Kanchiku, Yasuaki Imajo, et al. (Mar. 2010). “Biomechanical study ofthe effect of degree of static compression of the spinal cord in ossification of the posteriorlongitudinal ligament”. en. In: Journal of Neurosurgery: Spine 12.3, pp. 301–305. DOI: 10.3171/
2009.9.SPINE09314 (cit. on pp. 110, 111, 212).
Kato, Yoshihiko, Hideo Kataoka, Kazuhiko Ichihara, et al. (May 2008). “Biomechanical study ofcervical flexion myelopathy using a three-dimensional finite element method”. en. In: Journalof Neurosurgery: Spine 8.5, pp. 436–441. DOI: 10.3171/SPI/2008/8/5/436 (cit. on pp. 109,110).
Katscher, Ulrich and Peter Börnert (May 2006). “Parallel RF transmission in MRI”. en. In: NMR inBiomedicine 19.3, pp. 393–400. DOI: 10.1002/nbm.1049 (cit. on p. 49).
Katscher, Ulrich, Peter Börnert, Christoph Leussler, and Johan S. van den Brink (Jan. 2003).“Transmit SENSE: Transmit SENSE”. en. In: Magnetic Resonance in Medicine 49.1, pp. 144–150.DOI: 10.1002/mrm.10353 (cit. on p. 49).
Kavec, Martin, Jussi-Pekka Usenius, Pasi I. Tuunanen, Aimo Rissanen, and Risto A. Kauppinen(May 2004). “Assessment of cerebral hemodynamics and oxygen extraction using dynamicsusceptibility contrast and spin echo blood oxygenation level-dependent magnetic resonanceimaging: applications to carotid stenosis patients”. en. In: NeuroImage 22.1, pp. 258–267. DOI:10.1016/j.neuroimage.2004.01.009 (cit. on p. 66).
Keltner, John R., Mark S. Roos, Paul R. Brakeman, and Thomas F. Budinger (Oct. 1990). “Mag-netohydrodynamics of blood flow”. en. In: Magnetic Resonance in Medicine 16.1, pp. 139–149.DOI: 10.1002/mrm.1910160113 (cit. on pp. 49, 199).
Khuyagbaatar, Batbayar, Kyungsoo Kim, and Yoon Hyuk Kim (Aug. 2014). “Effect of bone fragmentimpact velocity on biomechanical parameters related to spinal cord injury: A finite elementstudy”. en. In: Journal of Biomechanics 47.11, pp. 2820–2825. DOI: 10.1016/j.jbiomech.
2014.04.042 (cit. on p. 109).
Khuyagbaatar, Batbayar, Kyungsoo Kim, Won Man Park, and Yoon Hyuk Kim (Dec. 2015). “Influ-ence of sagittal and axial types of ossification of posterior longitudinal ligament on mechanicalstress in cervical spinal cord: A finite element analysis”. en. In: Clinical Biomechanics 30.10,pp. 1133–1139. DOI: 10.1016/j.clinbiomech.2015.08.013 (cit. on pp. 111, 112, 117, 212,213).
Kiely, Paul D., John C. Quinn, Jerry Y. Du, and Darren R. Lebl (Feb. 2015). “Posterior SurgicalTreatment of Cervical Spondylotic Myelopathy: Review Article”. en. In: HSS Journal ® 11.1,pp. 36–42. DOI: 10.1007/s11420-014-9425-5 (cit. on p. 94).
Kim, Yoon Hyuk, Batbayar Khuyagbaatar, and Kyungsoo Kim (Sept. 2013). “Biomechanicaleffects of spinal cord compression due to ossification of posterior longitudinal ligament andligamentum flavum: A finite element analysis”. en. In: Medical Engineering & Physics 35.9,pp. 1266–1271. DOI: 10.1016/j.medengphy.2013.01.006 (cit. on pp. 110, 117, 212).
King, M. D., N. Van Bruggen, A. L. Busza, et al. (Apr. 1992). “Perfusion and diffusion MR imaging”.fr. In: Magnetic Resonance in Medicine 24.2, pp. 288–301. DOI: 10.1002/mrm.1910240210
(cit. on p. 77).
Kogan, Feliks, Anup Singh, Catherine Debrosse, et al. (Aug. 2013). “Imaging of glutamate in thespinal cord using GluCEST”. en. In: NeuroImage 77, pp. 262–267. DOI: 10.1016/j.neuroimage.
2013.03.072 (cit. on pp. 53, 55).
Korosec, Frank R., Richard Frayne, Thomas M. Grist, and Charles A. Mistretta (Sept. 1996).“Time-resolved contrast-enhanced 3D MR angiography”. en. In: Magnetic Resonance in Medicine36.3, pp. 345–351. DOI: 10.1002/mrm.1910360304 (cit. on p. 236).
Koser, David E., Emad Moeendarbary, Janina Hanne, Stefanie Kuerten, and Kristian Franze (May2015). “CNS Cell Distribution and Axon Orientation Determine Local Spinal Cord MechanicalProperties”. en. In: Biophysical Journal 108.9, pp. 2137–2147. DOI: 10.1016/j.bpj.2015.03.
039 (cit. on pp. 105, 106).
Koshimoto, Yoshio, Hiroki Yamada, Hirohiko Kimura, et al. (Mar. 1999). “Quantitative analysis ofcerebral microvascular hemodynamics with T2-weighted dynamic MR imaging”. In: Journalof Magnetic Resonance Imaging 9.3. Publisher: John Wiley & Sons, Ltd, pp. 462–467. DOI:10.1002/(SICI)1522-2586(199903)9:3<462::AID-JMRI15>3.0.CO;2-D (cit. on p. 63).
Krug, Johannes W, Georg Rose, Gari D Clifford, and Julien Oster (Dec. 2013). “ECG-basedgating in ultra high field cardiovascular magnetic resonance using an independent componentanalysis approach”. en. In: Journal of Cardiovascular Magnetic Resonance 15.1, p. 104. DOI:10.1186/1532-429X-15-104 (cit. on p. 199).
Kruse, S.A., A. Kolipaka, A. Manduca, and R.L. Ehman (2009). “Feasibility of Evaluating the SpinalCord with MR Elastography”. In: Proc. Intl. Soc. Mag. Reson. Med. 17. Honolulu, Hawai, USA,p. 0629 (cit. on pp. 108, 219).
Lad, Shivanand P., Chirag G. Patil, Scott Berta, et al. (Jan. 2009). “National trends in spinalfusion for cervical spondylotic myelopathy”. en. In: Surgical Neurology 71.1, pp. 66–69. DOI:10.1016/j.surneu.2008.02.045 (cit. on p. 95).
Ladd, Mark E., Peter Bachert, Martin Meyerspeer, et al. (Dec. 2018). “Pros and cons of ultra-high-field MRI/MRS for human application”. en. In: Progress in Nuclear Magnetic ResonanceSpectroscopy 109, pp. 1–50. DOI: 10.1016/j.pnmrs.2018.06.001 (cit. on pp. 38, 40).
Lammertsma, Adriaan A. and Terry Jones (Dec. 1983). “Correction for the Presence of Intravascu-lar Oxygen-15 in the Steady-State Technique for Measuring Regional Oxygen Extraction Ratioin the Brain: 1. Description of the Method”. en. In: Journal of Cerebral Blood Flow & Metabolism3.4, pp. 416–424. DOI: 10.1038/jcbfm.1983.67 (cit. on p. 68).
Lancellotti, Patrizio, Alain Nchimi, Céline Delierneux, et al. (Sept. 2015). “Biological Effectsof Cardiac Magnetic Resonance on Human Blood Cells”. en. In: Circulation: CardiovascularImaging 8.9. DOI: 10.1161/CIRCIMAGING.115.003697 (cit. on p. 50).
Larsson, Henrik B. W., Frédéric Courivaud, Egill Rostrup, and Adam E. Hansen (Nov. 2009).“Measurement of brain perfusion, blood volume, and blood-brain barrier permeability, usingdynamic contrast-enhanced T 1 -weighted MRI at 3 tesla”. en. In: Magnetic Resonance in Medicine62.5, pp. 1270–1281. DOI: 10.1002/mrm.22136 (cit. on p. 68).
Le Bihan, D, E Breton, D Lallemand, et al. (Aug. 1988). “Separation of diffusion and perfusionin intravoxel incoherent motion MR imaging.” en. In: Radiology 168.2, pp. 497–505. DOI:10.1148/radiology.168.2.3393671 (cit. on p. 76).
Leahy, J. C. and D. W. L. Hukins (Aug. 2001). “Viscoelastic properties of the nucleus pulposus ofthe intervertebral disk in compression”. In: Journal of Materials Science: Materials in Medicine12.8, pp. 689–692. DOI: 10.1023/A:1011212425029 (cit. on p. 107).
Lee, Gary, Caroline Jordan, Pamela Tiet, et al. (Mar. 2015). “Improved frequency selective fatsuppression in the posterior neck with tissue susceptibility matched pyrolytic graphite foam: PGFoam for Frequency Selective Fat Suppression”. en. In: Journal of Magnetic Resonance Imaging41.3, pp. 684–693. DOI: 10.1002/jmri.24581 (cit. on p. 47).
Lefranc, M., M. Lefranc, P. Monet, et al. (2012). “Perfusion MRI as a Neurosurgical Tool forImproved Targeting in Stereotactic Tumor Biopsies”. In: Stereotactic and Functional Neurosurgery90.4, pp. 240–247. DOI: 10.1159/000338092 (cit. on p. 65).
Leiner, Tim, Jesse Habets, Bastiaan Versluis, et al. (Aug. 2013). “Subtractionless first-pass singlecontrast medium dose peripheral MR angiography using two-point Dixon fat suppression”.en. In: European Radiology 23.8, pp. 2228–2235. DOI: 10.1007/s00330-013-2833-y (cit. onp. 234).
Levine, D N (Apr. 1997). “Pathogenesis of cervical spondylotic myelopathy.” en. In: Journal ofNeurology, Neurosurgery & Psychiatry 62.4, pp. 334–340. DOI: 10.1136/jnnp.62.4.334 (cit. onpp. 7, 109).
Levitt, Malcolm H (2001). Spin dynamics: basics of nuclear magnetic resonance. John Wiley & Sons(cit. on pp. 20, 21, 23, 25, 28).
Li, G. L., M. Farooque, A. Holtz, and Y. Olsson (June 1996). “Increased expression of growth-associated protein 43 immunoreactivity in axons following compression trauma to rat spinalcord”. en. In: Acta Neuropathologica 92.1, pp. 19–26. DOI: 10.1007/s004010050484 (cit. onp. 91).
Li, Xin-Feng and Li-Yang Dai (May 2009). “Three-Dimensional Finite Element Model of theCervical Spinal Cord: Preliminary Results of Injury Mechanism Analysis”. en. In: Spine 34.11,pp. 1140–1147. DOI: 10.1097/BRS.0b013e31819e2af1 (cit. on p. 109).
Lopez Rios, Nibardo, Ryan Topfer, Alexandru Foias, et al. (2019). “Integrated AC/DC coil anddipole Tx array for 7T MRI of the spinal cord”. In: Proc. Intl. Soc. Mag. Reson. Med. 27. Montreal,QC, Canada, p. 0220 (cit. on pp. 51, 53, 200).
Lorenz, Cory, Thomas Benner, Poe Jou Chen, et al. (Nov. 2006). “Automated perfusion-weightedMRI using localized arterial input functions”. en. In: Journal of Magnetic Resonance Imaging24.5, pp. 1133–1139. DOI: 10.1002/jmri.20717 (cit. on p. 62).
Lu, Hanzhang, Xavier Golay, James J. Pekar, and Peter C.M. van Zijl (Aug. 2003). “Functionalmagnetic resonance imaging based on changes in vascular space occupancy”. en. In: MagneticResonance in Medicine 50.2, pp. 263–274. DOI: 10.1002/mrm.10519 (cit. on p. 237).
Lu, Hanzhang, Meng Law, Yulin Ge, et al. (Apr. 2008). “Quantitative measurement of spinal cordblood volume in humans using vascular-space-occupancy MRI”. en. In: NMR in Biomedicine21.3, pp. 226–232. DOI: 10.1002/nbm.1185 (cit. on p. 82).
Lu, Hanzhang, Meng Law, Glyn Johnson, et al. (Dec. 2005). “Novel approach to the measurementof absolute cerebral blood volume using vascular-space-occupancy magnetic resonance imag-ing”. en. In: Magnetic Resonance in Medicine 54.6, pp. 1403–1411. DOI: 10.1002/mrm.20705
(cit. on pp. 237, 238).
Luciani, Alain, Alexandre Vignaud, Madeleine Cavet, et al. (Dec. 2008). “Liver Cirrhosis: IntravoxelIncoherent Motion MR Imaging—Pilot Study”. en. In: Radiology 249.3, pp. 891–899. DOI:10.1148/radiol.2493080080 (cit. on p. 78).
Lunsford, L Dade (1980). “Anterior surgery for cervical disc disease”. en. In: J. Neurosurg. 53, p. 8(cit. on p. 91).
Lévy, S., M. Benhamou, C. Naaman, et al. (2015). “White matter atlas of the human spinal cordwith estimation of partial volume effect”. In: NeuroImage 119, pp. 262–271. DOI: 10.1016/j.
neuroimage.2015.06.040 (cit. on p. 114).
Lévy, Simon, Pierre-Hugues Roche, and Virginie Callot (2019). “Dynamic Susceptibility Contrastimaging at 7T for spinal cord perfusion mapping in Cervical Spondylotic Myelopathy patients”.In: Proc. Int. Soc. Magn. Reson. Med. 28. Virtual Meeting, p. 3195 (cit. on p. 198).
Maleki, Nasim, Weiying Dai, and David C. Alsop (Apr. 2012). “Optimization of backgroundsuppression for arterial spin labeling perfusion imaging”. en. In: Magnetic Resonance Materialsin Physics, Biology and Medicine 25.2, pp. 127–133. DOI: 10.1007/s10334-011-0286-3 (cit. onp. 73).
Marchal, G, J Michiels, H Bosmans, and P Van Hecke (1992). “Contrast-enhanced MRA of thebrain”. eng. In: Journal of computer assisted tomography 16.1, pp. 25–29. DOI: 10.1097/
00004728-199201000-00005 (cit. on p. 56).
Martin, Allan R., Benjamin De Leener, Julien Cohen-Adad, et al. (Apr. 2018). “Monitoring formyelopathic progression with multiparametric quantitative MRI”. en. In: PLOS ONE 13.4. Ed. byMathias Toft, e0195733. DOI: 10.1371/journal.pone.0195733 (cit. on pp. 97, 219).
Martini, Frederic H., William C. Ober, and Judi L. Nath (May 2011). Visual Anatomy & Physiology.English. 1st edition. San Francisco: Pearson (cit. on p. 12).
Massire, Aurélien, Henitsoa Rasoanandrianina, Maxime Guye, and Virginie Callot (Jan. 2020).“Anterior fissure, central canal, posterior septum and more: New insights into the cervical spinalcord gray and white matter regional organization using T1 mapping at 7T”. en. In: NeuroImage205, p. 116275. DOI: 10.1016/j.neuroimage.2019.116275 (cit. on p. 52).
Massire, Aurélien, Henitsoa Rasoanandrianina, Manuel Taso, et al. (Sept. 2018). “Feasibility ofsingle-shot multi-level multi-angle diffusion tensor imaging of the human cervical spinal cordat 7T”. en. In: Magnetic Resonance in Medicine 80.3, pp. 947–957. DOI: 10.1002/mrm.27087
(cit. on pp. 51, 52, 55).
Massire, Aurélien, Manuel Taso, Pierre Besson, et al. (Dec. 2016). “High-resolution multi-parametric quantitative magnetic resonance imaging of the human cervical spinal cord at7T”. In: NeuroImage 143, pp. 58–69. DOI: 10.1016/j.neuroimage.2016.08.055 (cit. onpp. 51–53, 55, 210, 219).
Matsumoto, Morio, Yoshikazu Fujimura, Nobumasa Suzuki, et al. (1998). “MRI of cervical inter-vertebral discs in asymptomatic subjects”. en. In: The Journal of Bone and Joint Surgery 80.1,p. 6 (cit. on p. 95).
Matsunaga, Shunji, Makoto Kukita, Kyoji Hayashi, et al. (2002). “Pathogenesis of myelopathy inpatients with ossification of the posterior longitudinal ligament”. In: Journal of Neurosurgery:Spine 96.2. Publisher: Journal of Neurosurgery Publishing Group, pp. 168–172 (cit. on p. 89).
Mazuchowski, Edward L and Lawrence E Thibault (2003). “Biomechanical properties of thehuman spinal cord and pia mater”. In: (cit. on p. 106).
McGibney, G., M. R. Smith, S. T. Nichols, and A. Crawley (July 1993). “Quantitative evaluation ofseveral partial fourier reconstruction algorithms used in mri”. en. In: Magnetic Resonance inMedicine 30.1, pp. 51–59. DOI: 10.1002/mrm.1910300109 (cit. on p. 33).
Mian, Omar S., Yan Li, Andre Antunes, Paul M. Glover, and Brian L. Day (Feb. 2016). “Effect ofhead pitch and roll orientations on magnetically induced vertigo: Magnetically induced vertigo”.en. In: The Journal of Physiology 594.4, pp. 1051–1067. DOI: 10.1113/JP271513 (cit. on p. 49).
Milani, Bastien, Jean-Baptiste Ledoux, David C. Rotzinger, et al. (Jan. 2019). “Image acquisitionfor intravoxel incoherent motion imaging of kidneys should be triggered at the instant ofmaximum blood velocity: evidence obtained with simulations and in vivo experiments”. en. In:Magnetic Resonance in Medicine 81.1, pp. 583–593. DOI: 10.1002/mrm.27393 (cit. on pp. 77,200).
Miller, D L (Jan. 1993). “Direct origin of the artery of the cervical enlargement from the leftsubclavian artery.” In: American Journal of Neuroradiology 14.1, p. 242 (cit. on p. 17).
Miyazaki, Mitsue and Masaaki Akahane (Jan. 2012). “Non-contrast enhanced MR angiography:Established techniques”. en. In: Journal of Magnetic Resonance Imaging 35.1, pp. 1–19. DOI:10.1002/jmri.22789 (cit. on p. 56).
Morishita, Yuichiro, Shinichi Hida, Masatoshi Naito, and Ushio Matsushima (Dec. 2005). “Eval-uation of cervical spondylotic myelopathy using somatosensory-evoked potentials”. en. In:International Orthopaedics 29.6, pp. 343–346. DOI: 10.1007/s00264-005-0002-x (cit. onp. 96).
Murone, Ikuo (1974). “The importance of the sagittal diameters of the cervical spinal canal inrelation to spondylosis and myelopathy”. In: The Journal of bone and joint surgery. Britishvolume 56.1. Publisher: The British Editorial Society of Bone and Joint Surgery, pp. 30–36(cit. on p. 216).
Muthupillai, R, D. Lomas, P. Rossman, et al. (Sept. 1995). “Magnetic resonance elastography bydirect visualization of propagating acoustic strain waves”. en. In: Science 269.5232, pp. 1854–1857. DOI: 10.1126/science.7569924 (cit. on p. 108).
Nael, K., B. Mossadeghi, T. Boutelier, et al. (Apr. 2015). “Bayesian Estimation of Cerebral PerfusionUsing Reduced-Contrast-Dose Dynamic Susceptibility Contrast Perfusion at 3T”. en. In: AmericanJournal of Neuroradiology 36.4, pp. 710–718. DOI: 10.3174/ajnr.A4184 (cit. on p. 68).
Nair, G. and X. P. Hu (2010). “Perfusion Imaging of the Human Cervical Spinal Cord”. In:Proceedings of the 19th annual meeting of the International Society for Magnetic Resonance inMedicine. Stockholm, Sweden, p. 4083 (cit. on pp. 7, 79, 81, 211).
New, P W, R A Cripps, and B Bonne Lee (Feb. 2014). “Global maps of non-traumatic spinal cordinjury epidemiology: towards a living data repository”. en. In: Spinal Cord 52.2, pp. 97–109.DOI: 10.1038/sc.2012.165 (cit. on p. 95).
Newbould, Rexford D., Stefan T. Skare, Thies H. Jochimsen, et al. (July 2007). “Perfusion mappingwith multiecho multishot parallel imaging EPI”. en. In: Magnetic Resonance in Medicine 58.1,pp. 70–81. DOI: 10.1002/mrm.21255 (cit. on p. 64).
Nicotra, Alessia, Nicolas K. K. King, Maria Catley, et al. (Jan. 2013). “Evaluation of corticospinalexcitability in cervical myelopathy, before and after surgery, with transcranial magnetic stimula-tion: a pilot study”. en. In: European Spine Journal 22.1, pp. 189–196. DOI: 10.1007/s00586-
012-2554-y (cit. on p. 97).
Nir, Talia M., Neda Jahanshad, Julio E. Villalon-Reina, et al. (2013). “Effectiveness of regional DTImeasures in distinguishing Alzheimer’s disease, MCI, and normal aging”. en. In: NeuroImage:Clinical 3, pp. 180–195. DOI: 10.1016/j.nicl.2013.07.006 (cit. on p. 76).
Nishida, Norihiro, Fei Jiang, Junji Ohgi, et al. (2020). “Compression analysis of the gray andwhite matter of the spinal cord”. en. In: Neural Regeneration Research 15.7, p. 1344. DOI:10.4103/1673-5374.272604 (cit. on p. 105).
Nishida, Norihiro, Tsukasa Kanchiku, Yasuaki Imajo, et al. (May 2016). “Stress analysis of thecervical spinal cord: Impact of the morphology of spinal cord segments on stress”. en. In: TheJournal of Spinal Cord Medicine 39.3, pp. 327–334. DOI: 10.1179/2045772315Y.0000000012
Nishida, Norihiro, Tsukasa Kanchiku, Yoshihiko Kato, et al. (Sept. 2015a). “Cervical ossificationof the posterior longitudinal ligament: Biomechanical analysis of the influence of static anddynamic factors”. en. In: The Journal of Spinal Cord Medicine 38.5, pp. 593–598. DOI: 10.1179/
2045772314Y.0000000221 (cit. on pp. 111, 117).
Nishida, Norihiro, Tsukasa Kanchiku, Junji Ohgi, et al. (2015b). “Mechanical properties of nerveroots and rami radiculares isolated from fresh pig spinal cords”. en. In: Neural RegenerationResearch 10.11, p. 1869. DOI: 10.4103/1673-5374.170319 (cit. on p. 106).
Nishida, Norihiro, Yoshihiko Kato, Yasuaki Imajo, Syunichi Kawano, and Toshihiko Taguchi (July2012). “Biomechanical analysis of cervical spondylotic myelopathy: The influence of dynamicfactors and morphometry of the spinal cord”. en. In: The Journal of Spinal Cord Medicine 35.4,pp. 256–261. DOI: 10.1179/2045772312Y.0000000024 (cit. on pp. 110, 111, 117, 213).
– (Sept. 2011). “Biomechanical study of the spinal cord in thoracic ossification of the posteriorlongitudinal ligament”. en. In: The Journal of Spinal Cord Medicine 34.5, pp. 518–522. DOI:10.1179/2045772311Y.0000000029 (cit. on p. 110).
Northover, J. R., J. B. Wild, J. Braybrooke, and J. Blanco (Dec. 2012). “The epidemiologyof cervical spondylotic myelopathy”. en. In: Skeletal Radiology 41.12, pp. 1543–1546. DOI:10.1007/s00256-012-1388-3 (cit. on p. 90).
Nouri, Aria, Lindsay Tetreault, Anoushka Singh, Spyridon K. Karadimas, and Michael G. Fehlings(June 2015). “Degenerative Cervical Myelopathy: Epidemiology, Genetics, and Pathogenesis”.en. In: Spine 40.12, E675–E693. DOI: 10.1097/BRS.0000000000000913 (cit. on pp. 85–87, 89,95).
Novikov, Dmitry S., Valerij G. Kiselev, and Sune N. Jespersen (June 2018). “On modeling”. en. In:Magnetic Resonance in Medicine 79.6, pp. 3172–3193. DOI: 10.1002/mrm.27101 (cit. on p. 77).
Nurick, S (1972). “The pathogenesis of the spinal cord disorder associated with cervical spondylo-sis”. In: Brain 95.1. Publisher: Oxford University Press, pp. 87–100 (cit. on pp. 93, 239).
Nyquist, Harry (1928). “Thermal agitation of electric charge in conductors”. In: Physical review32.1. Publisher: APS, p. 110 (cit. on p. 39).
Oakland, R J, R M Hall, R K Wilcox, and D C Barton (Apr. 2006). “The Biomechanical Responseof Spinal Cord Tissue to Uniaxial Loading”. en. In: Proceedings of the Institution of MechanicalEngineers, Part H: Journal of Engineering in Medicine 220.4, pp. 489–492. DOI: 10.1243/
09544119JEIM135 (cit. on p. 104).
Ocali, Ogan and Ergin Atalar (Mar. 1998). “Ultimate intrinsic signal-to-noise ratio in MRI”. en.In: Magnetic Resonance in Medicine 39.3, pp. 462–473. DOI: 10.1002/mrm.1910390317 (cit. onp. 40).
Ogawa, S., T. M. Lee, A. R. Kay, and D. W. Tank (Dec. 1990). “Brain magnetic resonance imagingwith contrast dependent on blood oxygenation.” en. In: Proceedings of the National Academy ofSciences 87.24, pp. 9868–9872. DOI: 10.1073/pnas.87.24.9868 (cit. on p. 43).
Ogino, H, K Tada, K Okada, et al. (1983). “Canal diameter, anteroposterior compression ratio, andspondylotic myelopathy of the cervical spine”. eng. In: Spine 8.1, pp. 1–15 (cit. on pp. 90, 214).
Oglesby, Matthew, Steven J. Fineberg, Alpesh A. Patel, Miguel A. Pelton, and Kern Singh (June2013). “Epidemiological Trends in Cervical Spine Surgery for Degenerative Diseases Between2002 and 2009:” en. In: Spine 38.14, pp. 1226–1232. DOI: 10.1097/BRS.0b013e31828be75d
(cit. on p. 96).
Ordidge, R (1999). “The development of echo-planar imaging (EPI): 1977–1982”. In: MagneticResonance Materials in Physics, Biology and Medicine 9.3. Publisher: Springer, pp. 117–121(cit. on p. 33).
Ozawa, Hiroshi, Takeo Matsumoto, Toshiro Ohashi, Masaaki Sato, and Shoichi Kokubun (Oct.2001). “Comparison of spinal cord gray matter and white matter softness: measurement bypipette aspiration method”. en. In: Journal of Neurosurgery: Spine 95.2, pp. 221–224. DOI:10.3171/spi.2001.95.2.0221 (cit. on pp. 105, 106).
– (July 2004). “Mechanical properties and function of the spinal pia mater”. en. In: Journal ofNeurosurgery: Spine 1.1, pp. 122–127. DOI: 10.3171/spi.2004.1.1.0122 (cit. on p. 106).
Panagiotacopulos, N.D., W.G. Knauss, and R. Bloch (Oct. 1979). “On the mechanical properties ofhuman intervertebral disc material”. en. In: Biorheology 16.4-5, pp. 317–330. DOI: 10.3233/
BIR-1979-164-506 (cit. on p. 107).
Paxinos, George and Juergen K. Mai (2004). The human nervous system. Academic Press (cit. onp. 11).
Payabvash, Seyedmehdi (2018). “Quantitative diffusion magnetic resonance imaging in head andneck tumors”. In: 2018 8.10, pp. 1052–1065 (cit. on p. 78).
Pennell, D.R., A. Sharma, H.H Ong, and S.A. Smith (2014). “B0 fluctuations within the humanspinal cord during respiration at 7.0 Tesla.” In: Proc. Int. Soc. Magn. Reson. Med. 22. Milan,Italy, p. 1714 (cit. on p. 45).
Peters, Andrew M., Matthew J. Brookes, Frank G. Hoogenraad, et al. (July 2007). “T2* measure-ments in human brain at 1.5, 3 and 7 T”. en. In: Magnetic Resonance Imaging 25.6, pp. 748–753.DOI: 10.1016/j.mri.2007.02.014 (cit. on p. 43).
Pfeuffer, Josef, Gregor Adriany, Amir Shmuel, et al. (May 2002). “Perfusion-based high-resolutionfunctional imaging in the human brain at 7 Tesla”. en. In: Magnetic Resonance in Medicine 47.5,pp. 903–911. DOI: 10.1002/mrm.10154 (cit. on p. 211).
Pintaske, J??rg, Petros Martirosian, Hansj??rg Graf, et al. (Mar. 2006). “Relaxivity of Gadopente-tate Dimeglumine (Magnevist), Gadobutrol (Gadovist), and Gadobenate Dimeglumine (Multi-Hance) in Human Blood Plasma at 0.2, 1.5, and 3 Tesla:” en. In: Investigative Radiology 41.3,pp. 213–221. DOI: 10.1097/01.rli.0000197668.44926.f7 (cit. on p. 57).
Pohmann, Rolf, Oliver Speck, and Klaus Scheffler (Feb. 2016). “Signal-to-noise ratio and MR tissueparameters in human brain imaging at 3, 7, and 9.4 tesla using current receive coil arrays: SNRat 9.4T”. en. In: Magnetic Resonance in Medicine 75.2, pp. 801–809. DOI: 10.1002/mrm.25677
(cit. on pp. 40, 41).
Pruessmann, Klaas P (Aug. 2004). “Parallel Imaging at High Field Strength: Synergies and JointPotential”. en. In: Topics in Magnetic Resonance Imaging 15.4, pp. 237–244. DOI: 10.1097/01.
rmr.0000139297.66742.4e (cit. on p. 38).
Pruessmann, Klaas P., Markus Weiger, Markus B. Scheidegger, and Peter Boesiger (Nov. 1999).“SENSE: Sensitivity encoding for fast MRI”. In: Magnetic Resonance in Medicine 42.5. Publisher:John Wiley & Sons, Ltd, pp. 952–962. DOI: 10.1002/(SICI)1522-2594(199911)42:5<952::
AID-MRM16>3.0.CO;2-S (cit. on p. 33).
Ramalho, J., R. C. Semelka, M. Ramalho, et al. (July 2016). “Gadolinium-Based Contrast AgentAccumulation and Toxicity: An Update”. en. In: American Journal of Neuroradiology 37.7,pp. 1192–1198. DOI: 10.3174/ajnr.A4615 (cit. on pp. 68, 196, 197).
Ramo, Nicole L., Snehal S. Shetye, Femke Streijger, et al. (Mar. 2018). “Comparison of in vivoand ex vivo viscoelastic behavior of the spinal cord”. en. In: Acta Biomaterialia 68, pp. 78–89.DOI: 10.1016/j.actbio.2017.12.024 (cit. on p. 108).
Rasoanandrianina, Henitsoa (2019). “Toward the characterization of micro- and macro- trauma-tisms of the human cervical spinal cord in rugby: a multimodal approach combining magneticresonance imaging and biomechanical finite element modelling”. French. PhD thesis. Marseille:Aix-Marseille University (cit. on pp. 114, 116).
Reddig, Annika, Mahsa Fatahi, Björn Friebe, et al. (July 2015). “Analysis of DNA Double-StrandBreaks and Cytotoxicity after 7 Tesla Magnetic Resonance Imaging of Isolated Human Lympho-cytes”. en. In: PLOS ONE 10.7. Ed. by Maria Rosaria Scarfi, e0132702. DOI: 10.1371/journal.
pone.0132702 (cit. on p. 50).
Rhee, John M., Mohammed F. Shamji, W. Mark Erwin, et al. (Oct. 2013). “Nonoperative Man-agement of Cervical Myelopathy: A Systematic Review”. en. In: Spine 38, S55–S67. DOI:10.1097/BRS.0b013e3182a7f41d (cit. on p. 6).
Riederer, Stephen J., Eric G. Stinson, and Paul T. Weavers (2018). “Technical Aspects of Contrast-enhanced MR Angiography: Current Status and New Applications”. en. In: Magnetic Resonancein Medical Sciences 17.1, pp. 3–12. DOI: 10.2463/mrms.rev.2017-0053 (cit. on p. 236).
Rochefort, Ludovic de, Tian Liu, Bryan Kressler, et al. (Jan. 2010). “Quantitative susceptibility mapreconstruction from MR phase data using bayesian regularization: Validation and application tobrain imaging: Bayesian Regularized Solution for Quantitative Susceptibility Mapping”. en. In:Magnetic Resonance in Medicine 63.1, pp. 194–206. DOI: 10.1002/mrm.22187 (cit. on p. 43).
Rohrer, Martin, Hans Bauer, Jan Mintorovitch, Martin Requardt, and Hanns-Joachim Weinmann(Nov. 2005). “Comparison of Magnetic Properties of MRI Contrast Media Solutions at DifferentMagnetic Field Strengths:” en. In: Investigative Radiology 40.11, pp. 715–724. DOI: 10.1097/
Ronen, Jacob, Diana Goldin, Vadim Bluvshtein, et al. (Sept. 2004). “Survival after nontraumaticspinal cord lesions in Israel11No commercial party having a direct financial interest in theresults of the research supporting this article has or will confer a benefit upon the authors(s) orupon any organization with which the author(s) is/are associated.” en. In: Archives of PhysicalMedicine and Rehabilitation 85.9, pp. 1499–1502. DOI: 10.1016/j.apmr.2003.11.015 (cit. onp. 96).
Rooney, William D., Glyn Johnson, Xin Li, et al. (2007). “Magnetic field and tissue dependenciesof human brain longitudinal 1H2O relaxation in vivo”. In: Magnetic Resonance in Medicine 57,pp. 308–318. DOI: 10.1002/mrm.21122 (cit. on p. 40).
Runza, Massimo, Riccardo Pietrabissa, Sara Mantero, et al. (1999). “Lumbar dura mater biome-chanics: experimental characterization and scanning electron microscopy observations”. In:Anesthesia & Analgesia 88.6. Publisher: LWW, pp. 1317–1321 (cit. on p. 106).
Rydhög, Anna S., Matthias J.P. van Osch, Emelie Lindgren, et al. (Dec. 2014). “Intravoxel inco-herent motion (IVIM) imaging at different magnetic field strengths: What is feasible?” en. In:Magnetic Resonance Imaging 32.10, pp. 1247–1258. DOI: 10.1016/j.mri.2014.07.013 (cit. onp. 78).
Saha, S. and W.C. Hayes (Jan. 1976). “Tensile impact properties of human compact bone”. en.In: Journal of Biomechanics 9.4, pp. 243–251. DOI: 10.1016/0021-9290(76)90010-5 (cit. onp. 108).
Saliani, Ariane, Blanche Perraud, Tanguy Duval, et al. (2017). “Axon and Myelin Morphology inAnimal and Human Spinal Cord”. English. In: Frontiers in Neuroanatomy 11. DOI: 10.3389/
fnana.2017.00129 (cit. on p. 14).
Santillan, Alejandro, Veronica Nacarino, Edward Greenberg, et al. (Jan. 2012). “Vascular anatomyof the spinal cord”. en. In: Journal of NeuroInterventional Surgery 4.1, pp. 67–74. DOI: 10.1136/
neurintsurg-2011-010018 (cit. on pp. 17, 19).
Schmainda, Kathleen M., Scott D. Rand, Allen M. Joseph, et al. (Oct. 2004). “Characterization ofa First-Pass Gradient-Echo Spin-Echo Method to Predict Brain Tumor Grade and Angiogenesis”.In: American Journal of Neuroradiology 25.9, p. 1524 (cit. on p. 67).
Schmidt, Hendrik, Frank Heuer, Ulrich Simon, et al. (May 2006). “Application of a new calibrationmethod for a three-dimensional finite element model of a human lumbar annulus fibrosus”.en. In: Clinical Biomechanics 21.4, pp. 337–344. DOI: 10.1016/j.clinbiomech.2005.12.001
(cit. on p. 107).
Schmiedeskamp, Heiko, Matus Straka, Rexford D. Newbould, et al. (July 2012). “Combined spin-and gradient-echo perfusion-weighted imaging”. en. In: Magnetic Resonance in Medicine 68.1,pp. 30–40. DOI: 10.1002/mrm.23195 (cit. on p. 64).
Schreiber, Wolfgang G., Friedemann Gückel, Peter Stritzke, et al. (Oct. 1998). “Cerebral BloodFlow and Cerebrovascular Reserve Capacity: Estimation by Dynamic Magnetic ResonanceImaging”. en. In: Journal of Cerebral Blood Flow & Metabolism 18.10, pp. 1143–1156. DOI:10.1097/00004647-199810000-00011 (cit. on p. 63).
Scifert, Jeffrey, Koji Totoribe, Vijay Goel, and Jan Huntzinger (2002). “Spinal Cord MechanicsDuring Flexion and Extension of the Cervical Spine: A Finite Element Study”. en. In: 5.4, p. 7(cit. on p. 109).
Semelka, Richard C., Nikolaos L. Kelekis, David Thomasson, Mark A. Brown, and Gerhard A. Laub(July 1996). “HASTE MR imaging: Description of technique and preliminary results in theabdomen”. en. In: Journal of Magnetic Resonance Imaging 6.4, pp. 698–699. DOI: 10.1002/
jmri.1880060420 (cit. on p. 80).
Sengupta, Saikat, E. Brian Welch, Yansong Zhao, et al. (May 2011). “Dynamic B0 shimming at 7T”. en. In: Magnetic Resonance Imaging 29.4, pp. 483–496. DOI: 10.1016/j.mri.2011.01.002
(cit. on p. 47).
Sharma, Manoj, Noshir A Langrana, and Jorge Rodriguez (1995). “Role of ligaments and facets inlumbar spinal stability.” In: Spine 20.8, pp. 887–900 (cit. on p. 107).
Sheehy, Niall P., Gerard E. Boyle, and James F. M. Meaney (Aug. 2005). “Normal AnteriorSpinal Arteries within the Cervical Region: High-Spatial-Resolution Contrast-enhanced Three-dimensional MR Angiography”. en. In: Radiology 236.2, pp. 637–641. DOI: 10.1148/radiol.
2362040804 (cit. on pp. 83, 84, 210).
Shen, Yaqi, Frank L Goerner, Johannes T Heverhagen, et al. (June 2019). “In vitro T2 relaxivities ofthe Gd-based contrast agents (GBCAs) in human blood at 1.5 and 3 T”. en. In: Acta Radiologica60.6, pp. 694–701. DOI: 10.1177/0284185118799538 (cit. on pp. 57, 59).
Shen, Yaqi, Frank L. Goerner, Christopher Snyder, et al. (May 2015). “T1 Relaxivities of Gadolinium-Based Magnetic Resonance Contrast Agents in Human Whole Blood at 1.5, 3, and 7 T”. en.In: Investigative Radiology 50.5, pp. 330–338. DOI: 10.1097/RLI.0000000000000132 (cit. onpp. 57, 58).
Shilo, Malka and Amit Gefen (Jan. 2012). “Identification of capillary blood pressure levels at whichcapillary collapse is likely in a tissue subjected to large compressive and shear deformations”.en. In: Computer Methods in Biomechanics and Biomedical Engineering 15.1, pp. 59–71. DOI:10.1080/10255842.2010.539208 (cit. on p. 113).
Shimomura, Yutaka, Sinsuke Hukuda, and Syotaro Mizuno (June 1968). “Experimental Study ofIschemic Damage to the Cervical Spinal Cord”. en. In: Journal of Neurosurgery 28.6, pp. 565–581. DOI: 10.3171/jns.1968.28.6.0565 (cit. on pp. 7, 88, 117, 214).
Shin, Wanyong, Ty A. Cashen, Sandra W. Horowitz, Rahul Sawlani, and Timothy J. Carroll (July2006). “Quantitative CBV measurement from staticT1 changes in tissue and correction forintravascular water exchange”. en. In: Magnetic Resonance in Medicine 56.1, pp. 138–145. DOI:10.1002/mrm.20937 (cit. on p. 68).
Shinmoto, Hiroshi, Chiharu Tamura, Shigeyoshi Soga, et al. (Oct. 2012). “An Intravoxel IncoherentMotion Diffusion-Weighted Imaging Study of Prostate Cancer”. en. In: American Journal ofRoentgenology 199.4, W496–W500. DOI: 10.2214/AJR.11.8347 (cit. on p. 78).
Sidaros, A., A. W. Engberg, K. Sidaros, et al. (Feb. 2008). “Diffusion tensor imaging duringrecovery from severe traumatic brain injury and relation to clinical outcome: a longitudinalstudy”. en. In: Brain 131.2, pp. 559–572. DOI: 10.1093/brain/awm294 (cit. on p. 76).
Sigmund, E. E., G. Y. Cho, S. Kim, et al. (May 2011). “Intravoxel incoherent motion imaging oftumor microenvironment in locally advanced breast cancer: IVIM Imaging in Locally AdvancedBreast Cancer”. en. In: Magnetic Resonance in Medicine 65.5, pp. 1437–1447. DOI: 10.1002/
mrm.22740 (cit. on p. 78).
Singh, Anita, Ying Lu, Chaoyang Chen, and John M Cavanaugh (Jan. 2006). “Mechanical prop-erties of spinal nerve roots subjected to tension at different strain rates”. en. In: Journal ofBiomechanics 39.9, pp. 1669–1676. DOI: 10.1016/j.jbiomech.2005.04.023 (cit. on p. 106).
Singh, Anup, Mohammad Haris, Divya Rathore, et al. (Oct. 2007). “Quantification of physiologicaland hemodynamic indices usingT1 dynamic contrast-enhanced MRI in intracranial mass lesions”.en. In: Journal of Magnetic Resonance Imaging 26.4, pp. 871–880. DOI: 10.1002/jmri.21080
(cit. on p. 68).
Solomon, I. and N. Bloembergen (Aug. 1956). “Nuclear Magnetic Interactions in the HF Molecule”.en. In: The Journal of Chemical Physics 25.2, pp. 261–266. DOI: 10.1063/1.1742867 (cit. onp. 42).
Sourbron, Steven, Michael Ingrisch, Axel Siefert, Maximilian Reiser, and Karin Herrmann (July2009). “Quantification of cerebral blood flow, cerebral blood volume, and blood-brain-barrierleakage with DCE-MRI”. en. In: Magnetic Resonance in Medicine 62.1, pp. 205–217. DOI:10.1002/mrm.22005 (cit. on p. 68).
Sparrey, Carolyn J. and Tony M. Keaveny (Apr. 2011). “Compression behavior of porcine spinalcord white matter”. en. In: Journal of Biomechanics 44.6, pp. 1078–1082. DOI: 10.1016/j.
jbiomech.2011.01.035 (cit. on p. 104).
Sparrey, Carolyn J., Geoffrey T. Manley, and Tony M. Keaveny (Apr. 2009). “Effects of White, Grey,and Pia Mater Properties on Tissue Level Stresses and Strains in the Compressed Spinal Cord”.In: Journal of Neurotrauma 26.4, pp. 585–595. DOI: 10.1089/neu.2008.0654 (cit. on p. 110).
Speck, Oliver, Linda Chang, N. Menaka DeSilva, and Thomas Ernst (Sept. 2000). “PerfusionMRI of the human brain with dynamic susceptibility contrast: Gradient-echo versus spin-echotechniques”. In: Journal of Magnetic Resonance Imaging 12.3. Publisher: John Wiley & Sons, Ltd,pp. 381–387. DOI: 10.1002/1522-2586(200009)12:3<381::AID-JMRI2>3.0.CO;2-Y (cit. onpp. 64, 65).
Staff News Brief (Oct. 2017). “Siemens obtains first CE approval for ultra-high-field 7T MRscanner”. In: Appl Radiol (cit. on p. 37).
Standring, S. (2008). Gray’s Anatomy: The Anatomical Basis of Clinical Practice, Expert Consult -40th Edition (cit. on p. 114).
Stehling, Michael K, Robert Turner, and Peter Mansfield (1991). “Echo-planar imaging: magneticresonance imaging in a fraction of a second”. In: Science 254.5028. Publisher: AmericanAssociation for the Advancement of Science, pp. 43–50 (cit. on p. 33).
Stejskal, E. O. and J. E. Tanner (Jan. 1965). “Spin Diffusion Measurements: Spin Echoes in thePresence of a Time-Dependent Field Gradient”. en. In: The Journal of Chemical Physics 42.1,pp. 288–292. DOI: 10.1063/1.1695690 (cit. on p. 73).
Stieb, Sonja, Andreas Boss, Moritz C. Wurnig, et al. (2016). “Non-parametric intravoxel incoherentmotion analysis in patients with intracranial lesions: Test-retest reliability and correlation witharterial spin labeling”. en. In: NeuroImage: Clinical 11, pp. 780–788. DOI: 10.1016/j.nicl.
2016.05.022 (cit. on p. 78).
Stojanov, Dragan A., Aleksandra Aracki-Trenkic, Slobodan Vojinovic, Daniela Benedeto-Stojanov,and Srdjan Ljubisavljevic (Mar. 2016). “Increasing signal intensity within the dentate nucleusand globus pallidus on unenhanced T1W magnetic resonance images in patients with relapsing-remitting multiple sclerosis: correlation with cumulative dose of a macrocyclic gadolinium-basedcontrast agent, gadobutrol”. en. In: European Radiology 26.3, pp. 807–815. DOI: 10.1007/
s00330-015-3879-9 (cit. on p. 196).
Sun, Jingchao (2013). “Cervical spine trauma in motocylce accidents”. English. PhD thesis.Marseille: Aix-Marseille University (cit. on pp. 114, 116).
Tam, Samantha, Robert L. Barry, Robert Bartha, and Neil Duggal (Sept. 2010). “Changes inFunctional Magnetic Resonance Imaging Cortical Activation After Decompression of CervicalSpondylosis”. en. In: Neurosurgery 67.3, E863–E864. DOI: 10.1227/01.NEU.0000374848.
86299.17 (cit. on p. 216).
Tan, Yongming, Fuqing Zhou, Lin Wu, et al. (2015). “Alteration of Regional Homogeneity withinthe Sensorimotor Network after Spinal Cord Decompression in Cervical Spondylotic Myelopathy:A Resting-State fMRI Study”. en. In: BioMed Research International 2015, pp. 1–6. DOI: 10.
1155/2015/647958 (cit. on p. 98).
Tannous, Oliver, Ehsan Jazini, and Steven C. Ludwig (June 2014). “Anterior surgical treatmentfor cervical spondylotic myelopathy”. en. In: Seminars in Spine Surgery 26.2, pp. 73–80. DOI:10.1053/j.semss.2014.05.004 (cit. on p. 94).
Taso, M., L. Fradet, V. Callot, and P. J. Arnoux (Oct. 2015a). “Anteroposterior compression of thespinal cord leading to cervical myelopathy: a finite element analysis”. In: Computer Methods inBiomechanics and Biomedical Engineering 18.sup1. Publisher: Taylor & Francis, pp. 2070–2071.DOI: 10.1080/10255842.2015.1069625 (cit. on p. 115).
Taso, Manuel (2016). “Towards multi-physic characterization of spinal cord human pathologies :coupling between multi-parametric MRI and biomechanical finite element modeling”. French.PhD thesis. Marseille: Aix-Marseille University (cit. on pp. 114, 116).
Taso, Manuel, Pierre Jean Arnoux, Léo Fradet, et al. (2016). “Combining biomechanical finiteelement analysis and multi-parametric MRI to assess mechanical and structural damage incervical spondylotic myelopathy”. In: Proc. Intl. Soc. Mag. Reson. Med. 24. Singapore, p. 0847(cit. on pp. 115, 219).
Taso, Manuel, Arnaud Le Troter, Michaël Sdika, et al. (Aug. 2015b). “A reliable spatially normal-ized template of the human spinal cord — Applications to automated white matter/gray mattersegmentation and tensor-based morphometry (TBM) mapping of gray matter alterations occur-ring with age”. en. In: NeuroImage 117, pp. 20–28. DOI: 10.1016/j.neuroimage.2015.05.034
(cit. on p. 114).
Teeuwisse, Wouter M., Wyger M. Brink, and Andrew G. Webb (May 2012). “Quantitative assess-ment of the effects of high-permittivity pads in 7 Tesla MRI of the brain”. en. In: MagneticResonance in Medicine 67.5, pp. 1285–1293. DOI: 10.1002/mrm.23108 (cit. on p. 49).
Tetreault, Lindsay, Christina L. Goldstein, Paul Arnold, et al. (Oct. 2015). “Degenerative CervicalMyelopathy: A Spectrum of Related Disorders Affecting the Aging Spine”. en. In: Neurosurgery77, S51–S67. DOI: 10.1227/NEU.0000000000000951 (cit. on p. 91).
Tetreault, Lindsay A., Spyridon Karadimas, Jefferson R. Wilson, et al. (Sept. 2017). “The NaturalHistory of Degenerative Cervical Myelopathy and the Rate of Hospitalization Following SpinalCord Injury: An Updated Systematic Review”. en. In: Global Spine Journal 7.3_suppl, 28S–34S.DOI: 10.1177/2192568217700396 (cit. on p. 96).
Thormann, Markus, Holger Amthauer, Daniela Adolf, et al. (May 2013). “Efficacy of diphen-hydramine in the prevention of vertigo and nausea at 7T MRI”. en. In: European Journal ofRadiology 82.5, pp. 768–772. DOI: 10.1016/j.ejrad.2011.08.001 (cit. on p. 49).
Thron, Armin K (1988). Vascular anatomy of the spinal cord: neuroradiological investigations andclinical syndromes. Springer Science & Business Media (cit. on p. 15).
Topfer, Ryan, Alexandru Foias, Nikola Stikov, and Julien Cohen-Adad (Sept. 2018). “Real-timecorrection of respiration-induced distortions in the human spinal cord using a 24-channel shimarray: Real-Time B 0 Shimming in the Spinal Cord”. en. In: Magnetic Resonance in Medicine80.3, pp. 935–946. DOI: 10.1002/mrm.27089 (cit. on pp. 47, 200, 205).
Topfer, Ryan, Piotr Starewicz, Kai-Ming Lo, et al. (Nov. 2016). “A 24-channel shim array for thehuman spinal cord: Design, evaluation, and application: 24-Channel Shim Array for the SpinalCord”. en. In: Magnetic Resonance in Medicine 76.5, pp. 1604–1611. DOI: 10.1002/mrm.26354
(cit. on p. 47).
Triantafyllou, Christina, Jonathan R. Polimeni, and Lawrence L. Wald (Mar. 2011). “Physiologicalnoise and signal-to-noise ratio in fMRI with multi-channel array coils”. en. In: NeuroImage 55.2,pp. 597–606. DOI: 10.1016/j.neuroimage.2010.11.084 (cit. on pp. 201, 202).
Tunturi, Archie R (1978). “Elasticity of the spinal cord, pia, and dentieulate ligament in the dog”.en. In: J. Neurosurg. 48, p. 5 (cit. on p. 104).
Uchida, Kenzo, Hisatoshi Baba, Yasuhisa Maezawa, and Chikara Kubota (2002). “ProgressiveChanges in Neurofilament Proteins and Growth-Associated Protein-43 Immunoreactivities atthe Site of Cervical Spinal Cord Compression in Spinal Hyperostotic Mice”. In: Spine 27.5(cit. on p. 91).
Uchida, Kenzo, Hisatoshi Baba, Yasuhisa Maezawa, et al. (July 2003). “Increased expression ofneurotrophins and their receptors in the mechanically compressed spinal cord of the spinalhyperostotic mouse (twy/twy)”. en. In: Acta Neuropathologica 106.1, pp. 29–36. DOI: 10.1007/
s00401-003-0691-4 (cit. on p. 91).
Ugurbil, Kamil (May 2014). “Magnetic Resonance Imaging at Ultrahigh Fields”. en. In: IEEETransactions on Biomedical Engineering 61.5, pp. 1364–1379. DOI: 10 . 1109 / TBME . 2014 .
2313619 (cit. on p. 38).
Uh, Jinsoo, Kelly Lewis-Amezcua, Rani Varghese, and Hanzhang Lu (Mar. 2009). “On the mea-surement of absolute cerebral blood volume (CBV) using vascular-space-occupancy (VASO)MRI”. en. In: Magnetic Resonance in Medicine 61.3, pp. 659–667. DOI: 10.1002/mrm.21872
(cit. on pp. 238, 239).
United States Food and Drug Administration (2014). Criteria for significant risk investigationsof magnetic resonance diagnostic devices. FDA (Ed.) Guidance for Industry, Food, and DrugAdministration Staff (cit. on p. 48).
– (2017). FDA clears first 7T magnetic resonance imaging device (cit. on p. 37).
Van Vaals, Joop J., Marijn E. Brummer, W. Thomas Dixon, et al. (July 1993). ““Keyhole” methodfor accelerating imaging of contrast agent uptake”. en. In: Journal of Magnetic ResonanceImaging 3.4, pp. 671–675. DOI: 10.1002/jmri.1880030419 (cit. on p. 235).
Vannesjo, S. Johanna, Stuart Clare, Lars Kasper, Irene Tracey, and Karla L. Miller (June 2019). “Amethod for correcting breathing-induced field fluctuations in T2*-weighted spinal cord imagingusing a respiratory trace”. en. In: Magnetic Resonance in Medicine 81.6, pp. 3745–3753. DOI:10.1002/mrm.27664 (cit. on pp. 47, 200, 205).
Vannesjo, S. Johanna, Karla L. Miller, Stuart Clare, and Irene Tracey (Feb. 2018). “Spatiotemporalcharacterization of breathing-induced B0 field fluctuations in the cervical spinal cord at 7T”. en.In: NeuroImage 167, pp. 191–202. DOI: 10.1016/j.neuroimage.2017.11.031 (cit. on pp. 45,46, 205).
Vargas, M. I., B. M. A. Delattre, J. Boto, et al. (Aug. 2018). “Advanced magnetic resonance imaging(MRI) techniques of the spine and spinal cord in children and adults”. en. In: Insights intoImaging 9.4, pp. 549–557. DOI: 10.1007/s13244-018-0626-1 (cit. on p. 81).
Vargas, Maria Isabel, Isabelle Barnaure, Joanna Gariani, et al. (2017). “Vascular Imaging Tech-niques of the Spinal Cord”. In: Seminars in Ultrasound, CT and MRI 38, pp. 143–152. DOI:https://doi.org/10.1053/j.sult.2016.07.004 (cit. on p. 7).
Vargas, Maria Isabel, Duy Nguyen, Magalie Viallon, et al. (Oct. 2010). “Dynamic MR angiography(MRA) of spinal vascular diseases at 3T”. en. In: European Radiology 20.10, pp. 2491–2495.DOI: 10.1007/s00330-010-1815-6 (cit. on p. 83).
Vargas, M.I., J. Gariani, R. Sztajzel, et al. (May 2015). “Spinal Cord Ischemia: Practical ImagingTips, Pearls, and Pitfalls”. en. In: American Journal of Neuroradiology 36.5, pp. 825–830. DOI:10.3174/ajnr.A4118 (cit. on p. 84).
Verma, Tanya and Julien Cohen-Adad (Dec. 2014). “Effect of respiration on the B0 field in thehuman spinal cord at 3T: Effect of Respiration on B0 Field in Human Spinal Cord”. en. In:Magnetic Resonance in Medicine 72.6, pp. 1629–1636. DOI: 10.1002/mrm.25075 (cit. on pp. 45,46).
Vignaud, Alexandre, Xavier Violas, Alain Rahmouni, Philippe Robert, and Alexis Amadon (2014).“Comparison of marketed Gadolinium-based Contrast Agents Relaxivities on Clinical MR scannerat 1.5T, 3T and 7T in water and plasma for a large range of physiological concentrations”. In:Proc. Intl. Soc. Mag. Reson. Med. 22. Milan, Italy, p. 3228 (cit. on pp. 57–59).
Vohanka, S and J Dvorak (1993). “Motor and somatosensory evoked potentials in cervical spinalstenosis”. In: (cit. on p. 96).
Vonken, Evert-jan Ph.A., Matthias J.P. van Osch, Chris J.G. Bakker, and Max A. Viergever (Aug.1999). “Measurement of cerebral perfusion with dual-echo multi-slice quantitative dynamicsusceptibility contrast MRI”. In: Journal of Magnetic Resonance Imaging 10.2, pp. 109–117. DOI:10.1002/(SICI)1522-2586(199908)10:2<109::AID-JMRI1>3.0.CO;2-# (cit. on pp. 63,64).
Vuong, Shawn M., William J. Jeong, Humberto Morales, and Todd A. Abruzzo (Oct. 2016). “Vas-cular Diseases of the Spinal Cord: Infarction, Hemorrhage, and Venous Congestive Myelopathy”.en. In: Seminars in Ultrasound, CT and MRI 37.5, pp. 466–481. DOI: 10.1053/j.sult.2016.
05.008 (cit. on p. 17).
Wagnac, Eric (2011). “Expérimentation et modélisation détaillée de la colonne vertébrale pourétudier le rôle des facteurs anatomiques et biomécaniques sur les traumatismes rachidiens”.French. PhD thesis. Marseille-Montreal: Aix-Marseille Université & École Polytechnique deMontréal (cit. on pp. 114, 116).
Wagnac, Eric, Pierre-Jean Arnoux, Anaïs Garo, and Carl-Eric Aubin (Sept. 2012). “Finite elementanalysis of the influence of loading rate on a model of the full lumbar spine under dynamicloading conditions”. en. In: Medical & Biological Engineering & Computing 50.9, pp. 903–915.DOI: 10.1007/s11517-012-0908-6 (cit. on pp. 114, 116).
Wallace, Tess E., Onur Afacan, Tobias Kober, and Simon K. Warfield (Aug. 2019). “Rapid mea-surement and correction of spatiotemporal B 0 field changes using FID navigators and amulti-channel reference image”. en. In: Magnetic Resonance in Medicine, mrm.27957. DOI:10.1002/mrm.27957 (cit. on p. 47).
Wang, C., D. Ren, Y. Guo, et al. (Jan. 2017a). “Distribution of intravoxel incoherent motionMRI-related parameters in the brain: evidence of interhemispheric asymmetry”. en. In: ClinicalRadiology 72.1, 94.e1–94.e6. DOI: 10.1016/j.crad.2016.09.007 (cit. on p. 78).
Wang, Chunyao, Xiao Han, Wen Jiang, et al. (Apr. 2017b). “Perfusion of Spinal Cord in postopera-tive patient with Cervical Spondylotic Myelopathy using MR DSC technique”. In: Proceedingsof the 25th annual meeting of the International Society for Magnetic Resonance in Medicine.Honolulu, Hawai, USA, p. 2507 (cit. on p. 81).
Wang, Chunyao, Xiao Han, Wen Jiang, et al. (2018). “Spinal Cord Perfusion is Associated withDiffusion and clinical mJOA score in Preoperative Patients with Cervical Spondylotic Myelopa-thy”. en. In: Proceedings of the 26th annual meeting of the International Society for MagneticResonance in Medicine. Paris, France, p. 5397 (cit. on p. 81).
Wang, Danny J.J., Jeffry R. Alger, Joe X. Qiao, et al. (2013). “Multi-delay multi-parametricarterial spin-labeled perfusion MRI in acute ischemic stroke — Comparison with dynamicsusceptibility contrast enhanced perfusion imaging”. en. In: NeuroImage: Clinical 3, pp. 1–7.DOI: 10.1016/j.nicl.2013.06.017 (cit. on p. 72).
Wang, Yi, Steen Moeller, Xiufeng Li, et al. (June 2015). “Simultaneous multi-slice Turbo-FLASHimaging with CAIPIRINHA for whole brain distortion-free pseudo-continuous arterial spinlabeling at 3 and 7T”. en. In: NeuroImage 113, pp. 279–288. DOI: 10.1016/j.neuroimage.
2015.03.060 (cit. on p. 211).
Ward, K.M, A.H Aletras, and R.S Balaban (Mar. 2000). “A New Class of Contrast Agents for MRIBased on Proton Chemical Exchange Dependent Saturation Transfer (CEST)”. en. In: Journal ofMagnetic Resonance 143.1, pp. 79–87. DOI: 10.1006/jmre.1999.1956 (cit. on p. 44).
Weisskoff, Robert, Chun S. Zuo, Jerrold L. Boxerman, and Bruce R. Rosen (June 1994). “Mi-croscopic susceptibility variation and transverse relaxation: Theory and experiment”. en. In:Magnetic Resonance in Medicine 31.6, pp. 601–610. DOI: 10.1002/mrm.1910310605 (cit. onpp. 64, 66).
Welker, K., J. Boxerman, A. Kalnin, et al. (June 2015). “ASFNR Recommendations for ClinicalPerformance of MR Dynamic Susceptibility Contrast Perfusion Imaging of the Brain”. en. In:American Journal of Neuroradiology 36.6, E41–E51. DOI: 10.3174/ajnr.A4341 (cit. on pp. 63,64).
White, Nathan S., Carrie R. McDonald, Niky Farid, et al. (Sept. 2014). “Diffusion-WeightedImaging in Cancer: Physical Foundations and Applications of Restriction Spectrum Imaging”.en. In: Cancer Research 74.17, pp. 4638–4652. DOI: 10.1158/0008-5472.CAN-13-3534 (cit. onp. 74).
Wiesinger, Florian, Peter Boesiger, and Klaas P. Pruessmann (Aug. 2004a). “Electrodynamics andultimate SNR in parallel MR imaging”. en. In: Magnetic Resonance in Medicine 52.2, pp. 376–390.DOI: 10.1002/mrm.20183 (cit. on p. 38).
Wiesinger, Florian, Pierre-Francois Van de Moortele, Gregor Adriany, et al. (Nov. 2004b). “Parallelimaging performance as a function of field strength - An experimental investigation usingelectrodynamic scaling”. en. In: Magnetic Resonance in Medicine 52.5, pp. 953–964. DOI: 10.
1002/mrm.20281 (cit. on p. 38).
– (May 2006). “Potential and feasibility of parallel MRI at high field”. en. In: NMR in Biomedicine19.3, pp. 368–378. DOI: 10.1002/nbm.1050 (cit. on p. 38).
Wilcox, R. K., D. J. Allen, R. M. Hall, et al. (Oct. 2004). “A dynamic investigation of the burstfracture process using a combined experimental and finite element approach”. en. In: EuropeanSpine Journal 13.6, pp. 481–488. DOI: 10.1007/s00586-003-0625-9 (cit. on p. 109).
Wilcox, Ruth K, Thomas O Boerger, David J Allen, et al. (2003). “A dynamic study of thoracolumbarburst fractures”. In: JBJS 85.11. Publisher: LWW, pp. 2184–2189 (cit. on p. 109).
Wilder, Frances Vaughn, Lissa Fahlman, and Robert Donnelly (Jan. 2011). “Radiographic cervi-cal spine osteoarthritis progression rates: a longitudinal assessment”. en. In: RheumatologyInternational 31.1, pp. 45–48. DOI: 10.1007/s00296-009-1216-9 (cit. on p. 95).
Willats, Lisa, Alan Connelly, Soren Christensen, et al. (Apr. 2012). “The Role of Bolus Delayand Dispersion in Predictor Models for Stroke”. en. In: Stroke 43.4, pp. 1025–1031. DOI:10.1161/STROKEAHA.111.635888 (cit. on p. 62).
Wilson, Jefferson R., Sean Barry, Dena J. Fischer, et al. (Oct. 2013). “Frequency, Timing, andPredictors of Neurological Dysfunction in the Nonmyelopathic Patient With Cervical SpinalCord Compression, Canal Stenosis, and/or Ossification of the Posterior Longitudinal Ligament:”en. In: Spine 38, S37–S54. DOI: 10.1097/BRS.0b013e3182a7f2e7 (cit. on p. 95).
Wintermark, M., P.C. Sanelli, G.W. Albers, et al. (Nov. 2013). “Imaging Recommendations forAcute Stroke and Transient Ischemic Attack Patients: A Joint Statement by the American Societyof Neuroradiology, the American College of Radiology, and the Society of NeuroInterventionalSurgery”. en. In: American Journal of Neuroradiology 34.11, E117–E127. DOI: 10.3174/ajnr.
A3690 (cit. on p. 66).
Wirestam, R., M. Borg, S. Brockstedt, et al. (Mar. 2001). “Perfusion-related parameters inintravoxel incoherent motion MR imaging compared with CBV and CBF measured by dy-namic susceptibility-contrast MR technique”. en. In: Acta Radiologica 42.2, pp. 123–128. DOI:10.1080/028418501127346459 (cit. on p. 78).
Wong, Sau May, C. Eleana Zhang, Frank C.G. van Bussel, et al. (2017). “Simultaneous investigationof microvasculature and parenchyma in cerebral small vessel disease using intravoxel incoherentmotion imaging”. en. In: NeuroImage: Clinical 14, pp. 216–221. DOI: 10.1016/j.nicl.2017.
01.017 (cit. on p. 78).
Wu, Dan and Jiangyang Zhang (Dec. 2019). “Evidence of the diffusion time dependence ofintravoxel incoherent motion in the brain”. en. In: Magnetic Resonance in Medicine 82.6,pp. 2225–2235. DOI: 10.1002/mrm.27879 (cit. on p. 78).
Wu, Wen-Chau, Ya-Fang Chen, Han-Min Tseng, Shun-Chung Yang, and Pei-Chi My (Aug. 2015).“Caveat of measuring perfusion indexes using intravoxel incoherent motion magnetic resonanceimaging in the human brain”. en. In: European Radiology 25.8, pp. 2485–2492. DOI: 10.1007/
s00330-015-3655-x (cit. on p. 78).
Yoganandan, Narayan, Srirangam Kumaresan, and Frank A. Pintar (Dec. 2000). “Geometric andMechanical Properties of Human Cervical Spine Ligaments”. en. In: Journal of BiomechanicalEngineering 122.6, pp. 623–629. DOI: 10.1115/1.1322034 (cit. on pp. 106, 107).
Yu, Wen-Ru, Darryl C. Baptiste, Tianyi Liu, et al. (Feb. 2009). “Molecular mechanisms of spinalcord dysfunction and cell death in the spinal hyperostotic mouse: Implications for the patho-physiology of human cervical spondylotic myelopathy”. en. In: Neurobiology of Disease 33.2,pp. 149–163. DOI: 10.1016/j.nbd.2008.09.024 (cit. on p. 91).
Yuan, Mei, Yu-Dong Zhang, Chan Zhu, et al. (Mar. 2016). “Comparison of intravoxel incoherentmotion diffusion-weighted MR imaging with dynamic contrast-enhanced MRI for differentiatinglung cancer from benign solitary pulmonary lesions: Distinguishing Lung Cancer from BenignSPLs”. en. In: Journal of Magnetic Resonance Imaging 43.3, pp. 669–679. DOI: 10.1002/jmri.
25018 (cit. on p. 78).
Yue, Wai-Mun, Seang-Beng Tan, Mann-Hong Tan, Dean Chi-Siong Koh, and Chong-Tien Tan(2001). “The Torg–Pavlov ratio in cervical spondylotic myelopathy: a comparative study be-tween patients with cervical spondylotic myelopathy and a nonspondylotic, nonmyelopathicpopulation”. In: Spine 26.16. Publisher: LWW, pp. 1760–1764 (cit. on p. 90).
Zakariaee, SeyedSalman, MohammadAli Oghabian, Kavous Firouznia, et al. (2018). “Assessmentof the Agreement between Cerebral Hemodynamic Indices Quantified Using Dynamic Suscep-tibility Contrast and Dynamic Contrast-enhanced Perfusion Magnetic Resonance Imagings”.en. In: Journal of Clinical Imaging Science 8.1, p. 2. DOI: 10.4103/jcis.JCIS_74_17 (cit. onpp. 67–69).
Zhang, Bei, Alan C. Seifert, Joo-won Kim, Joseph Borrello, and Junqian Xu (Oct. 2017). “7Tesla 22-channel wrap-around coil array for cervical spinal cord and brainstem imaging: 7TCervical Spinal Cord Coil”. en. In: Magnetic Resonance in Medicine 78.4, pp. 1623–1634. DOI:10.1002/mrm.26538 (cit. on pp. 51–53).
Zhang, Chuan (2014). “Application of magnetic resonance imaging in cervical spondyloticmyelopathy”. en. In: World Journal of Radiology 6.10, p. 826. DOI: 10.4329/wjr.v6.i10.826
(cit. on p. 97).
Zhang, X., E. T. Petersen, E. Ghariq, et al. (Oct. 2013). “In vivo blood T1 measurements at1.5 T, 3 T, and 7 T”. en. In: Magnetic Resonance in Medicine 70.4, pp. 1082–1086. DOI:10.1002/mrm.24550 (cit. on pp. 57, 71).
Zhao, Wei, Julien Cohen-Adad, Jonathan R. Polimeni, et al. (July 2014). “Nineteen-channelreceive array and four-channel transmit array coil for cervical spinal cord imaging at 7T: RFCoil for Spinal Cord MRI at 7T”. en. In: Magnetic Resonance in Medicine 72.1, pp. 291–300. DOI:10.1002/mrm.24911 (cit. on p. 53).
Zhou, Ming, Noboru Goto, Chen Zhang, and Wei Tang (June 1996). “Aging process of the humanlumbar spinal cord: A morphometric analysis”. en. In: Neuropathology 16.2, pp. 106–111. DOI:10.1111/j.1440-1789.1996.tb00164.x (cit. on p. 12).
Zhu, Yudong (Apr. 2004). “Parallel excitation with an array of transmit coils”. en. In: MagneticResonance in Medicine 51.4, pp. 775–784. DOI: 10.1002/mrm.20011 (cit. on p. 49).
Zileli, Mehmet, Sachin A. Borkar, Sumit Sinha, et al. (Sept. 2019). “Cervical Spondylotic Myelopa-thy: Natural Course and the Value of Diagnostic Techniques –WFNS Spine Committee Recom-mendations”. In: Neurospine 16.3. Publisher: Korean Spinal Neurosurgery Society, pp. 386–402.DOI: 10.14245/ns.1938240.120 (cit. on pp. 6, 96, 97).
Østergaard, Leif, Robert M. Weisskoff, David A. Chesler, Carsten Gyldensted, and Bruce R.Rosen (Nov. 1996). “High resolution measurement of cerebral blood flow using intravasculartracer bolus passages. Part I: Mathematical approach and statistical analysis”. en. In: MagneticResonance in Medicine 36.5, pp. 715–725. DOI: 10.1002/mrm.1910360510 (cit. on p. 63).
AbstractSpinal cord compression induced by spine degeneration is a common cause of spinal cord dysfunction. Previous
research has shown evidence of ischemia firing cell apoptosis exacerbated by inflammation, which eventually resultsin myelopathy and functional impairment. However, little is known about the timescale of the processes and theirinteraction. If decompression surgery is recommended for severe Degenerative Cervical Myelopathy (DCM), theprogression and management of mild cases is more challenging. Biomarker of perfusion deficit would particularly helpto make decision.
This PhD is part of a global project aiming at associating biomechanical simulations of the induced constraints toin-vivo measurements of perfusion using MRI. More specifically, this work aimed at developing an MRI technique tomap spinal cord perfusion and at designing realistic finite element simulations of typical DCM compressions.
Given the low perfusion levels and small size of the human spinal cord, developments were conducted at 7T to benefitfrom ultra-high field sensitivity. The Intra-Voxel Incoherent Motion (IVIM) technique was first investigated. Signal-to-noiseratio was maximized and errors from in-vivo data were assessed using Monte-Carlo simulations. Dynamic SusceptibilityContrast (DSC) imaging, which makes use of contrast injection, was then explored. Acquisition and post-processingpipelines were implemented to address physiological biases (heartbeat, breathing, motion). Finally, geometrical featuresof typical DCM compressions were synthesized from literature and anatomical MRI of patients. Simulations wereperformed using a detailed spine model and resulting constraints were quantified along the compression process, spinalcord length and across spinal pathways.
The IVIM technique showed poor sensitivity despite the high signal-to-noise ratio obtained. By contrast, well-definedrelative blood volume and flow maps were obtained in healthy volunteers with DSC, depicting the higher perfusion ofgray matter with respect to white matter. Sensitivity was mitigated in DCM patients, however new guidelines to improverobustness of the technique could be identified. Based on stress distribution only, biomechanical simulations couldexplain the gray matter infarction reported in DCM patients but not directly the demyelination of the corticospinal tract.
In conclusion, the DSC technique has a great potential for human spinal cord perfusion mapping in clinical routine.Given the large variability of DCM patterns and resulting symptoms, the definition of standard simulation designs iscomplex. In this context, a patient-specific approach is advised to reliably establish the relationship between mechanicalcompression and resulting ischemia.
RésuméLes compressions médullaires induites par la dégénérescence du rachis sont une cause fréquente de dysfonction-
nement de la moelle épinière. Des recherches antérieures ont démontré des signes d’ischémie déclenchant l’apoptosedes cellules, exacerbés par la suite par un processus d’inflammation, menant finalement à la myélopathie et l’altérationfonctionnelle. Cependant, la durée des processus dégénératifs et leur interaction restent peu connues. Si la chirurgie dedécompression est recommandée pour les Myélopathies Cervicales Dégénératives (DCM) sévères, le suivi et la prise encharge des cas légers sont plus problématiques. Un biomarqueur du déficit de perfusion serait d’une aide particulière-ment précieuse dans la prise de décision.
Ce travail de thèse s’inscrit dans un projet plus global visant à combiner la simulation biomécanique des contraintesinduites avec des mesures de perfusion in-vivo par IRM. Plus particulièrement, ce travail visait à développer unetechnique IRM de cartographie de la perfusion médullaire et à concevoir des simulations par éléments finis réalistes decas de compressions DCM typiques.
Compte tenu des faibles niveaux de perfusion et de la petite taille de la moelle épinière humaine, les développementsont été réalisés à 7T pour bénéficier de la sensibilité accrue à ultra-haut champ. La technique de Mouvement IncohérentIntra-Voxel (IVIM) a tout d’abord été étudiée. Le rapport signal/bruit a été maximisé et les erreurs obtenues in-vivoont été évaluées à l’aide de simulations de Monte-Carlo. L’imagerie par Contraste de Susceptibilité Dynamique (DSC),basée sur l’injection d’un agent de contraste, a ensuite été explorée. Un protocole d’acquisition et de post-traitement aété mis en place pour minimiser les biais physiologiques (battements cardiaques, respiration, mouvement). Enfin, descaractéristiques géométriques typiques des compressions DCM ont été extraites de la littérature et d’IRM anatomiques depatients. Des simulations biomécaniques ont été implémentées à l’aide d’un modèle détaillé du rachis et les contraintesrésultantes ont été quantifiées au long du processus de compression, le long de la moelle ainsi que par région médullaire.
La technique IVIM a démontré une faible sensibilité malgré le rapport signal/bruit élevé obtenu. En revanche, descartes bien définies de volume et flux sanguin relatifs ont été obtenues chez des volontaires sains par DCM, mettanten évidence la perfusion plus élevée de la substance grise par rapport à la substance blanche. La sensibilité a été pluslimitée chez les patients DCM, mais de nouvelles consignes pour améliorer la robustesse de la technique ont pu êtreidentifiées. Les simulations biomécaniques pourraient expliquer l’ischémie fréquemment observée chez les patientsDCM dans la substance grise, mais elles ne peuvent expliquer directement la démyélinisation de la voie corticospinale sil’on se base sur la distribution des contraintes uniquement.
En conclusion, la technique DSC a un grand potentiel pour la cartographie de la perfusion de la moelle épinièrehumaine en routine clinique. Étant donné la grande variabilité des motifs de compression DCM et des symptômes quien résultent, la définition de simulations standards est complexe. Dans ce contexte, une approche spécifique au patientest recommandée pour pouvoir établir de manière fiable une relation entre la compression mécanique et l’ischémieinduite.