HandBook of Biomedical
HandBook of Biomedical
HandBook of Biomedical
Nicholas Ayache Editors
Handbook of
Biomedical
Imaging
Methodologies and Clinical Research
Handbook of Biomedical Imaging
Nikos Paragios • James Duncan
Nicholas Ayache
Editors
Handbook of Biomedical
Imaging
Methodologies and Clinical Research
123
Editors
Nikos Paragios James Duncan
Department of Applied Mathematics Department of Biomedical Engineering,
École Centrale de Paris Diagnostic Radiology and Electrical
Chatenay-Malabry, France Engineering
Yale University
Nicholas Ayache New Haven, CT, USA
Inria Sophia Antipolis - Méditerranée
Sophia Antipolis Cedex, France
Part I Methodologies
v
vi Contents
Y Boykov
In the last 20 years the computer vision and medical imaging communities have
produced a number of useful algorithms for localizing object boundaries in images.
The most basic methods like thresholding and region growing are simple heuristics
that work well only for a fairly limited class of problems: either there should be
100 % consistent intensity edges on the object boundary, or there should be 0 %
overlap between the object and background intensity histograms. In practice, there
are relatively few applications where object appearance satisfies such assumptions
(one good example is [24]). More robust segmentation techniques are needed in
most applications that do not support such strong assumptions.
More advanced segmentation methods typically compute optimal con-
tours/surfaces for specific energy functionals combining different boundary and/or
region-based cues for an object of interest. Examples of such energy-based object
extraction methods are snakes [36], balloons [18], other active contour models [30],
geometric methods [14, 68], “shortest path” techniques [21, 50], ratio cycles [33],
ratio cuts [65], random walker [27], graph cuts [4, 8, 9, 37, 41], continuous max-
flow [2], total variation (TV) [15], and TV-based convex relaxation methods [16].
implicit level set [14, 17, 52] graph cut [8, 9, 4, 39]
(region-based) PDE cuts [11] continuous max-flow [2]
TV convex relaxation [16]
Fig. 1 Object extraction methods using contour/surface energy functionals. Only a few represen-
tative references are shown for each method
To solve an image segmentation problem, one should first decide how to numerically
represent contours or surfaces. Many existing segmentation methods (Fig. 1) use
explicit representation of contours/surfaces based on meshes or splines defined by a
set of moving or “active” control points forming a chain [1, 18, 25, 30, 36]. A 2D
1
Impossibility theorem in [38] shows that no clustering algorithm can simultaneously satisfy three
basic axioms on scale-invariance, richness, and consistency. Thus, any clustering method has some
bias.
Object Segmentation and Markov Random Fields 5
Each surface representation approach may have some advantages and disad-
vantages. For example, methods using control points may suffer from mesh
irregularities and from rigid topological structure of surfaces they represent. Dis-
crete approaches based on graphs/trees and dynamic programming must address
potential geometric metrication artifacts. Some types of representation are specific
2
If necessary, one can build a graph with resolution finer than the pixel grid.
6 Y. Boykov
could be unacceptable. For example, the trivial null solution is a global minima
in some segmentation problems since length/area of the segmentation boundary is
a typical regularizing component in most energy functionals. Some methods add
a ballooning term to their energy or constrain solution space to avoid trivial/null
solutions. Computing local minima could be another reasonable and efficient
alternative if good initial solution is available. Interestingly, graph cut approach
can also be used for local optimization when the search space is appropriately
constrained near given initial solution [11].
variational techniques using the same energy may depend on their implementation
details.
Discrete optimization methods in (B) are numerically robust and “repeatable”.
For example, assuming the same energy function, one would always get identical
segments even though one can choose from a number of different combina-
torial min-cut/max-flow algorithms for computing minimum s-t cuts on graphs
[10, 23, 26].
[10, 20, 35] studied practical efficiency of combinatorial min-cut/max-flow
algorithms on applications in computer vision. It was shown that some max-flow
techniques could solve 2D and 3D segmentation problems in close to real-time using
regular PCs. Graph cut methods allow a user to change hard and soft constraints on-
a-fly [4, 7, 8] enabling fast interactive editing of the segments. Significant speed-ups
were demonstrated for dynamic segmentation problems using flow-recycling [39]
and cut-recycling [34]. While straightforward implementation of graph cuts may
require a lot of memory in 3D applications, [46, 49] showed that multi-level and
adaptive banded techniques can alleviate the problem. Recent region-push-relabel
algorithm [20]3 demonstrated good scalability to large 3D volumes under limited
memory resources and significant speed-ups for multi-processor PCs.
3
[20] can be seen as a hierarchical version of standard push-relabel method [26].
Object Segmentation and Markov Random Fields 9
In this sections we review relationship between graph cut methods for object
extraction and estimation of Markov Random Fields. Greig et al. [28] were
first to recognize that powerful max-flow/min-cut algorithms from combinatorial
optimization can be applied to problems in computer vision. In particular, they
4
[37] is a notable exception.
10 Y. Boykov
showed that graph cuts can be used for restoration of binary images.5 This problem
can be formulated as Maximum A Posterior estimation of a Markov Random Field
(MAP-MRF) that required minimization of posterior energy
X X
E.I / D – In Pr Ip jI C ıIp ¤Iq (1.1)
p2P fp;qg2N
where
1 if Ip ¤ Iq
ıIp ¤ Iq D
0 if Ip D Iq :
5
A typed or hand-written letter is an example of a binary image. Restoration of such an image may
involve removal of a salt and pepper noise.
Object Segmentation and Markov Random Fields 11
This section describe basic MRF object segmentation framework in more detail.
First, consider some terminology. A graph G D hV ; E i is defined as a set of nodes
or vertices V and a set of edges E connecting “neighboring” nodes. For simplicity,
we mainly concentrate on undirected graphs where each pair of connected nodes is
described by a single edge e D fp; qg 2 E 6 . A simple 2D example of an undirected
graph that can be used for image segmentation is shown in Fig. 2(b).
The nodes of our graphs represent image pixels or voxels. There are also two
specially designated terminal nodes S (source) and T (sink) that represent “object”
and “background” labels. Typically, neighboring pixels are interconnected by edges
in a regular grid-like fashion. Edges between pixels are called n-links where n stands
for “neighbor”. Note that a neighborhood system can be arbitrary and may include
diagonal or any other kind of n-links. Another type of edges, called t-links, are used
to connect pixels to terminals. All graph edges e 2 E including n-links and t-links
are assigned some nonnegative weight (cost) we . In Fig. 2(b) edge costs are shown
by the thickness of edges.
An s-t cut is a subset of edges C E such that the terminals S and T become
completely separated on the induced graph G .C / D hV ; E nC i. Note that a cut
(see Fig. 2(c)) divides the nodes between the terminals. As illustrated in Fig. 2
(c-d), any cut corresponds to some binary partitioning of an underlying image
into “object” and “background” segments. Note that in the simplistic example of
Fig. 2 the image is divided into one “object” and one “background” regions. In
general, cuts can generate binary segmentation with arbitrary topological properties.
6
Each pair of connected nodes on a directed graph is linked by two distinct (directed) edges (p, q)
and (q, p). Directed edges can be useful in applications (see Sect. 3.3).
12 Y. Boykov
Fig. 2 A simple 2D segmentation example for a 3 X 3 image. The seeds are O D fvg and B D
fpg. The cost of each edge is reflected by the edge’s thickness. The boundary term (1.4)
defines the costs of n-links while the regional term (1.3) defines the costs of t-links. Inexpensive
edges are attractive choices for the minimum cost cut. Hard constraints (seeds) (1.8,1.9) are
implemented via infinity cost t-links. A globally optimal segmentation satisfying hard constraints
can be computed efficiently in low-order polynomial time using max-flow /min-cut algorithms on
graphs [23, 26, 19]
Examples in Sect. 4 illustrate that object and background segments may consist of
several isolated connected blobs that also may have holes.
The goal is to compute the best cut that would give an “optimal” segmentation.
In combinatorial optimization the cost of a cut is defined as the sum of the costs of
edges that it severs
X
jC j D we
e2C
Note that severed n-links are located at the segmentation boundary. Thus, their
total cost represents the cost of segmentation boundary. On the other hand, severed
t-links can represent the regional properties of segments. Thus, a minimum cost cut
Object Segmentation and Markov Random Fields 13
Consider an arbitrary set of data elements (pixels or voxels) P and some neighbor-
hood system represented by a set N of all (unordered) pairs fp, qg of neighboring
elements in P. For example, P can contain pixels (or voxels) in a 2D (or 3D)
grid and N can contain all unordered pairs of neighboring pixels (voxels) under
a standard 8 (or 26-) neighborhood system. Let A D .A1 ; : : : ; Ap ; : : : ; AjPj / be a
binary vector whose components Ap specify assignments to pixels p in P. Each Ap
can be either “obj” or “bkg” (abbreviations of “object” and “background”). Vector A
defines a segmentation. Then, the soft constraints that we impose on boundary and
region properties of A are described by the cost function
where
X
R.A/ D Rp Ap .regional term/ (1.3)
p2P
X
B.A/ D Bp;q ıAp ¤Aq .boundary term/ (1.4)
fp;qg2N
and
1 if Ap ¤ Aq
ıAp ¤Aq D
0 if Ap D Aq :
a b c
Pr(I)
1.0
0.9
background
object
0.1
0.0 I
dark bright
Image Histograms Segmentation
Fig. 3 Synthetic Gestalt example. The optimal object segment (red area in (c)) finds a balance
between “region” and “boundary” terms in (1.2). The solution is computed using graph cuts. Some
ruggedness of the segmentation boundary is due to metrication artifacts that can be realized by
graph cuts in textureless regions. Such artifacts can be minimized [9]
R p () may reflect on how the intensity of pixel p fits into given intensity models (e.g.
histograms) of the object and background
This function penalizes a lot for discontinuities between pixels of similar intensities
when jIp Iq j < . However, if pixels are very different, jIp Iq j > , then the
penalty is small. Intuitively, this function corresponds to the distribution of noise
among neighboring pixels of an image. Thus, can be estimated as “camera noise”.
A simple example of Fig. 3 illustrates some interesting properties of our cost
function (1.2). The object of interest is a cluster of black dots in Fig. 3(a) that we
Object Segmentation and Markov Random Fields 15
would like to segment as one blob. We combine boundary and region terms (1.3,1.4)
taking 0 in (1.2). The penalty for discontinuity in the boundary cost is
1 if Ip ¤ Iq
Bp;q D
0:2 if Ip D Iq :
Ip Rp (“obj”) Rp (“bkg”)
dark 2.3 C1
bright 0.1 0
The optimal segmentation in Fig. 3(c) finds a balance between the regional and
the boundary term of energy (1.2). Individually, bright pixels slightly prefer to stay
with the background (see table above). However, spatial coherence term (1.4) forces
some of them to agree with nearby dark dots which have a strong bias towards the
object label (see Table).
In the simple example of Fig. 3 the regional properties of the object of interest
are distinct enough to segment it from the background. In real examples, however,
objects may not have sufficiently distinct regional properties. In such cases it
becomes necessary to further constraint the search space of possible solutions before
computing an optimal one.
Assume that O and B denote the subsets of pixels a priori known to be a part
of “object” and “background”, correspondingly. Naturally, the subsets O P and
B P are such that O \ B D Ø. For example, consider sets O (red pixels) and
B (blue pixels) in Fig. 4(b). Our goal is to compute the global minimum of (1.2)
among all segmentations A satisfying hard constraints
8p 2 O W Ap D “obj” (1.8)
8p 2 B W Ap D “bkg” (1.9)
16 Y. Boykov
a
source
s
cut b c d
p q
t
sink
directed graph image undir. result dir. result
Fig. 5 Segmentation via cuts on a directed graph. Compare the results on an undirected graph (c)
with the results on a directed graph in (d)
object segment from brighter tissue (bone) in the background. On the other hand,
the correct object boundary in (d) goes from brighter tissue (liver) in the object to
darker tissue (muscle) in the background. Note that directed edge weights
8
< 1 if Ip Iq
w.p;q/ D .Ip Iq /
2
: exp 2 2 if Ip > Iq
would specifically encourage cuts from brighter tissue in the object to darker tissue
in the background. The results in Fig. 5(d) show optimal segmentation on a directed
graph using such edge weights.
4 Some examples
We demonstrate a few examples of original image data and segments gener ated by
graph cuts for a given set of hard constraints. User can enter hard constraints (seeds)
via mouse operated brush of red (for object) or blue (for background) color. We used
simple 4-neighborhood systems in 2D examples and 26-neighborhood system in 3D
examples. All running times are given for 1.4GHz Pentium III. Our implementation
is based on “max-flow” algorithm from [10].
Figures 6, and 7 show segmentation results that we obtained on a 3D medical
volumes. Each object was segmented in 10 to 30 seconds. In the examples of Fig. 6
and 7 the objects were extracted from 3D volumes after entering seeds in only one
slice shown in (a).
Object Segmentation and Markov Random Fields 19
Fig. 8 Kidney in a 3D MRI angio data [55x80x32] segmented into cortex, medulla, and collecting
system
20 Y. Boykov
We did not use regional term (1.3) for the experiments in Figs. 6, and 7.
In some applications, however, the regional term may significantly simplify, if
not completely automate, the segmentation process. In Fig. 8 we demonstrate
segmentation on 3D kidney MR data that benefited from regional term (1.3).
We segmented out cortex, medulla, and collecting system of a kidney in three
consecutive steps. First, the whole kidney is separated from the background and
the latter is cropped. The remaining pixels belong to three distinct types of kidney
tissue (cortex, medulla, or collecting system) with identifiable regional properties.
At this point it becomes useful to engage the regional term (1.3) of energy.
The results in Fig. 8 are shown without seeds since the process involved three
different segmentations. Using regional bias allows to get 3D segmentation results
by entering only a few seeds in one slice. Initial optimal segments are computed
in 1-10 seconds and minor correction can be incor porated in less then a second.
This example also demonstrates unrestricted topological properties of our segments.
Fully automatic segmentation of kidney might be possible with more sophisticated
models for regional.
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Fuzzy methods in medical imaging
I. Bloch
Abstract Fuzzy sets theory is of great interest in medical image processing, for
dealing with imprecise information and knowledge. It provides a consistent mathe-
matical framework for knowledge representation, information modeling at different
levels, fusion of heterogeneous information, reasoning and decision making. In this
chapter, we provide an overview of the potential of this theory in medical imaging,
in particular for classification, segmentation and recognition of anatomical and
pathological structures.
1 Introduction
Imprecision is often inherent to images, and its causes can be found at several levels:
observed phenomenon (imprecise limits between structures or objects), acquisition
process (limited resolution, numerical reconstruction methods), image processing
steps (imprecision induced by a filtering for instance). Fuzzy sets have several
advantages for representing such imprecision. First, they are able to represent
several types of imprecision in images, as for instance imprecision in spatial location
of objects, or imprecision in membership of an object to a class. For instance,
partial volume effect, which occurs frequently in medical imaging, finds a consistent
representation in fuzzy sets (membership degrees of a voxel to tissues or classes
directly represent partial membership to the different tissues mixed up in this voxel,
leading to a consistent modeling with respect to reality). Second, image information
can be represented at different levels with fuzzy sets (local, regional, or global), as
well as under different forms (numerical, or symbolic). For instance, classification
based only on grey levels involves very local information (at the pixel level);
I. Bloch ()
Signal and Image Processing, Telecom ParisTech - CNRS LTCI,
46 rue Barrault, Paris 75013, France
e-mail: [email protected]
2 Low-level processing
The use of fuzzy sets in medical imaging at low level concerns mainly classification,
often based on grey levels.
2.1 Representation
We denote by S the spatial domain (Rn in the continuous case or Zn in the discrete
case). Fuzzy sets can be considered from two points of view. In the first one, a
membership function is a function from the space S on which the image is
defined into Œ0; 1. The value .x/ is the membership degree of x (x 2 S ) to
a spatial fuzzy object. In the second one, a membership function is defined as
a function 0 from a space of attributes A into Œ0; 1. At numerical level, such
attributes are typically the grey levels. The value 0 .g/ represents the degree to
which a grey level g supports the membership to an object or a class. There is an
obvious relation between and 0 in grey level based processing: .x/ D 0 Œg.x/,
where g.x/ denotes the grey level of x in the considered image.
Fuzzy methods in medical imaging 27
Fig. 1 MR image of the brain (left) (courtesy Prof. C. Adamsbaum, Saint-Vincent de Paul
Hospital, Paris), and estimation of the partial membership to the pathology (right) in the
pathological area (white means that there is only pathological tissue in the considering voxel,
black means no pathological tissue, and intermediate values represent the partial volume effect,
i.e. voxels that have also a non zero membership value to the white matter class)
m1 m2
Learning of membership functions is a difficult task that still does not have a definite
answer. Several methods have been proposed in the literature, often based on the
minimization of some criteria. Among these methods, the most used is the fuzzy
C-means algorithm (FCM) [5]. The idea is to define a membership function of a
point to each class (which is then a fuzzy set), instead of deriving crisp assignments.
The FCM algorithm iteratively modifies
P Pa fuzzy partition so as to minimize an
objective function defined as: Jm D CjD1 N m
ij jjxi mj jj , under the constraint
2
PC i
that 8i; j D1 ij D 1, where C denotes the number of class, N the number
of points to be classified, ij the membership function of point i to class j , and
m is a parameter belonging to 1; C1Œ called fuzzy factor, which controls the
amount of “fuzziness” of the classification. The membership function is deduced
from the cluster center position as: ij D PC jjxi1mi jj 2 , and the cluster center
j D1 Œ jjxi mj jj/ m1
P m
xi
position is obtained by: mj D Pi ijm . From an initialization of cluster centers,
i ij
the membership values and cluster centers are alternatively updated using these
two equations, until convergence. Convergence towards a local minimum of the
objective function has been proved. An example is provided in Fig. 2, in the case
of a 1-dimensional 2-class problem. It also illustrates one of the main drawbacks
of this approach: the membership functions are not decreasing with respect to the
distance to the cluster center. This is due to the normalization constraint, and this
phenomenon gets even worse with more classes.
Fuzzy methods in medical imaging 29
Fig. 3 MR image of the brain, showing three main classes: brain, ventricles and pathology (the
white area on the left image), and result of the estimation of the three classes
Despite their drawbacks, these methods are quite widely used, mostly as an
initialization for further more sophisticated processing. For instance, an adaptive
C-means algorithm was used in [69] in order to take the partial volume effect into
account in a deformable model approach. An original fuzzy classification method
taking spatial context into account was also used as the initialization of a deformable
model in [38] for segmenting brain tumors of different types, shapes and locations
in 3D MRI. Some results are shown in Sect. 6.
In this section, we summarize the main techniques for local filtering in a broad sense,
aiming at enhancing the contrast of an image, at suppressing noise, at extracting
contours, etc. Note that these aims are different and often contradicting each other.
However, the principles of the techniques are similar, and they can be grouped into
two classes: techniques based on functional optimization on the one hand, and rule
based techniques on the other hand. These aspects have been largely developed in
the literature (see e.g. [2, 6, 42, 67]), and we provide here just the main lines.
Functional approaches consist in minimizing or maximizing a functional, which
can be interpreted as an analytical representation of some objective. For instance,
enhancing the contrast of an image according to this technique amounts to reduce
the fuzziness of the image. This can be performed by a simple modification of
membership functions (for instance using intensification operators), by minimizing
a fuzziness index such as entropy, or even by determining an optimal threshold value
Fuzzy methods in medical imaging 31
(for instance optimal in the sense of minimizing a fuzziness index) which provides
an extreme enhancement (until binarization) [51, 52].
Other methods consist in modifying classical filters (median filter for instance)
by incorporating fuzzy weighting functions [43].
Rule based techniques rely on ideal models (of filters, contours, etc.). These
ideal cases being rare, variations and differences with respect to these models are
permitted through fuzzy representations of the models, as fuzzy rules. For instance,
a smoothing operator can be expressed by [62, 63]:
IF a pixel is darker than its neighbors
THEN increase its grey level
ELSE IF the pixel is lighter than its neighbors
THEN decrease its grey level
OTHERWISE keep it unchanged
In this representation, the emphasized terms are defined by fuzzy sets or fuzzy oper-
ations. Typically, the grey level characteristics are defined by linguistic variables,
the semantics of which are provided by fuzzy sets on the grey level interval. Actions
are fuzzy functions applied on grey levels and on pixels. The implementation of
these fuzzy rules follows the general principles of fuzzy logic [30].
More complex rules can be found, for instance in [41, 56], where a contour
detector is expressed by a set of rules involving the gradient, the symmetry and
the stiffness of the contour. Fuzzy rule based systems have also been proposed for
contour linking, based on proximity and alignment criteria.
Note that rules are sometimes but a different representation of functional
approaches. Their main advantage is that they are easy to design (in particular for
adaptive operators) and to interpret, and they facilitate the communication with the
user.
3 Intermediate level
Several operations have been defined in the literature on fuzzy objects, in particular
spatial fuzzy objects, since the early works of Zadeh [71] on set operations, and of
Rosenfeld on geometrical operations [60].
Typical examples of geometrical operations are area and perimeter of a fuzzy
object. They can be defined as crisp numbers, where the computation involves each
point up to its degree of membership. But since objects are not well defined, it can
also be convenient to consider that measures performed on them are imprecise too.
This point of view leads to definitions as fuzzy numbers [30].
Such geometrical measures can typically be used in shape recognition, where
geometrical attributes of the objects are taken into account.
As an example, fuzzy measures have been used in [58] for detecting masses in
digital breast tomosynthesis. The measures are performed on detected fuzzy regions,
32 I. Bloch
that are considered as candidate particles (Fig. 4). A decision concerning their
recognition is performed by combining fuzzy attributes. Fuzzy decision trees can
be used to this aim [20, 53].
It has been shown in [65, 66] that using fuzzy representations of digital objects
allow deriving more robust measures than using crisp representations, and in
particular dealing properly with the imprecision induced by the digitization process.
Such measures can also be used as descriptors for indexation and data mining
applications.
Let us now consider topological features and the example of fuzzy connectivity.
The degree of connectivity between two points x and y in a fuzzy object in a
finite discrete space is defined as [60]: c .x; y/ D maxLxy minti 2Lxy .ti /, where
Lxy is any path from x to y. This definition was exploited in fuzzy connectedness
notions [68], now widely used in medical image segmentation and incorporated in
freely available softwares such as ITK1 .
Morphological operations have also been defined on fuzzy objects (see e.g. [17]).
We give here general definitions, for fuzzy erosion and dilation, from which several
other morphological operations can be derived:
In these equations, denotes the fuzzy set to be dilated or eroded, the fuzzy
structuring element, t a conorm (fuzzy intersection), T the t-conorm (fuzzy union)
associated to t with respect to the complementation c.
1
http://www.itk.org/
Fuzzy methods in medical imaging 33
Such fuzzy morphological operations have been used in medical imaging for
instance for taking into account the spatial imprecision on the location of vessel
walls for 3D reconstruction of blood vessels by fusing angiographic and ultrasonic
acquisitions [19]. They also constitute a good formal framework for defining fuzzy
spatial relations, as will be seen in Sect. 4. Another application of fuzzy morphology
is for defining median fuzzy sets and series of interpolating fuzzy sets [12], which
can typically be used for representing variability based on several instances of an
anatomical structures or for atlas construction. An example is illustrated in Fig. 5.
Some approaches using fuzzy rules can also be found at intermediate level. Let us
just mention two examples. The first one [28] deals with the segmentation of osseous
surface in ultrasound images. It uses fuzzy representations of image intensity and
gradient, as well as their fusion, in rules that mimic the reasoning process of a
medical expert and that include knowledge about the physics of ultrasound imaging.
This approach was successfully tested on a large image data set.
The second example is completely different and fuzzy rules are used in [24] to
tune the parameters of a deformable model for segmenting internal structures of
the brain. This approach elegantly solves the difficult problem of parameter tuning
in such segmentation methods, and proved to provide very good results on normal
cases.
4 Higher level
The main information contained in the images consists of properties of the objects
and of relations between objects, both being used for pattern recognition and
scene interpretation purposes. Relations between objects are particularly important
since they carry structural information about the scene, by specifying the spatial
arrangements between objects. These relations highly support structural recognition
based on models. This models can be of iconic type, as an anatomical atlas, or
of symbolic type, as linguistic descriptions or ontologies. Although the use of
iconic representations for normal structure recognition is well acknowledged, they
remain difficult to exploit in pathological cases. Anatomical knowledge is also
34 I. Bloch
Fig. 6 Fuzzy region between the lungs, segmentation of the lungs and the heart on an axial slice
and a coronal one
An example of using the second type of question was used for segmenting the
heart in low resolution CT images [46], relying on the anatomical knowledge “the
heart is between the lungs”. The translation of this knowledge uses an original
definition of the concept “between” [15], that defines a fuzzy region of interest in
which the heart can then be segmented using a deformable model integrating the
spatial relation contraints, as in [26]. An example is shown in Fig. 6.
Further examples in brain imaging will be illustrated in Sect. 6.
5 Fusion
As seen in the previous sections, a lot of approaches, whatever their level, involve
fusion steps.
Information fusion becomes increasingly important in medical imaging due to
the multiplication of imaging techniques. The information to be combined can be
issued from several images (like multi-echo MR images for instance), or from one
image only, using for instance combination of several relations between objects or
several features of the objects, or from images and a model, like an anatomical atlas,
or knowledge expressed in linguistic form or as ontologies.
The advantages of fuzzy sets and possibilities rely in the variety of combination
operators, offering a lot of flexibility in their choice, and which may deal with
heterogeneous information [32, 70]. We proposed a classification of these operators
with respect to their behavior (in terms of conjunctive, disjunctive, compromise
[32]), the possible control of this behavior, their properties and their decisiveness,
which proved to be useful for several applications in image processing [7]. It is
of particular interest to note that, unlike other data fusion theories (like Bayesian or
Dempster-Shafer combination), fuzzy sets provide a great flexibility in the choice of
the operator, that can be adapted to any situation at hand. Indeed, image fusion has
often to deal with situations where an image is reliable only for some classes, or does
36 I. Bloch
Fig. 7 Dual echo MR image of the brain, showing three main classes: brain, ventricles and
pathology (the white area on the middle image). Right: final decision after fuzzy combination
(note that the decision is taken at each pixel individually, without spatial regularization)
not provide any information about some class, or is not able to discriminate between
two classes while another does. In this context, some operators are particularly
powerful, like operators that behave differently depending on whether the values
to be combined are of the same order of magnitude or not, whether they are small or
high, and operators that depend on some global knowledge about source reliability
about classes, or conflict between images (global or related to one particular class).
The combination process can be done at several levels of information representation,
from pixel level to higher level. A noticeable advantage of this approach is that it is
able to combine heterogeneous information, like it is usually the case in multi-image
fusion.
At a numerical level, the typical application is multi-source classification. We
show an example of image fusion problem in brain imaging, where we combine
dual-echo brain MR images in order to provide a classification of the brain into
three classes: brain, ventricles and CSF, and pathology. These images are shown
in Fig. 7. The membership functions for these classes have been estimated in a
completely unsupervised way on both images, as described before. We then use
these membership functions in a fuzzy fusion scheme [13]. Since both images
provide similar information about the ventricles, we use a mean operator to
combine the membership functions obtained in both images for this class. Brain
and pathology cannot be distinguished in the first echo and we obtain only one class
for this image, denoted by 1c . In the second image, we obtain two classes denoted
by 2c and 2pat h respectively. We combine 1c and 2c using an arithmetical mean
again. As for the pathology, we combine 1c and 2pat h using a symmetrical sum
ab
defined as: 1abC2ab . This guarantees that no pathology is detected in the areas
where pat h D 0, and this reinforces the membership to that class otherwise, in
2
order to include the partial volume effect areas in the pathology (this corresponds to
what radiologists do). After the combination, the decision is made according to the
maximum of membership values. The result is shown in Fig. 7 (right).
Fuzzy methods in medical imaging 37
Let us now illustrate how fuzzy spatial relations can be used for recognizing struc-
tures in a scene based on a model. The chosen example concerns the recognition of
internal brain structures (ventricular system and grey nuclei) in 3D MRI. Two types
of approaches have been developed, that correspond to the two types of questions
raised in Sect. 4.
In the first approach, which relies on the first type of question, spatial relations
evaluated between spatial entities (typically objects or regions) are considered as
attributes in a graph. The model is a graph derived from an anatomical atlas.
Each node represents an anatomical structure, and edges represent spatial relations
between these structures. A data graph is constructed from the MRI image where
recognition has to be performed. Each node represents a region obtained from a
segmentation method. Since it is difficult to segment directly the objects, usually
the graph is based on an over-segmentation of the image, for instance based on
watersheds. Attributes are computed as for the model. The use of fuzzy relations is
particularly useful in order to be less sensitive to the segmentation step.
38 I. Bloch
In the second type of approach, relying on the second type of question, we use
spatial representations of spatial knowledge [16, 26]. It consists in first recognizing
simple structures (typically brain and lateral ventricles), and then progressively
more and more difficult structures, based on relations between these structures and
Fuzzy methods in medical imaging 39
previously recognized ones. The order in which structures can be recognized can be
provided by the user, or estimated as suggested in [34, 35]. Each relation describing
the structure to be recognized is translated into a spatial fuzzy set representing
the area satisfying this relation, to some degree. The fuzzy sets representing all
relations involved in the recognition process are combined using a numerical fusion
operator. While we first used an atlas in [16], this constraint has been relaxed in our
recent work [26,35]. This presents two main advantages: the high computation time
associated with the computation of a deformation field between the atlas and the
image is left aside and the procedure is potentially more robust because it uses only
knowledge expressed in symbolic form, which is generic instead of being built from
a single individual as in the iconic atlas.
Finally, a refinement stage is introduced using a deformable model. This stage
uses an initial classification (using a low level approach based on grey levels) as a
starting point and has the potential to correct possible imperfections of the previous
stage together with regularizing the contours of structures. This deformable model
makes use of a fusion of heterogeneous knowledge: edge information derived from
the image, regularization constraints and spatial relations contained in the linguistic
description. All pieces of information are combined in the energy of a parametric
deformable model. For instance the caudate nucleus can be recognized based on
its grey level (roughly known depending on the type of acquisition), and, more
importantly, on its relations to the lateral ventricles (exterior and close to them).
Here, the primary role of spatial relations is to prevent the deformable model from
progressing beyond the limit of structures with weak boundaries.
Figure 9 shows 3D views of some cerebral objects recognized in an MR image
with our method. In particular, the importance of spatial relations is illustrated in
the case of the caudate nucleus. The lower part of this structure has a very weakly
defined boundary and the use of a spatial relation is essential to achieve a good
segmentation.
One of the advantages of this approach is that it can be extended to pathological
cases, since spatial relations remain quite stable in the presence of pathologies,
unlike shapes and absolute locations. Moreover, it is possible to learn the parameters
of the relations, and their stability according to the type of pathology [3, 37]. Two
examples of segmentation and recognition results in pathological cases are shown in
Fig. 10, based on a segmentation of the tumor (based on fuzzy classification) [38].
7 Conclusion
In this chapter, several examples illustrating the potential of fuzzy methods for
medical imaging have been described. While low level methods are still the most
widely used, recently several higher level approaches were developed, based on
40 I. Bloch
thalamus (2)
lateral ventricles (2)
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Curve Propagation, Level Set Methods
and Grouping
N. Paragios
Abstract Image segmentation and object extraction are among the most
well addressed topics in computational vision. In this chapter we present a
comprehensive tutorial of level sets towards a flexible frame partition paradigm that
could integrate edge-drive, regional-based and prior knowledge to object extraction.
The central idea behind such an approach is to perform image partition through the
propagation planar curves/surfaces. To this end, an objective function that aims to
account for the expected visual properties of the object, impose certain smoothness
constraints and encode prior knowledge on the geometric form of the object to be
recovered is presented. Promising experimental results demonstrate the potential of
such a method.
1 Introduction
Image segmentation has been a long term research initiative in computational vision.
Extraction of prominent edges [14] and discontinuities between in-homogeneous
image regions was the first attempt to address segmentation. Statistical methods
that aim to separate regions according to their visual characteristics was an attempt
to better address the problem [11], while the snake/active contour model [16] was a
breakthrough in the the domain.
Objects are represented using parametric curves and segmentation is obtained
through the deformation of such a curve towards the lowest potential of an objective
function. Data-driven as well as internal smoothness terms were the components of
such a function. Such a model refers to certain limitations like, the initial conditions,
the parameterisation of the curve, the ability to cope with structures with multiple
components, and the estimation of curve geometric properties.
N. Paragios ()
Center for Visual Computing, Department of Applied Mathematics,
Ecole Centrale Paris, Paris, France
e-mail: [email protected]
Balloon models [8] where a first attempt to make the snake independent with
respect to the initial conditions, while the use of regional terms forcing visual
homogeneity [45] was a step further towards this direction. Prior knowledge was
also introduced at some later point [37] through a learning stage of the snake
coefficients. Geometric alternatives to snakes [3] like the geodesic active contour
model [4] were an attempt to eliminate the parameterisation issue.
Curves are represented in an implicit manner through the level set method [24].
Such an approach can handle changes of topology and provide sufficient support to
the estimation of the interface geometric properties. Furthermore, the use of such
a space as an optimisation framework [44], and the integration of visual cues of
different nature [25] made these approaches quite attractive to numerous domains
[23]. One can also point recent successful attempts to introduce prior knowledge
[19, 32] within the level set framework leading to efficient object extraction and
tracking methods [33].
To conclude, curve propagation is an established technique to perform object
extraction and image segmentation. Level set methods refer to a geometric
alternative of curve propagation and have proven to be a quite efficient optimisation
space to address numerous problems of computational vision. In this chapter, first
we present the notion of curve optimisation in computer vision, then establishes
a connection with the level set method and conclude with the introduction of
ways to perform segmentation using edge-driven, statistical clustering and prior
knowledge terms.
where N is the inward normal and Fgm depends on the spatial derivatives of the
curve, the curvature, etc. On the other hand, Fimg is the force that connects the
propagation with the image domain and Fpr () is a speed term that compares the
evolving curve with a prior and enforces similarity with such a prior. The tangential
component of this flow has been omitted since it affects the internal position of the
control points and doesn’t change the form of the curve itself.
Such an approach refers to numerous limitations. The number and the sampling
rule used to determined the position of the control points can affect the final
segmentation result. The estimation of the internal geometric properties of the
curve is also problematic and depends on the sampling rule. Control points move
according to different speed functions and therefore a frequent re-parameterisation
of the contour is required. Last, but no least the evolving contour cannot change the
topology and one cannot have objects that consist of multiple components that are
not connected.
The level set method was first introduced in [10] and re-invented in [24] to
track moving interfaces in the community of fluid dynamics and then emerged in
computer vision [3, 21]. The central idea behind these methods is to represent the
(closed) evolving curve with an implicit function that has been constructed as
follows:
8
< 0; s 2
.s/ D –; s 2 i n
:
C –; s 2 out
where epsilon is a positive constant, in the area inside the curve and out the area
outside the curve as shown in [Fig. (1)]. Given the partial differential equation that
dictates the deformation of one now can derive the one for using the chain rule
according to the following manner:
48 N. Paragios
Fig. 2 Demonstration of curve propagation with the level set method; handling of topological
changes is clearly illustrated through various initialization configurations (a,b,c)
@ . .pI // @ .pI / @
. .pI // D C D F .r N / C D 0 (3)
@ @ „ ƒ‚@ … @
FN
Let us consider the arc-length parameterisation of the curve (c). The values of
along the curve are 0 and therefore taking the derivative of along the curve
will lead to the following conditions:
@ ..c// @ @
D0! ..c// D 0 ! r.c/ T .c/ D 0 (4)
@c @ @c
Curve Propagation, Level Set Methods and Grouping 49
where T (c) is the tangential vector to the contour. Therefore one can conclude that
r is orthogonal
h to the contour
i and can be used (upon normalisation) to replace the
r
inward normal N D jrj leading to the following condition on the deformation
of :
F jj C D 0 ! D F jj (5)
Such a flow establishes a connection between the family of curves that have
been propagated according to the original flow and the ones recovered through the
propagation of the implicit function . The resulting flow is parameter free, intrinsic,
implicit and can change the topology of the evolving curve under certain smoothness
assumptions on the speed function F. Last, but not least, the geometric properties of
the curve like its normal and the curvature can also be determined from the level set
function [24]. One can see a demonstration of such a flow in [Fig. (2)].
In practice, given a flow and an initial curve the level set function is constructed
and updated according to the corresponding motion equation in all pixels of the
image domain. In order to recover the actual position of the curve, the marching
cubes algorithm [20] can be used that is seeking for zero-crossings. One should pay
attention on the numerical implementation of such a method, in particular on the
estimation of the first and second order derivatives of , where the ENO schema
[24] is the one to be considered. One can refer to [36] for a comprehensive survey
of the numerical approximation techniques.
In order to decrease computational complexity that is inherited through the
deformation of the level set function in the image domain, the narrow band
algorithm [7] was proposed. The central idea is update the level set function only
within the evolving vicinity of the actual position of the curve. The fast marching
algorithm [35, 40] is an alternative technique that can be used to evolve curves
in one direction with known speed function. One can refer to earlier contribution
in this book [Chap. 7] for a comprehensive presentation of this algorithm and its
applications. Last, but not least semi-implicit formulations of the flow that guides
the evolution of were proposed [12, 42] namely the additive operator splitting.
Such an approach refers to a stable and fast evolution using a notable time step
under certain conditions.
The implementation of curve propagation flows was the first attempt to use the level
set method in computer vision. Geometric flows or flows recovered through the
optimisation of snake-driven objective functions were considered in their implicit
nature. Despite the numerous advantages of the level set variant of these flows,
their added value can be seen as a better numerical implementation tool since the
definition of the cost function or the original geometric flow is the core part of the
50 N. Paragios
solution. If such a flow or function does not address the desired properties of the
problem to be solved, its level set variant will fail. Therefore, a natural step forward
for these methods was their consideration in the form of an optimisation space.
Such a framework was derived through the definition of simple indicator func-
tions as proposed in [44] with the following behaviour
8
< 1; > 0
0; ¤ 0
ı ./ D ; H ./ D 0; D 0 (6)
1; D 0 :
0; < 0
Once such indicator functions have been defined, an evolving interface can be
considered directly on the level set space as
D fs 2 W ı ./ D 1g (7)
while one can define a dual image partition using the H indicator functions as:
i n D fs 2 W H ./ D 1g
(8)
out D fs 2 W H ./ D 0g ; i n [ out D
8
ˆ
<1 ; > ˛
H˛ ./ D 0 ; < –˛
:̂ 1 1 C
C 1
sin
; jj < ˛
2 ˛ ˛
Such an indicator function has smooth, continuous derivatives and the following
nice property:
@
H˛ ./ D ı˛ ./
@
Last, but not least one consider the implicit function to be a signed distance
transform D(s, ),
8
< 0; s2
.s/ D D .s; / ; s 2 i n (10)
:
D .s; / ; s 2 i n D out
Curve Propagation, Level Set Methods and Grouping 51
3 Data-driven Segmentation
The first attempt to address such task was made in [21] where a geometric flow
was proposed to image segmentation. Such a flow was implemented in the level set
space and aimed to evolve an initial curve towards strong edges constrained by the
curvature effect. Within the last decade numerous advanced techniques have taken
advantage of the level set method for object extraction.
The geodesic active contour model [4, 17] - a notable scientific contribution in the
domain - consists of
Z 1
ˇ ˇ
E ./ D g .jrI ..p//j / ˇ 0 .p/ˇ dp (11)
0
where I is the output of a convolution between the input image and a Gaussian
kernel and g is a decreasing function of monotonic nature. Such a cost function
seeks a minimal length geodesic curve that is attracted to the desired image features,
and is equivalent with the original snake model once the second order smoothness
component was removed. In [4] a gradient descent method was used to evolve
an initial curve towards the lowest potential of this cost function and then was
implemented using the level set method.
A more elegant approach is to consider the level set variant objective function of
the geodesic active contour;
“
E ./ D ı˛ . .!// g .jrI .!/j/ jr .!/j d! (12)
where is now represented in an implicit fashion with the zero-level set of . One
can take take the derivative of such a cost function according to :
r
D ı˛ ./ div g.I / (13)
jrj
52 N. Paragios
where ! and jr I (!)j were omitted from the notation. Such a flow aims to shrink
an initial curve towards strong edges. While the strength of image gradient is a solid
indicator of object boundaries, initial conditions on the position of the curve can
be issue. Knowing the direction of the propagation is a first drawback (the curve
has either to shrink or expand), while having the initial curve either interior to the
objects or exterior is the second limitation. Numerous provisions were proposed to
address these limitations, some of them aimed to modify the boundary attraction
term [29], while most of them on introducing global regional terms [45].
In [26] the first attempt to integrate edge-driven and region-based partition com-
ponents in a level set approach was reported, namely the geodesic active region
model. Within such an approach, the assumption of knowing the expected intensity
properties (supervised segmentation) of the image classes was considered. Without
loss of generality, let us assume an image partition in two classes, and let rin (I ),
rout (I ) be regional descriptors that measure the fit between an observed intensity
I and the class interior [rin (I )] and exterior to [rout (I )] the curve. Under such an
assumption one can derive a cost function that separates the image domain into two
regions:
• according to a minimal length geodesic curve attracted by the regions boundaries,
• according to an optimal fit between the observed image and the expected
properties of each class,
“
E ./ D w ı˛ . .!// g .jrI .!/j/ jr .!/j d!
“ “ (14)
C H˛ . .!// ri n .I / d! C .1 H˛ . .!/// rout .I / d!
where w is a constant balancing the contributions of the two terms. One can see this
framework as an integration of the geodesic active contour model [4] and the region-
based growing segmentation approach proposed in [45]. The objective is to recover
a minimal length geodesic curve positioned at the object boundaries that creates
an image partition that is optimal according to some image descriptors. Taking the
partial derivatives with respect to , one can recover the flow that is to be used
towards such an optimal partition:
r
D ı˛ ./.ri n .I / .rout .I // C !ı˛ ./ div g.I / (15)
jrj
Curve Propagation, Level Set Methods and Grouping 53
Fig. 3 Multi-class image segmentation [27] through integration of edge-driven and region-based
image metrics; The propagation with respect to the four different image classes as well as the final
presentation result is presented
where the term ı ˛ () was replaced with ı ˛ () since it has a symmetric behaviour.
In [26] such descriptor function was considered to be the -log of the intensity
conditional density [pin (I ), pin (I )] for each class
In [34] the case of supervised image segmentation for more than two classes
was considered using the frame partition concept introduced in [44]. One can also
refer to other similar techniques [1]. Promising results were reported from such
an approach for the case of image in [27] [Figure (3)] and for supervised texture
segmentation in [28].
However, segmentation often refers to unconstrained domains of computational
vision and therefore the assumption of known appearance properties for the objects
to be recovered can be unrealistic. Several attempts were made to address this
limitation. To this end, in [5, 43] an un-supervised region based segmentation
54 N. Paragios
approach based on the Mumford-Shah [22] was proposed. The central idea behind
these approaches of bi-modal [5] and tri-modal [43] segmentation was that image
regions are piece-wise constant intensity-wise.
The level set variant of the Mumford-Shah [22] framework consists of minimising
“ “ E .; i n ; out / D
w ı˛ . .!// jr .!/j d! C H˛ . .!// .I .!/ i n /2 d!
(16)
“
C 1 H˛ . .!// .I .!/ out /2 d!
where both the image partition [] and the region descriptors [in , out ] for the inner
and the outer region are to be recovered. The calculus of variations with respect to
the curve position and the piece-wise constants can be consider to recover the lowest
potential of such a function,
“ “
H ./I .!/d! .1 H .//I .!/d!
i n D “ ; out D “ ;
H ./d! .1 H .// d! (17)
h i
r
D ı˛ ./ ..I .!/ i n //2 .I .!/ out /2 // C w div jrj
Such a framework was the basis to numerous image segmentation level set
approaches, while certain provisions were made to improve its performance. In [18]
the simplistic Gaussian assumption of the image reconstruction term (piece-wise
constant) was replaced with a non-parametric approximation density function while
in [31] a vectorial unsupervised image/texture segmentation approach was proposed.
Last, but not least in [41] the same framework was extended to deal with multi-
class segmentation. The most notable contribution of this approach is the significant
reduction of the computational cost and the natural handling (opposite to [44]) of
not forming neither vacuums nor overlapping regions. Such an approach can address
the N -class partition problem, using log2 (N)
level set functions.
4 Prior Knowledge
Statistical representation of shapes is the first step of such an approach. Given a set
of training examples, one would like to recover a representation of minimal length
that can be used to reproduce the training set. To this end, all shapes of the training
set should be registered to the same pose. Numerous methods can be found in the
literature for shape registration, an adequate selection for building shape models in
the space of implicit functions is the approach proposed in [15] where registration is
addressed on this space. Without loss of generality we can assume that registration
problem has been solved.
Let SA D f 1 , 2 , : : : , n g be the implicit representations of n training samples
according to a signed Euclidean distance transform. Simple averaging of the shape
belonging to the training set can be used to determine a mean model
1X
n
M D i (18)
n i D1
that was considered in [9, 19, 39]. Such a model is a not an signed Euclidean implicit
function, an important limitation. However, one can recover a mean model in the
form of a planar curve M through the marching cubes algorithm [20]. Once such
a model has been determined, one can impose shape prior knowledge through the
constraint that the object to be recovered at the image plane that is a clone of the
average shape M according to some transformation:
D A .M / (19)
function aims at finding a minimal length geodesic curve that is attracted to the
object boundaries and is not far from being a similarity transformation of the prior
model:
M .A .M / ! 0
Such an approach can be very efficient when modelling shapes of limited variation.
On the other hand, one can claim that for shapes with important deviation from
the mean model the method could fail. Furthermore, given the small number of
constraints when determining the transformation between the image and the model
space the estimation [A ] could become a quite unstable task.
Towards a more stable approach to determine the optimal transformation between
the evolving contour and the average model, in [32] a direct comparison between the
contour implicit function and the model distance transform was used to enforce prior
knowledge:
.!/ D M .A .!//
Despite the fact that distance transforms are robust to local deformations, invariant
to translation and rotation, they are not invariant to scale variations. Slight modifi-
cation of the above condition [30] could also lead to scale invariant term:
s .!/ D M .A .!//
The minimisation of the SSD between the implicit representations of the evolving
contour and the distance transform of the average prior model can be considered to
impose prior knowledge, or
“
E .; A / D ı˛ ./ .s .!/ M .A .!///2 d! (21)
a term that is evaluated within the vicinity of the zero level-set contour (modulo
the selection of ˛). The calculus of variations within a gradient descent method can
provide the lowest potential of the cost function. Two unknown variables are to be
recovered, the object position (form of function ),
d @
D ı˛ ./ .. s M .A /2 2ı˛ ./ s .s M .A // (22)
d @ „ ƒ‚ …
„ ƒ‚ … shape consistency force
area force
This flow consists of two terms: (i) a shape consistency force that updates the
interface towards a better local much with the prior and (ii) a force that aims at
updating the level set values such that the region on which the objective functions is
evaluated (˛, ˛) becomes smaller and smaller in the image plane. In order to better
Curve Propagation, Level Set Methods and Grouping 57
understand the influence of this force, one can consider a negative value, within
the range of (˛, ˛); Such a term does not change the position of the interface and
therefore it could be omitted:
d
D 2ı˛ ./ s .s M .A // (23)
d
Towards recovering the transformation parameters [A ] between the evolving
contour and the average model, a gradient descent approach could be considered
in parallel: A
8d R
ˆ
ˆ D 2 ı– ./ .s M . A // .rM . A @@ A d
ˆ
ˆ
dt
ˆ
ˆ R
< d Tx D 2 ı– ./ .s M . A // .rM . A @T@ x A d
dt
R (24)
ˆd
ˆ
ˆ
ˆ Ty D 2 ı– ./ .s M . A // .rM . A @T@ y A d
ˆ dt R
:̂ d
dt
s D 2 ı– ./ .s M . A // .– C rM . A @s@ A d
One can refer to very promising results - as shown in [Fig. (4)] - on objects that
refer to limited shape variability using such a method [32]. However, often the object
under consideration presents important shape variations that cannot be accounted for
with simple average models. Decomposition and representation of the training set
through linear shape spaces is the most common method to address such a limitation.
In [19] a principal component analysis on the registered set of the space of distance
functions (training examples) was considered to recover a model that can account for
important shape variations. Similar approach was consider in [2, 33, 39]. Principal
component analysis refers to a linear transformation of variables that retains - for
a given number n of operators - the largest amount of variation within the training
data.
Let iD1 : : : n be a column vector representation of the training set of n implicit
function elements registered to the same pose. We assume that the dimensionality
of this vector is d. Using the technique introduced in [32] one can estimate a mean
vector M that is part of the space of implicit functions and subtract it from the
input to obtain zero mean vectors fQi D i – M g.
Given the set of training examples and the mean vector, one can define the d d
covariance matrix:
X ˚
Q
D E Q i Qi (25)
Fig. 4 Level set methods, prior knowledge, average models and similarity invariant object
extraction [32] in various pose conditions (i,ii, iii)
P
One can approximate Q with the sample covariance matrix that is given by
Q N Q N where QN is the matrix formed by concatenating the set of implicit
˚ P
functions Qi i D1:::n : Then, the eigenvectors of Q can be computed through the
singular value decomposition (SVD) of QN :
QN D UDUT (26)
P
The eigenvectors of the covariance matrix Q are the columns of the matrix U
(referred to as the basis vectors henceforth) while the elements of the diagonal
matrix D are the square root of the corresponding eigenvalues and refer to the
variance of the data in the direction of the basis vectors. Such information can
be used to determine the number of basis vectors (m) required to retain a certain
percentage of the variance in the data.
Then, one can consider a linear shape space that consists of the (m) basis vectors
required to retain a certain percentage of the training set:
X
m
D M C j Uj (27)
j D1
Curve Propagation, Level Set Methods and Grouping 59
Fig. 5 Level set methods, prior knowledge, linear shape spaces and Object Extraction [33];
segmentation of lateral brain ventricles (Top Left) surface evolution, (Top Right) projected surface
in the learning space and ground-truth surface (from the training set), (Bottom) surface cut and its
projection in the learning space during surface evolution
Such linear space can now be used as prior model that refers to a global transfor-
mation A of the average model M and its local deformation D (1 , . . . , m )
through a linear combination of the the basis vectors Uj . Then, object extraction is
equivalent with finding a shape for which there exists such a transformation that
will map each value of current representation to the “best” level set representation
belonging to the class of the training shapes:
0 0 112
Z X
m
E .; A ; / D ı– ./ @s @M .A / C j Uj .A /AA d (28)
j D1
where the rotation factor Uj (A ) has to be accounted for when applying the principal
modes of variations to deform the average shape.
In order to minimise the above functional with respect to the evolving level set
representation, the global linear transformation A and the modes weights j , we
use the calculus of variations. The deformation of is guided by a flow similar to
(1.22) that is also the case with respect to the pose parameters A as shown in ().
Last, but not least he differentiation with respect to the coefficients D (1 , . . . ,
m ) leads to a linear system that has a closed form solution V D b with:
R
V .i; j / D ı– ./ Ui .A / Uj .A /
R (29)
b.i / D ı– ./ .s M . A // Ui .A /
5 Discussion
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Kernel Methods in Medical Imaging
1 Introduction
Machine learning has shown dramatic progress over the last decades, creating tools
like the well-known Support Vector Machine (SVM), which have been intensively
applied to many different fields and have proved their efficiency. Learning tools
have often changed the whole perspective of the issues they have been applied
to. For example, in computer vision, the detection of objects in images, and the
automatic classification of images into categories (landscape, car, etc.) rely now
most often on intensive patch-based learning, whereas it was previously commonly
thought that a complete image segmentation would be required. The results of this
machine learning approach are often surprisingly good, showing that under certain
conditions, many tasks are much easier to solve by incorporating prior knowledge
retrieved from a set of examples.
In medical imaging, approaches are often example-based, in the sense that the aim
often consists in the automatization of a task already performed by hand by medical
people on a few examples, such as segmentation, registration, detection (of tumors,
of organs) or classification. As medical imaging deals with images, there is also
much inspiration to get from what has already been achieved in computer vision, in
object detection [9] as well in shape priors [5].
We start here with a tutorial on machine learning techniques. We present basic
concepts, and then focus on kernel methods. We introduce standard tools like kernel
ridge regression, SVM and kernel PCA. Then we apply some of these tools to the
case of medical image prediction, when the Magnetic Resonance scan of a patient is
known and we would like to guess what the corresponding Computed Tomography
scan would look like.
This section describes the central ideas of kernel methods in a nutshell by providing
an overview of the basic concepts. We first state mathematically the problems of
classification and regression. Then we introduce the concept of kernel and explain
the kernel trick which leads to kernel PCA as well as kernel ridge regression. The
last concept introduced is the support vector (SV), which is the basis of the SVM.
We have tried to keep this tutorial as basic as possible and refer to [11] for further
details.
2.1 Basics
Suppose we are given a set of m objects .xi /16i 6m 2 X m with labels .yi /16i 6m 2
Y m . If the number of possible labels is finite and small, then we can be interested
in classification, i.e. in finding the label to assign to a new object based on the given
examples. Otherwise, if the labels are values in a vector space, we can be interested
in regression, i.e. in extrapolating previously observed values to any new object.
Thus classification and regression tasks can be embedded in a similar framework,
one aiming to predict discrete labels and the other one to continuous values.
The objects .xi /16i 6m are often named patterns, or cases, inputs, instances, or
observations. The .yi /16i 6m are called labels, or targets, outputs or sometimes also
observations. The set of all correspondences .xi ; yi /16i 6m given as examples is
called the training set, whereas we name test set the set of new objects for which
we would like to guess the label by extracting knowledge from the examples in the
training set.
In both cases, classification or regression, we aim to generalize the correspon-
dences .xi ; yi / to a function f defined on the set X of all possible objects and with
Kernel Methods in Medical Imaging 65
values in the set Y of all possible labels. The label predicted for a new test object x
would then be f .x/. Here we have no particular assumption on the spaces X and
Y except that Y should be a vector space if we are interested in regression (in order
to extrapolate continuously between any two values). But we have a strong intuitive
assumption on f : it should generalize as well as possible the given examples, i.e.
if x is close to an already observed input xi , its output f .x/ should be close to the
already observed output yi . The whole difficulty consists in defining precisely what
we mean by “close” in the spaces X and Y . More precisely, we need to quantify
the similarity of inputs in X and the cost of assigning wrong outputs in Y .
Loss function
On the other hand, expressing a similarity measure in X is much more difficult and
lies at the core of machine learning. Either the space X has been carefully chosen
so that the representation of the observed objects xi are meaningful, in the sense that
their “natural” distance in X (say the Euclidean distance if X is a vector space) is
meaningful, in which case learning will be easy; either X is non-trivial and we need
to choose a set of N sensible features (seen as a function ˆ from X to H D RN ),
so that if we compute these features ˆ.xi / for each xi , we can consider a more
natural distance in the feature space H . From a certain point of view, choosing a
sensible feature map ˆ or choosing a sensible distance in X (or in the feature space
H ) are equivalent problems, and hence equivalently hard in the general case.
2.2 Kernels
This section aims to define kernels and to explain all facets of the concept. It
is a preliminary step to the following sections dedicated to kernel algorithms
themselves.
A kernel is any symmetric similarity measure on X
k WX X ! R
.x; x 0 / 7! k.x; x 0 /;
that is, a symmetric function that, given two inputs x and x 0 , returns a real number
characterizing their similarity (cf. [1, 3, 4, 7, 10]).
In the general case, either X is not a vector space, or the natural Euclidean inner
product in X is not particularly relevant as a similarity measure. Most often, a set of
possibly-meaningful features is available, and we can consequently use the feature
map
ˆWX !H
x 7! x WD ˆ.x/:
ˆ will typically be a nonlinear map with values in a vector space. It could for
example compute products of components of the input x. We have used a bold face
x to denote the vectorial representation of x in the feature space H . We will follow
this convention throughout the chapter.
We can use the non-linear embedding of the data into the linear space H via ˆ
to define a similarity measure from the dot product in H ,
˝ ˛ ˝ ˛
k.x; x 0 / WD x; x0 H D ˆ.x/; ˆ.x 0 / H : (1)
The freedom to choose the mapping ˆ will enable us to design a large variety
of similarity measures and learning algorithms. The transformation of xi into
ˆ.xi / D xi can be seen as a change of the inputs, i.e. as a new model of the
Kernel Methods in Medical Imaging 67
initial problem. However, we will see later that, in some cases, we won’t need to
do this transformation explicitly, which is very convenient if the number of features
considered (or the dimension of H ) is high.
is the length (or norm) of x in the feature space. Similarly, k.x; x 0 / computes the
cosine of the angle between the vectors x and x0 , provided they are normalized to
length 1. Likewise, the distance between two vectors is computed as the length of
the difference vector:
˝ ˛
kx x0 k2H D kxk2 C kx0 k2 2 ˆ.x/; ˆ.x 0 / D k.x; x/ C k.x 0 ; x 0 / 2k.x; x 0 /:
The interesting point is that we could consider any such similarity measure k and
forget about the associated ˆ: we would still be able to compute lengths, distances
and angles with the only knowledge of k thanks to these formulas. This framework
allows us to deal with the patterns geometrically through a understated non-linear
embedding, and thus lets us study learning algorithms using linear algebra and
analytic geometry. This is known as the kernel trick: any algorithm dedicated to
Euclidean geometry involving only distances, lengths and angles can be kernelized
by replacing all occurrences of these geometric quantities by their expressions as a
function of k. Next section is dedicated to such kernelizations.
Examples of kernels
Let us introduce the most-commonly used kernels. They are namely: the polynomial
kernel
˝ ˛d
k.x; x 0 / D x; x 0 ;
for suitable choices of d and . Let us focus on the Gaussian case: the similarity
measure k.x; x 0 / between x and x 0 is always positive, and is maximal when x D x 0 .
All points x have the same unit norm (since k.x; x/ D 1 8x) and consequently the
images of all points x in the associated feature space H lie on the unit sphere.
68 G. Charpiat et al.
One could wonder what is the feature map ˆ which was used to build the Gaussian
kernel. In fact kernel theory goes far beyond the way we introduced kernels. Let us
consider any symmetric function k, not necessarily related to a feature map. Let us
suppose also that k, seen as an operator, is positive definite, that is to say that for
any non-zero L2 function ˛ W X ! R:
Z
˛.x/k.x; x 0 /˛.x 0 / dx dx 0 > 0:
X X
ˆ W X ! F .X /
x 7! x WD k.x; /: (2)
k.x; / W X ! R
x 0 7! k.x; x 0 /: (3)
ˆ has now values in the space F .X / of functions over X instead of having values
in just a finite dimensioned vector space like RN .
The magic comes from Moore-Aronszajn theorem [2] which states that it
is always possible, for any symmetric positive definite function k, to build a
reproducing kernel Hilbert space (RKHS) H F .X / so that
˝ ˛ ˝ ˛
8x; x 0 2 X ; k.x; x 0 / D k.x; /; k.x 0 ; / H D ˆ.x/; ˆ.x 0 / H : (4)
Because of such a property, symmetric positive definite kernels are also called
reproducing kernels. This theorem highlights the duality between reproducing
kernels k and feature maps ˆ: choosing the feature space or choosing the kernel
is equivalent, since one determines the other.
We can make explicit the inner product on H in the Gaussian case. The associated
norm is
Z X 1 n 2 1 n 2
2n d X 2n
kf kH D
2
f .x/ dx D d f
X nD0 nŠ 2
n dx n
nD0
n
nŠ 2 dx L2 .X /
n
Kernel Methods in Medical Imaging 69
which penalizes all fast variations of f at all derivative orders. We refer to [6] for
a more general mathematical study of radial basis functions. Intuitively, consider
2 d2 P . 2 =2/n d 2n
the operator P D e 2 dx2 WD n nŠ dx 2n
. In the Fourier domain, it writes
2 w2 =2 2 w2 =2 i wx
e , whereas k.x; / becomes e e . Thus 1 P .k.x; // D ıx ./ is
a Dirac peak ˛ D.X / of distributions over X . The inner product
˝ in the space
hf; giH WD 1 P .f / ; g D.X / on H will therefore satisfy:
1
hk.x; /; f iH WD P .k.x; // ; f D hıx ; f iD.X / D f .x/
D.X /
The kernel k should be chosen carefully, since it is the core of the generalization
process: if the neighborhood induced by k is too small (for instance if k is a
Gaussian with a tiny standard deviation ), then we will overfit the given examples
without being able to generalize to new points (which would be found very
dissimilar to all examples). On the contrary, if the neighborhood is too large (for
instance if k is a Gaussian with a standard deviation so huge that all examples are
considered as very similar), then it is not possible to distinguish any clusters or
classes.
Kernels as regularizers
w c+
c− c
Fig. 1 A very simple classifier in the feature space: associate to any new point x the class whose
mean ci is the closest. The decision boundary is an hyperplane
We now have all the concepts required to transform existing algorithms dealing
linearly with data into kernel methods. We consider standard, simple algorithms
such as PCA and linear regression and build out of them more efficient tools which
take advantage of the prior knowledge provided by the definition of a kernel and of
their ability to deal linearly with non-linear quantities.
To show the spirit of kernelization, let us first describe a very simple learning
algorithm for binary classification. The label space Y contains only two elements,
C1 and 1, and the training set consists of labeled examples of the two classes.
The basic idea is to assign any previously unseen pattern x to the class with closest
mean. Let us work directly in the feature space H and deal with x D ˆ.x/ instead
of x since the metric which makes sense is the one in the feature space. In H , the
means of the two classes are:
1 X 1 X
cC D xi and c D xi ; (5)
mC m
fi jyi DC1g fi jyi D1g
where mC and m are the number of examples with positive and negative labels,
respectively. Half way between cC and c lies the point c WD .cC C c /=2. We
compute the class of x, based on the angle between the vector x c and the vector
w WD cC c (see Fig. 1):
y D sgn h.x c/; wiH D sgn h.x .cC C c /=2/; .cC c /iH
D sgn .hx; cC iH hx; c iH C b/ (6)
Kernel Methods in Medical Imaging 71
1
where we have defined the offset b WD .kc k2H kcC k2H /: (7)
2
Note that (6) induces a decision boundary which has the form of a hyperplane in the
feature space. We can now call the kernel trick in order to express all quantities as
a function of the kernel, which is the only thing we can easily compute (unless ˆ is
explicit and simple). But this trick deals only with norms, distances and angles of
features points of the form x D ˆ.x/, for which we already know x. Therefore we
need to express the vectors ci and w in terms of x1 ; : : : ; xm .
To this end, substitute (5) into (6) to get the decision function
1 X 1 X
y D sgn hx; xi iH hx; xi iH C b
mC m
fi jyi DC1g fi jyi D1g
1 X 1 X
D sgn k.x; xi / k.x; xi / C b : (8)
mC m
fi jyi DC1g fi jyi D1g
1 1 X 1 X
b WD k.xi ; xj / k.xi ; xj / : (9)
2 m2 m2C
f.i;j /jyi Dyj D1g f.i;j /jyi Dyj DC1g
1 X 1 X
pC .x/ WD k.x; xi / and p .x/ WD k.x; xi /: (10)
mC m
fi jyi DC1g fi jyi D1g
Given some point x, the label is then simply computed by checking which of
the two values pC .x/ or p .x/ is larger, which leads directly to (8). Note that this
decision is the best we can do if we have no prior information about the probabilities
of the two classes.
The classifier (8) is a particular case of a more general family of classifiers,
which areP of the form of an affine
combination of kernels on the input domain,
m
y D sgn i D1 ˛i k.x; xi / C b . The affine combination corresponds to a separat-
ing hyperplane in the feature space. In this sense, the ˛i can be considered a dual
representation of the hyperplane’s normal vector [7]. These classifiers are example-
72 G. Charpiat et al.
based in the sense that the kernels are centered on the training patterns; that is, one of
the two arguments of the kernel is always a training pattern. A test point is classified
by comparing it to all the training points with a nonzero weight ˛i . One of the great
benefits that SVM brings in the next section is the assignment of a zero weight to
most training points and the sensible selection of the ones kept for classification.
Suppose we are given a set of unlabeled points, or a set of points of the same class. In
the case of a vector space, we could perform a principal component analysis (PCA)
to extract the main axes of the cloud of points. These main axes can then be used as
a low-dimensional coordinate system expressing most of the information contained
in the initial vector coordinates.
PCA in feature space leads to an algorithm called kernel PCA [12]. By solving an
eigenvalue problem, the algorithm computes nonlinear feature extraction functions
X
m
fn .x/ D ˛in k.xi ; x/; (11)
i D1
where, up to a normalizing constant, the ˛in are the components of the nth
eigenvector of the kernel matrix Kij WD .k.xi ; xj //.
In a nutshell, this can be understood as follows. To perform PCA in H , we need
to find eigenvectors v and eigenvalues of the so-called covariance matrix C in the
feature space, where
1 X
m
C WD ˆ.xi /ˆ.xi /> : (12)
m i D1
Here, ˆ.xi /> denotes the transpose of ˆ.xi /. When H is very high dimensional,
the computational costs of doing this directly are prohibitive. Fortunately, one can
show that all solutions to
Cv D v (13)
with 6D 0 must lie in the span of ˆ-images of the training data. Thus, we may
expand the solution v as
X
m
vD ˛i ˆ.xi /; (14)
i D1
thereby reducing the problem to that of finding the ˛i . It turns out that this leads to
a dual eigenvalue problem for the expansion coefficients,
K˛ D m˛; (15)
To extract nonlinear features from a test point x, we compute the dot product
between ˆ.x/ and the nth normalized eigenvector in feature space,
X
m
hvn ; ˆ.x/i D ˛in k.xi ; x/: (16)
i D1
Usually, this will be computationally far less expensive than taking the dot product
in the feature space explicitly.
Let us now consider the case of regression: we know the values yi 2 R of a function
at m given points .xi /16i 6m and we would like to interpolate it to any new point
x 2 X . The notion of regression requires the one of regularization, so we choose
a kernel k and use the associated norm k kH . The problem can be expressed
mathematically as the search for the best function f W X ! R which minimizes
a weighted sum of the prediction errors .f .xi / yi /2 at known points and the
regularity cost kf kH :
( m )
X
inf .f .xi / yi / C kf kH
2 2
(17)
f WX !R
i D1
Representer Theorem The solution f of (17) in the RKHS belongs to the span of
functions k.xi ; / and thus admits a representation of the form
X
m
f .x/ D ˛j k.xj ; x/: (18)
j D1
More details can be found in ([11], p. 89). Using (18) and (4), the problem (17)
becomes:
8 9
<X m X 2 X =
infm ˛j k.xj ; xi / yi C ˛i ˛j k.xi ; xj / : (19)
˛2R : ;
i D1 j i;j
By
computing the derivative with respect to ˛, denoting by K the m m matrix
k.xi ; xj / i;j , and by Y the vector .yi /16i 6m we obtain:
2K.K˛ Y / C 2K˛ D 0
.K C Id/ ˛ D Y: (20)
The kernelized examples in the previous section are able to deal linearly with
the non-linear priors on the data (i.e., the kernel, which induces a feature space
and a metric therein) and are consequently able to deal with far more general
tasks than usual linear classification or regression. However the computation of the
label to assign to a new test point involves its distances to all training points, and
consequently these algorithms are naturally slow if the training set is big. Instead
of using tricks to reduce the training set size or to avoid the computation of all
distances for each new point, one can wonder whether there would exist another,
similar approach, which would naturally and directly lead to a huge compression of
the training data, keeping only a few meaningful training points to predict the labels
of new test points. Such an approach does exist. We present here the fundaments of
support vector classification.
We are given a set of points xi with a binary label yi 2 f1; 1g and we would like
to attribute to any new point x 2 X a class label f .x/. We consider a kernel k and
search for the best hyperplane in the feature space H which separates the training
points xi D ˆ.xi / into two classes, so that f has the form:
f .x/ D sgn hw; xi iH C b (21)
jhw; xi iH C bj D 1: (22)
Note that the margin, i.e. the distance between the hyperplane and the closest point,
is then 1=kwkH . We would like the margin to be as large as possible in order to
ensure the quality and the robustness of the classification (see Fig. 2). Therefore we
would like to minimize kwkH .
We would like also the predictions f .xi / on training points to be as good as
possible. Since the labels are binary, i.e. yi 2 f1; 1g, a correct labelling f .xi / of
the point xi means yi f .xi / > 0. Because of constraint (22), this is equivalent to:
8i; yi hw; xi iH C b > 1: (23)
Kernel Methods in Medical Imaging 75
Fig. 2 Example of a good and two bad hyperplane classifiers for a same training set. The larger
the margin is, the better the classifier is likely to perform
Soft margin
However, in practice, it may happen that the two classes overlap in the feature
space and consequently cannot be separated by an hyperplane satisfying (23) for
all examples i . Outliers may also be present in the training set and it may be better
to relax the constraints (23) than to overfit the data. Let us denote by i non-negative
slack variables, and relax (23) to:
8i; yi hw; xiP
iH C b > 1 i : (24)
We would prefer the sum of the slacks i i to be as small as possible, so we build
a soft margin classifier by solving
1 X m
minimize .w; / D kwk2 C C i (25)
w2H ;b2R;2Rm
C 2 i D1
where the constant C > 0 determines the trade-off between margin maximization
and training error minimization.
X
m
L.w; b; ; ˛/ D .w; / ˛i yi .hxi ; wi C b/ 1 C i : (27)
i D1
76 G. Charpiat et al.
X
m
and ˛i yi D 0 and 8i; ˛i D C or fi D 0 and ˛i C g : (30)
i D1
Incorporating (29, 30) into (27) makes w, b and vanish, and together with the
kernel trick (4) we obtain
X
m
1 X
m
maximize W .˛/ D ˛i ˛i ˛j yi yj k.xi ; xj / (31)
˛2R
m
i D1
2 i;j D1
X
m
subject to ˛i yi D 0 and 8i; 0 ˛i C: (32)
i D1
Once the quadratic energy (31) in ˛ with linear constraints (32) has been maximized,
equation (29) gives us an algorithm of the form (21) we were searching for:
X
f .x/ D sgn ˛i yi k.xi ; x/ C b (33)
i
with ˛i D 0 for most i . The few data points xi which have a non-zero coefficient
˛i are called support vectors. To compute the value of the threshold b, one uses
equation (30) which states that for any support vector xi with ˛i < C , the slack i
Kernel Methods in Medical Imaging 77
Atlas registration is the process of aligning a new image with a template image
already segmented into bone, air and tissue regions. This yields a segmentation
for the new image. The implicit assumption is that there exists a continuous one-
to-one transformation between the new patient and the template, and that this
transformation can be easily computed. In the case of medical scans, it turns out
that these assumptions are not always satisfied, for instance pockets of gas in
the abdominal region are unlikely to occur in the same number and shape for
78 G. Charpiat et al.
different patients. Even if the assumptions were satisfied, one may be trying to solve
a problem more difficult than necessary by searching for a topology-preserving
transformation.
Even a rough registration, which does not assume one-to-one correspondence
between images, brings useful information since the location of a point in a scan
is clearly correlated with the type of tissue which can be found at that point. This
correlation is not always decisive enough to determine fully the tissue class, for
instance when several scenarios can be thought of at a same place (abdomen or
random pocket of gas), or when the registration lacks accuracy.
On the other hand, a patch-based approach would consist in extracting local
information from a patch in the MR image centered on the pixel considered,
and in classifying this pixel according to similar patches previously observed.
This would not require any prior registration, would not assume a one-to-one
correspondence between all MR scans and consequently would be able to deal with
several possibilities of scenarios for the same location. It would, in some way, build
a prediction by picking parts from different examples. This approach is much more
flexible than template registration. However it ignores the important information
given by the location.
We proposed in [8] to make simultaneous use of both the local and global
information given by patches and registration, respectively. We first estimate a rough
registration of the test image to a template image, and call normalized coordinates
the resulting new positions of pixels.
The key in working with kernel methods is in designing a kernel, or features, which
are adapted to the application. In our case an input will be a pair xi D .pi ; ci / of
the local patch pi and its normalized coordinates ci ; we define a similarity measure
between inputs by
kp p k2 kc c k2
i j i j
k.xi ; xj / D exp 2
exp 2
: (35)
2 patch 2 pos
The parameters patch and pos involved express the weighting between the different
information sources. Their optimal values can be determined by the standard
technique of cross-validation: to estimate the relevance of any particular choice of
.patch ; pos /, the training set is partitioned into n subsets, and each subset is used for
testing the algorithm trained with these parameters on the remaining n 1 subsets.
The sum of the losses of all subsets is the energy to minimize with respect to the
parameters.
Kernel Methods in Medical Imaging 79
Fig. 3 Left: MR (T2 MEDIC) of a rabbit. Middle: Three class labels as predicted using SVM.
Right: Three class labels obtained by thresholding a CT image of the rabbit. Many differences
between b) and c) are due not to false classifications, but to some slight movement between MR
and CT scans, which explains the misalignment between the test image a) and the ground truth c)
For our application, cross-validation typically yields optimal values for pos that
are far bigger than 1. This implies that registration errors of a few pixels will not
affect the accuracy of our algorithm.
In the CT prediction problem, we may be interested in the classification of MR
pixels into three classes, namely bone, air and tissue, because in first approximation
there is a one-to-one correspondence between these classes and the CT values. We
build three binary classifiers with SVM, one for each class against the two others, or
more exactly we compute the quantity whose sign is checked in (33), and then return
the class which achieves the greatest score. We show examples of results in Fig. 3.
If the position is very informative, we can learn locally, i.e. cut the template image
into regions and train independently a classifier/regression for each region. For brain
images for example, intersubject variability is much smaller than for whole body
images. Thus non-rigid registration between subjects is possible with only minor
misalignments, and it is reasonable to compare patches only within a localized
neighborhood. We use kernel ridge regression in order to take into account the
variability of CT values. More precisely, from pairs of patches and normalized
coordinates, we do not predict the CT value itself but the variation between the
CT value and the one in the template at that position. Results are shown in Fig. 4.
80 G. Charpiat et al.
4 Discussion
After a tutorial on kernel methods, we have presented a way to use these machine
learning tools to extract information from a set of medical images for MR-based CT
prediction, in a framework which makes use of both local and global information.
This presents the advantage of requiring neither a precise registration between
template and test image, nor a one-to-one correspondence between them. We hope
we have woken up the reader’s enthusiasm for machine learning in medical imaging,
there are still plenty of other ways to use machine learning tools in this field!
References
9. F. Jurie and C. Schmid. Scale-invariant shape features for recognition of object categories. In
International Conference on Computer Vision & Pattern Recognition, volume II, pages 90–96,
2004.
10. J. Mercer. Functions of positive and negative type and their connection with the theory of
integral equations. Philosophical Transactions of the Royal Society, London, A 209:415–446,
1909.
11. B. Schölkopf and A. J. Smola. Learning with Kernels: Support Vector Machines, Regular-
ization, Optimization, and Beyond (Adaptive Computation and Machine Learning). The MIT
Press, December 2001.
12. B. Schölkopf, A. J. Smola, and K.-R. Müller. Kernel principal component analysis. In
B. Schölkopf, C. J. C. Burges, and A. J. Smola, editors, Advances in Kernel Methods - Support
Vector Learning, pages 327–352. MIT Press, Cambridge, MA, 1999. Short version appeared
in Neural Computation 10:1299–1319, 1998.
Geometric Deformable Models
1 Introduction
Deformable models (also called “snakes” and “active contours”) have been exten-
sively studied and widely used in biomedical image analysis applications such as
image segmentation, geometrical modeling, surgery simulation, etc. Deformable
models are curves or surfaces that deform within two-dimensional (2D) or three-
dimensional (3D) digital images under the influence of both internal and external
forces and/or user defined constraints. Traditional deformable models [27, 47, 70,
73, 99, 120] are represented using explicit parametric forms during deformation,
Y. Bai ()
HeartFlow, Inc., 1400B Seaport Blvd, Redwood City, CA 94063, USA
e-mail: [email protected]
X. Han
Elekta Inc., 13723 Riverport Dr., Suite 100, St. Louis, MO, 63043, USA
e-mail: [email protected]
J.L. Prince
Department of Electrical and Computer Engineering, Johns Hopkins University,
201B Clark Hall, 3400 N Charles St, Baltimore, MD 21218, USA
e-mail: [email protected]
priors of Leventon et al. [57]. We then survey the recent research developments
of GDMs to achieve more flexible and general topology control, integration of
statistical priors of shape, intensity and motion, higher resolution and better effi-
ciency, robust optimization, and extensions to the segmentation of multiple objects.
For other excellent tutorials and reviews of earlier development of deformable
models, we refer interested readers to [71, 75, 119, 121].
2 Overview
GDMs are based on the theory of front evolution [2, 52, 90] and are implemented
using the level set numerical method [76, 95]. The model contour(s) (curves in
2D or surfaces in 3D) are embedded as the zero level set of a higher dimensional
level set function ˆ.x; t/ and propagates implicitly through the temporal evolution
of ˆ.x; t/. Due to numerical stability and computational convenience, ˆ.x; t/ is
often chosen to be a signed distance function of the embedded contour(s). Such a
signed distance function can be computed very efficiently using the fast marching
method [94, 109] or the fast sweeping method [130].
For image segmentation problems, a GDM is either formulated as an energy
minimization problem where the solution is sought through gradient descent
optimization, or by directly designing the various forces that drive the model
contour(s) towards desired object boundaries. In either case, the final evolution
equation regarding the level set function ˆ.x; t/ can be summarized in the following
general form:
@ˆ.x; t/
D ŒFprop .x; t/ C Fcurv .x; t/jrˆ.x; t/j C F adv .x; t/ rˆ.x; t/;
@t
where Fprop , Fcurv , and Fadv are spatially-varying force terms that drive the front
evolution. In particular, Fprop is an expansion or contraction force, Fcurv is the part
of the force that depends on the intrinsic geometry, especially the curvature of the
implicit contour and/or its derivatives, and Fadv is an advection force that passively
transports the contour.
Numerical schemes to solve the above level set PDE must be carefully designed.
The time derivative can be approximated by a forward difference scheme. The
spatial derivatives are computed using upwind scheme for terms Fprop and Fadv ,
and using central difference scheme for term Fcurv [76, 95]. No parameterization of
the deforming contour is needed during the evolution. The parametric representation
is computed (if necessary) using an isocontour algorithm (e.g., [65]) only after the
evolution is complete.
86 Y. Bai et al.
Fig. 1 Topology equivalence of implicit contour topology and the digital object boundary
topology: 4-connectivity for dark points and 8-connectivity for others. (a) Original contour.
(b) The contour passes over a simple point. (c) The contour splits at a nonsimple point
Segmentation algorithms that only make use of low-level image information (such
as intensity gradients) often fail to produce satisfactory results in medical imaging
applications due to image noise, limited image resolution and contrast, and other
imaging artifacts that often present in typical medical image data. In these cases,
simple geometric regularization no longer suffices, and higher-level prior knowledge
about the shape of desired object(s) can help.
The first published method that applies shape priors in GDM segmentation was
proposed by Leventon et al. [57]. The method consists of two major stages. In the
first stage, a statistical object shape model is computed from a set of training samples
D fˆ1 ; ˆ2 ; ; ˆn g, where each training shape ˆi ; 1 i n is embedded as
the zero level set of a signed distance function. Using principal component analysis
(PCA), the covariance matrix of the training set is decomposed as U †U T , where
U is a matrix whose column vectors represent the set of orthogonal modes of shape
variation and † is a diagonal matrix of corresponding singular values. The first k
columns of U form the eigenspace of the (typical) shapes. One can project a given
shape ˆ onto this shape space using
˛ D UkT .ˆ N̂ /
88 Y. Bai et al.
Fig. 2 Topologically-constrained segmentations. (a) shows the reconstructed surface; (b) shows
close-up views of the standard GDM results; and (c) shows close-up views of the TGDM results
where N̂ is the mean shape, and ˛ is the k-dimensional vector of coefficients that
represent ˆ in the space spanned by Uk . The shape model construction is illustrated
in the top panel of Fig. 3. A training set of corpus callosa segmentation is analyzed
by PCA and the three primary modes of variations of the shape distribution are
shown in the figure. Assuming a Gaussian distribution for ˛, the probability of a
new shape can be computed as:
1 1
P .˛/ D p exp ˛ T †1
k ˛
.2/k j†k j 2
@ˆ
D .c C /gjrˆ.t/j C rg rˆ.t/ C ˇ.ˆ .t/ ˆ.t//:
@t
Geometric Deformable Models 89
Mode 1
Mode 2
Mode 3
Fig. 3 Top: The three primary modes of variations of the corpus callosum training data set.
Bottom: Four steps in the segmentation of two different corpora callosa. The last image in each
case shows the final segmentation in red. The cyan contour is the standard evolution without the
shape influence. Image courtesy of the authors of [57]
The first two terms are the typical GAC model (as mentioned earlier) and the last
term is the shape prior term. The parameter ˇ is used to balance the influence of
the shape model and the GAC model. The bottom panel of Fig. 3 compares the
performance of the GAC model with and without using the shape prior. Due to
weak edges, the GAC without the shape prior leaks out and fails to capture the
desired shape; whereas the GAC with the proposed shape prior is well constrained
and successfully converges to the boundary of the corpus callosum.
Fig. 4 Segmentation of a
“C” shape using a spherical
initialization. First row: GDM
without topology control;
second row: TGDM result;
third row: GGDM result.
Image courtesy of the authors
of [93]
where ˆ denotes the level set function, @D denotes the contour boundary, ds is the
arc-length measure, and d > 0 and l > 0 are real numbers. These two terms probe
in the vicinity of the contour boundary in the inner and outer normal directions,
respectively, and penalize cases when points away from the zero level set have small
Geometric Deformable Models 91
Fig. 5 (a)-(e): carpal bone segmentation. (f): a toy problem in which the “stuck” situation of
TGDM is avoided by the global regularizing flow. (See text for details.) Image courtesy of the
authors of [103]
absolute distance values. The energy functional has the effect similar to building
“barriers” between merging or splitting contours, thus preventing such topological
changes to happen.
Sundaramoorthi and Yezzi [103] proposed to use a PDE-based geometric flow to
achieve topology preservation. The flow minimizes the following energy functional:
Z Z
1 dOs ds
E
.C / D
2 C C jjC.Os / C.s/jj
where C is a contour, dOs and ds are the arc-length measures, jj jj is the Euclidean
norm, and
> 0 is a free parameter. Minimization of this energy functional leads to
a repulsive force that prevents the model contour from self-intersecting or splitting.
It also imposes a global regularization of the evolving contour. Fig. 5 demonstrates
the benefit of this global regularizing force. Figs. 5(a)–(e) compare the segmentation
92 Y. Bai et al.
results of TGDM and the global regularizing flow for a carpal bone image. Fig. 5(a)
shows the contour initialization. Fig. 5(b) shows the final segmentation of the global
regularization flow. A magnified view of the bone joint part is shown in Fig. 5(c),
and the results of TGDM and the new method in this area are shown in Figs. 5(d)
and (e), respectively. Clearly, the latter approach keeps the contours more separated.
Fig. 5(f) is another demonstration using a toy problem. Since TGDM only uses
a hard constraint that does not come into play until topology is about to change
in the next step, it does not regularize the contour as the global regularizing flow
does. A similar double integral energy was also used by Rochery et al. [83] for
the extraction of a road network and by Guyader and Vese [40] who integrate this
energy over regions and formulate it directly in the level set framework.
Following the work of Leventon et al., many GDM methods that incorporate prior
shape information have been recently proposed [24, 25, 87, 88, 107, 108, 124].
An extensive review can be found in [32]. We briefly summarize the major
contributions.
Most of the shape-constrained GDM methods assume a linear model for shape
variations, which tend to have two major limitations [21, 30, 31, 86]. First, the
training shapes do not always satisfy a Gaussian distribution as typically assumed.
Second, the space of signed distance functions is not linear, i.e. a linear combination
of signed distance functions is in general no longer a signed distance function. To
address these limitations, Cremers et al. [30,31,86] proposed a statistical shape prior
based on an extension of classical kernel density estimators (cf. [81,85]) to the level
set domain. This prior statistically approximates an arbitrary distribution of training
shapes (without making the restrictive assumption of a Gaussian distribution). In
the limit of infinite sample size, the distribution inferred by the kernel density
estimator converges towards a distribution on the manifold of signed distance
functions. In addition, the cited works also embed an intrinsic alignment in the
energy function so that the shape prior is invariant to certain group transformations
such as translation and scaling. Fig. 6 compares the segmentation result of using a
kernel prior against the results of using a uniform prior, a linear prior, and a manual
segmentation. It can be seen that in this example, the result of using a kernel prior
is closest to the manual segmentation.
Another development in shape prior modeling is the incorporation of object
dynamics. In applications such as cardiac segmentation and tracking, it is important
to take into account temporal correlations of the images. Cremers et al. [29]
proposed to extend the shape modeling to learn the temporal dynamics of a
deforming shape for the segmentation of an image sequence. The dynamical
statistical shape model is constructed by approximating the shape vectors of a
sequence of silhouettes by a Markov chain, which is then integrated into a Bayesian
segmentation framework. Kohlberger et al. [54] proposed to treat time as an ordinary
Geometric Deformable Models 93
Fig. 6 Comparison of the segmentations obtained with the kernel prior (white) and with alterna-
tive approaches (black). Image courtesy of the authors of [86]
fourth dimension and applied a 4D PCA analysis on the training sequences to derive
a 4D shape model. In this method, a whole volume sequence is segmented at the
same time as a 4D image.
5 Fast GDMs
Since GDMs represent the model contour(s) using a higher-dimensional level set
function, a heavy computational cost can be incurred with a naive implementation.
To improve computational efficiency, narrowband methods in conjunction with
reinitialization techniques [82, 95] are widely used to restrict the computation to the
neighborhood of the evolving contour(s). However, the overall computation load
can still be prohibitive when the grid size is large.
Several fast implementations of GDMs have been proposed. Goldenberg
et al. [38] and Weickert et al. [113] proposed to adapt the additive operator splitting
(AOS) scheme [114] for GDMs, which relaxes the stability constraint on the size
of the time step associated with the explicit numerical schemes. The AOS scheme
is very stable; but when large time steps are used, splitting artifacts may arise
due to reduced rotational invariance. Kenigsberg et al. [48] and Papandreou and
Maragos [77] proposed to use multigrid techniques to address this problem and
to allow the use of even larger time steps than the AOS scheme. When sub-voxel
accuracy is not of concern, Shi and Karl [96]’s method can provide a very high
efficiency since it eliminates the need to solve the level set PDE. The method
directly tests an optimality condition for the final curve location based on the speed
functions, and uses only simple operations like insertion and deletion on two lists
of boundary points to evolve the curve.
The reinitialization of the level set function can also be accelerated or even
omitted. Krissian and Westin [56] proposed a fast implementation of the Chamfer
distance to save computation time while maintaining the sub-voxel accuracy of
the interface. Li et al. [58, 59] proposed a distance-preserving energy function
that forces the level set function to be close to a signed distance function, which
94 Y. Bai et al.
eliminates the need for re-initialization and improves the overall efficiency. Another
distance-preserving level set method was later proposed by Estellers et al. [35]; it
is more efficient due to the use of a splitting strategy and advanced `1 optimization
techniques.
Several new methods, constituting a new variational model for image segmenta-
tion that is closely related to the GDM, have been recently proposed [13, 19, 39].
These methods represent objects by soft membership functions rather than signed
distance functions and the smoothness of the segmentation results is controlled
by total variation regularization. The resulting models are convex and thus global
optimal solutions can be guaranteed to be found. Also, the development of efficient
convex relaxation methods [13, 39] allows such models to be computed much faster
than traditional GDMs. One weakness, however, is that geometric properties of
objects such as surface curvature and distances between coupled surfaces cannot
be easily modeled and there is no control of the final segmentation topology. Such
models have also been extended to the segmentation of multiple objects (cf. [6,60]).
The development of adaptive grid GDMs was motivated by the observation that the
resolution of a GDM is directly limited by the resolution of the computational grid.
One can improve the model resolution by using highly refined grids at the cost of
losing efficiency and increasing the size—i.e., number of vertices—of the resulting
contour(s). A more elegant approach to address the resolution and efficiency tradeoff
is to use adaptive grid techniques [53], which locally refine or deform a coarse grid
to concentrate computational efforts where more accuracy is needed. Incorporation
of topological constraints also becomes feasible. Two types of adaptive grids have
been used: the moving grid and the quadtree/octree grid. We briefly summarize
these two types of approaches in the following.
A 2D moving grid GDM method was introduced in [41]; it maintains a fixed
reference grid, but moves the actual physical grid points according to the desired
image features [15, 63]. The adaptively deformed grid is obtained by first solving
a Poisson equation using a DCT solver, and then solving an ordinary differential
equation. After that, the level set PDE is solved on the deformed grid with narrow-
banding. Since a uniform reference grid is always kept, the topology preserving
principle on uniform grids (cf. Sect. 2.2) can be directly applied, by performing the
simple point check directly on the reference grid.
An octree grid in 3D (or similarly a quadtree grid in 2D) is a hierarchical cartesian
grid that is locally refined in regions of interest. These adaptive grids are widely
used to improve accuracy in the solution of PDE’s [74, 104] and in medical image
segmentation [8, 34, 122]. The cost for generating an adaptive octree grid is much
smaller compared to that for a moving grid, since no partial differential equations
Geometric Deformable Models 95
Fig. 7 Extraction of inner and outer surfaces using three computational grids. (a)–(c) triangle
meshes: (a) coarse uniform grid TGDM result; (b) fine uniform grid TGDM result; (c) OTGDM
result. (d) and (f): close-up views of inner and outer surfaces reconstructed by three types of grid:
red–coarse uniform grid TGDM result, blue–fine uniform grid TGDM result, yellow–OTGDM
result; (e) and (g): close-up views of octree grids used by OTGDM (shown in blue)
7 Miscellaneous
The conventional level set implementation of GDMs can only deal with a two-phase
image, i.e. a single object on a single background. Extensions to multiple objects in
which n level set functions are used to model n objects with different characteristics
have been proposed [79, 89, 129, 131]. In [106, 125], a joint shape modeling of
n neighboring structures is also implemented using n level set functions. Such
a strategy incurs great computational cost when the number of objects is large
[3, 14, 62, 64, 69, 79, 89, 105, 111, 129, 131].
The multi-phase level set (MPLS) method [111] is an elegant framework pro-
posed to address the above issue. MPLS generalizes the Chan and Vese model [20]
to segment images with more than two regions. Using heaviside functions, the
MPLS method needs only log n level set functions for n phases in the piecewise
constant case, and can represent boundaries with complex topologies including
triple junctions. In the piecewise smooth case, only two level set functions formally
suffice to represent any partition, based on the four color theorem [4]. Fig. 8 shows
how the model works on a color image, where three level set functions are used
to represent up to eight phases (or colors). In this example, the MPLS method
detects six regions and their junctions, which would require at least six level set
functions using the conventional approach. The MPLS framework has been adopted
by many others to extend their work to deal with multiple regions, such as Bertelli
et al. [10] who extended their graph-partitioning method in [100], Kim et al. [51]
who extended their mutual information based approach, and Cremers et al. [33] who
integrated multiple competing shape priors into shape-based GDMs.
The multi-object geometric deformable model (MGDM) was recently developed
to further improve memory requirements, flexibility in speed specification, and
topology control [12]. MGDM represents multiple objects with label and distance
functions rather than separate level set functions. To good approximation only four
functions in 2-D and six functions in 3-D are required to represent any number of
objects and to carry out shape evolution without reconstructing independent level
set functions. Boundary-specific speed functions and topology control of individual
objects and groups of objects can be specified. MGDM was used to parcellate the
cerebellum into individual lobules from magnetic resonance brain images in [11].
Geometric Deformable Models 97
Fig. 8 Color noisy picture with junctions. Three level set functions are used to represent up to
eight constant regions. Six segments are detected. Bottom row shows the final zero-level sets of
1 ; 2 ; 3 . Image courtesy of the authors of [111]
Most existing GDMs allow only local interactions or competitions between different
parts of an implicit contour or between multiple contours. Recently, it has been
shown that enabling long-range interactions can improve the robustness of GDMs
and enable modeling of shapes with complex geometries.
Sebastian et al. [91] proposed a skeletally coupled deformable model which
combines the advantages of curve evolution deformable models, seeded region
growing and region competition. The method uses a curve evolution implementation
of region growing from initialized seeds, where growth is modulated by a skeletally-
mediated competition between neighboring regions. The inter-seed skeleton, which
is interpreted as the predicted boundary of collision between two regions, is used to
couple the growth of seeds and to mediate long-range competition between them.
The long range predicted competition made possible by the inter-seed skeletons
helps achieve a more global minimizer.
Rochery et al. [83] extended the GDM formulation to higher order energy
functionals. Instead of a single integral over the contour, the new functionals consist
98 Y. Bai et al.
of arbitrary order polynomials that include multiple integrals over the contour
so that arbitrary long-range interactions between subsets of the contour can be
modeled. We note that the authors of [103] and [40] also proposed to use quadratic
energy functionals, although the methods were specifically designed for topology
preservation purposes.
Xiang et al. [115] proposed a physics-based active contour model using a long-
ranged interaction between image boundaries and the moving contours, which was
inspired by the elastic interaction effects between line defects in solids. Another
interesting physics-based model called magnetostatic active contour model was
recently proposed by Xie and Mirmehdi [117,118]. Their model simulates magnetic
interactions between the evolving contour and target object boundaries to improve
the method robustness against arbitrary model initialization and weak edges. The
model was further generalized and extended to 3D in [126].
In most GDM formulations, the final solution is sought through gradient descent
types of approaches that can easily get trapped in undesirable local minima. A multi-
resolution implementation can partially address this problem. Recently, more efforts
are made towards the design of novel optimization methods that are robust to image
noise and insensitive to model initialization.
Li and Yezzi [61] proposed a dual front implementation of GDMs that was
motivated by minimal path techniques [28]. The method seeks a global optimum
inside an active region surrounding the current model position. By tuning the size of
the active region, it achieves an optimal solution with variable degrees of localness
and globalness.
Sundaramoorthi and Yezzi [101, 102] and Charpiat et al. [22, 23] observed that
using the canonical L2 norm as the Riemannian metric in gradient flow optimization
often leads to undesirable local minimum and irregular flows. They both proposed
to optimize the solution in other functional spaces such as the Sobolev space. The
resulting Sobolev gradient flows are more global in the sense that the deformation of
each point is affected by all the other points on the contour. These flows also favor
global motions (such as translations) over local deformations, which helps avoid
getting trapped at undesired local optima.
8 Conclusion
well as prior knowledge about object topology and shape. Undoubtedly, they will
continue to play an important role in various image processing and computer vision
applications for a long time.
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Active Shape and Appearance Models
Abstract Statistical models of shape and appearance are powerful tools for medical
image analysis. The shape models can capture the mean and variation in shape of a
structure or set of structures across a population. They can be used to help interpret
new images by finding the parameters which best match an instance of the model to
the image. Two widely used methods for matching are the Active Shape Model and
the Active Appearance Model. We describe the models and the matching algorithms,
and give examples of their use.
1 Introduction
Although organs and structures in the body can exhibit a huge range of variation
across a population, the shape of many can be characterised as being a transformed
version of some template or reference shape. For instance, almost everyone’s face
can be thought of as a variant of an ‘average’ face, with two eyes, a nose and a
mouth, though in different positions on each individual. Similarly, almost every
human femur has a shape which is a transformed version of the average. We can
thus capture the range of shapes of such objects by recording the average shape, and
the ways in which they may vary across a population. In this chapter we describe a
simple method of achieving this.
We represent a shape using a set of points (sometimes called ‘landmarks’), which
define equivalent positions on each example. It should be noted that this can only
be applied to objects whose shape can be consistently described in this manner.
It cannot be applied to structures where we cannot define a simple correspondence
across shapes. For instance, since two trees may have different numbers of branches,
there is no simple way of placing meaningful landmarks across a set of trees.
For anatomical structures where this assumption holds, we can construct statis-
tical shape models to summarise the variation across a population. Such models
can be used for image interpretation. The parameters of a model define a specific
shape. Given a new image, our goal is to find the model parameters which generate a
shape as close as possible to that of the object in the image. This requires additional
information in the form of a description of how any shape appears - what patterns of
intensity information are associated with a particular shape. This too can be learned
from a training set of images. However, there are many ways in which we can
represent the intensity information. For instance, we could model the intensities
across the whole of the object, or we can focus on areas around the boundaries of
interest. Which approach is most useful depends on the application.
Given a model of shape, and some representation of intensities associated with the
shape, matching the model to the image becomes an optimisation problem. Since we
typically have many model parameters, it is a potentially difficult one. We describe
two approaches, the Active Shape Model and the Active Appearance Model, both
of which have been found to be effective. Both are iterative, local search algorithms.
Thus they both require a sensible initialisation if they are to avoid falling into local
minima.
x D .x1 ; : : : ; xn ; y1 ; : : : ; yn /T (1)
For instance, Fig. 1 gives an example of a set of 46 points used to define the shape
of the outline of a vertebra in a DXA image
Active Shape and Appearance Models 107
x D xN C Pb (2)
Shape Mode 1 (b1 = −3σ1 , 0, +3σ1 ) Shape Mode 2 (b2 = −3σ2 , 0, +3σ2 )
Fig. 2 First two modes of a shape model of a vertebra (Parameters varied by ˙3 s.d. from the
mean)
b D PT .x xN / (3)
Figure 2 shows the effect of changing the first two shape parameters on a model of
the outline of a vertebra, trained from 350 examples such as that shown in Fig. 1.
Figure 3 shows the effect of varying the parameter controlling the first mode of
shape variation of a 3D model of a set of deep brain structures, constructed from
shapes extracted from MR images of 69 different subjects1 . Note that since the
method only represents points, it easily model multiple structures.
Given a new image containing the structure of interest, we wish to find the pose
parameters, t, and the shape parameters, b, which best approximate the shape of the
object. To do this we require a model of how well a given shape would match to
the image.
1
Provided by David Kennedy at the Centre for Morphometric Analysis
Active Shape and Appearance Models 109
Fig. 3 Two views of the first mode of a shape model of structures in the brain
Suppose we have a set of local models, each of which can estimate how well
the image information around a point matches that expected from the training set,
returning a value qi .Xi ; Yi /. We then seek the shape and pose parameters which
generate points X D fXi ; Yi g so as to maximise
X
n
Qasm .t; b/ D qi .Xi ; Yi / (4)
i D1
b
a
Fig. 4 ASM search requires models of the image around each point
The approach has been found to be very effective, and numerous variants
explored. In the following we will summarise some of the more significant
approaches to each step.
The simplest approach is to have qi .X; Y / return the edge strength at a point.
However we will usually have a direction and scale associated with each point,
allowing the local models to be more specific. For instance, since most points are
defined along boundaries (or surfaces in 3D), the normal to the boundary/surface
defines a direction, and a scale can be estimated from the global pose transformation.
Since we have a training set, a natural approach is to learn statistical models of
the local structure from that around each point in the known examples [10]. For each
model point in each image, we can sample at a set of nearby positions. For instance,
at points along smooth curves we can sample profiles (Fig. 4a), whereas at corner
points we can sample on a grid around the point (Fig. 4b).
The samples around model point i in training image j can be concatenated
into a vector, gij . Typically each such vector is normalised to introduce invariance
to overall intensity effects (for instance, by subtracting the mean intensity and
scaling so the vector is of unit length). We then can estimate the probability density
distribution pi .g/, which may be a Gaussian, or something more sophisticated if
sufficient samples are available.
Given such a PDF for each point, we can evaluate a new proposed position by
sampling the image around the point into a new vector g, and setting qi .Xi / D
log pi .g/.
Active Shape and Appearance Models 111
After locating the best local match for each model point, X0 , we update the model
pose and shape parameters so as to best match these new points. This can be
considered as a regularisation step, forcing points to form a ‘reasonable’ shape -
one defined by the original model.
The simplest approach is to find t and b so as to minimise
X
t
b2
M D i
< Mthresh (6)
i D1
i
X
t
b2
log p.t; bjX0 / D const jTt1 .X0 / .Nx C Pb/j2 =r2 i
(7)
i D1
i
where r2 is the variance of the residuals (those not explained by the model) in the
model frame and we assume all pose parameters are equally likely. We can thus find
the most likely values for t; b by optimising (7). Again, this is a non-linear sum of
squares problem, for which fast iterative algorithms exist (for instance, see [38]).
Information about the uncertainty of the estimates of the best matching point
positions can also be included into the optimisation [17].
Since the models for each point may return false matches (for instance by latching
on to the wrong nearby structure), it can be effective to use a more robust method in
which outliers are detected and discarded [27].
The Active Shape Model treats the search for each model point as independent.
However, there will usually be correlations between the local appearance around
nearby points. This can be modelled, but leads to a more difficult optimisation
problem. The Active Appearance Model algorithm is a local optimisation technique
which can match models of appearance to new images efficiently.
a b
Fig. 5 Sample points can be on a dense grid, or along profiles around boundaries
More formally, let W .y W b; t/ apply a deformation of space such that the mean
model points xN are mapped to the points defined by the shape model
2
We use a variant of the notation introduced by Matthews and Baker [22]
3
Note that we sample the features at points based on the best shape model approximation to the
shape X, not on X itself. Thus any approximation errors in the shape are absorbed into uncertainty
in the feature samples, ensuring we are better able to reconstruct the original training set if required.
114 T.F. Cootes et al.
It is often the case that there is significant correllation between the shape and
the feature samples. We can model this explicitly by generating joint vectors j D
.bT jWaT /T , where W is a diagonal weighting matrix, chosen to account for the
difference in units between the shape and the features. A useful choice of W D ˛I,
where ˛ is chosen so that the shape and scaled feature components have similar
variance. If we apply a third PCA to these joint vectors, we can construct a combined
linear model of the form
b
D j D Qc (9)
Wa
which can be decomposed into separate shape and feature terms,
x D xN C Qs c
(10)
f D Nf C Qf c
where c is a set of parameters which control both the shape and the feature model
(see [7] for more details).
Given a new image we wish to find the model parameters which generate a shape
and features most similar to those in the image. This is an interpretation through
synthesis approach.
For a given choice of parameters, p D .tT ; cT /T , we can generate shape
parameters b using Eq. (9) and corresponding features f using Eq. (10).
Let f0 D F .Ii ; W .y W b; t// be the features sampled from the image given the
current shape. The residual difference between those features given by the model
and those sampled from the image is
r.p/ D f0 f (11)
The residual is a function of the model parameters. The way in which the residual
varies as we vary the parameters is approximated by Jacobian, J,
@ri
Jij D (12)
@pj
To match the model to the image we seek the parameters which minimise the sum
of squares of the residual,
This problem can be solved efficiently with a fast iterative gradient descent
method. If our current parameters are p, we seek an update step, ıp which improves
our match. It can be shown [7, 22] that a good estimate of the step is given by
ıp D Rr (14)
This requires an estimate of the Jacobian at the current parameters, which can
be relatively expensive to compute. However, since the residual is measured in
the normalised reference frame, for many problems it is found that the Jacobian
is approximately constant over a reasonable range of parameters. Thus we can
precompute it, by numeric differentiation on the training set [7, 22]. Alternatively
good results can be obtained by treating (14) as a regression problem and learning R
from large numbers of randomly sampled displacements across the training set [5].
A simple algorithm to search for the best match given this relationship is then
1. Evaluate the residual r.p/ D f0 f
2. Evaluate the current error E0 D jrj2
3. Predict the displacement, ıp D Rr
4. If jr.p C ıp/j2 < E0 then accept the new estimate, p WD p C ıp, otherwise
perform line search along p C ˛ıp
5. Repeat until convergence
Typically only a small number of iterations are required. The algorithm is
usually used in a multi-resolution framework, in which models trained at a coarse
resolution are used to get an approximate estimate, which is then refined using
higher resolution models.
parameters linearly. Refering to Eq. (8), if ıt and ıb are the pose and shape updates,
the new parameter values, t0 and b0 should be chosen so that
However, this is more complex, and in practise it seems that a linear scheme is
generally sufficient (though slightly less efficient), as long as the pose is dealt with
correctly.
The simplest approach is to sample intensity values at each point. The resulting
feature vector of intensities can be normalised to allow for some variations in
imaging conditions. However, methods based just on intensities can be sensitive
to variation in brightness across the image and other effects. More robust results can
be obtained by modeling some filtered version of the original image.
Edge-based representations tend to be less sensitive to imaging parameters than
raw intensity measures. Thus an obvious alternative to modeling the intensity
values directly is to record the local image gradient in each direction at each pixel.
Although this yields more information at each pixel, and at first glance might seem
to favor edge regions over flatter regions, it is only a linear transformation of the
original intensity data. Where model building involves applying a linear PCA to the
samples, the resulting model is almost identical to one built from raw intensities,
apart from some effects around the border, where computing the gradients includes
some background information into the model.
However, nonlinear normalization of the gradient at each pixel in the region to
be modeled has been found to be a useful representation. If the local gradients at
a pixel are gx , gy , we compute normalized features .gx0 ; gy0 / D .gx ; gy /=.g C g0 /
where g is the magnitude of the gradient, and g0 is the mean gradient magnitude
over a region. Building texture models of this normalized value has been shown to
give more robust matching than matching intensity models [34].
Stegmann and Larsen [24] demonstrated that combining multiple feature bands
(e.g., intensity, hue, and edge information) improved face feature location accuracy.
Scott et al. [18] have shown that including features derived from "cornerness"
measures can further improve performance.
Liu [21] uses features learnt from the training set (see below).
The original AAM manipulates the combined shape and feature parameter vector, c.
However, a very similar formulation can be used to instead drive the shape and pose
parameters, treating them as independent of the feature parameters [6, 22].
Active Shape and Appearance Models 117
In this formulation the explicit parameters are t and b. The feature parameters, a,
are set to the best match to the normalised features sampled from the image, f0 ,
Again the updates, ıt and ıb can be computed using a matrix multiplication with
this residual,
ıt D Rs1 rs .t; b/
(19)
ıb D Rs2 rs .t; b/
where the update matrices Rs1 and Rs2 are derived from numerical estimates of the
Jacobian of rs , or learnt from training data.
The advantage of this approach is that there are fewer shape parameters than
combined parameters, thus the method has the potential to be more efficient and
more robust. However, whether it does indeed give better results than the formu-
lation manipulating the combined parameters seems to be somewhat dependent
on the nature of the application being addressed, so it is advisable to try both
methods. In particular, where there is significant correlation between shape and
texture parameters, the combined parameter update may be more robust.
Liu [21] describes a variant in which the image features are selected from a large
basis set using an Adaboost approach, chosen so as to best discriminate between
the correct position and nearby incorrect positions. Given this feature model, it is
possible to evaluate the quality of fit of a particular choice of shape parameters. Liu
presents an efficient gradient-descent search algorithm for optimising the shape and
pose parameters.
Batur and Hayes demonstrated that modifying the update matrix R, depending
on the current estimates of the model parameters, can lead to more accurate and
reliable matching [2].
Cootes and Taylor demonstrated that the estimate of the Jacobian can be refined
during the search itself, leading to a better overall result [3].
Various authors have extended the AAM to use robust estimates for the model
building and parameter updates [13, 16, 25].
Stegmann et al. have done extensive work with Active Appearance Models, and
have made their software available [23].
118 T.F. Cootes et al.
5 Examples of application
Fig. 6 Typical training image and second mode of a shape model of a spine
6 Discussion
The statistical models of shape and appearance described above are able to capture
the variation in structure across a population. Such models are very useful for
searching new images and for giving concise descriptions of new examples of the
modelled structure.
Though they can only be used for objects which can be modelled as a deformed
version of some template, they still have wide application, as many structures and
organs of interest satisfy this constraint.
The choice of which approach (ASM or AAM) is most suitable is somewhat
application specific. ASMs, relying on multiple local searches, can be made very
efficient and are simpler to implement. AAMs are more complex, as they take
account of correlations in the texture across the whole of the modelled region.
However, both methods have been shown to give good results in different domains.
A limitation of using a single global shape model is that it can overconstrain the
final solution, particularly when there is a lot of local variation in shape which may
not be adequately captured in a small training set. Approaches to overcoming this
include artificially introducing extra shape variation into the model [8,11], applying
local search to locally deform the fit of the best global result [9] and using a set of
linked local models to optimise the result of a global model [31].
120 T.F. Cootes et al.
One of the most effective new techniques for matching shape models to new
images is a variant of the Active Shape Model which uses Random Forest regressors
at each point to vote for the best position of the points. Votes are accumulated from
a region around the current position, and the shape model is fitted so as to maximise
the total votes under each model point - see [20]. The ability of the Random Forest
to capture non-linear relationships between image structure and point positions is
particularly useful for achieving robust results.
Perhaps the most challenging problem associated with the use of such models is
obtaining the point correspondences required for training. Though in 2D they can
often be supplied manually, for large 3D datasets this is not practical. Considerable
research has been done into the subject of automatically finding correspondences
across large groups of shapes and images. Though it is still an active area, practical
methods are now available, including [4, 12, 14, 19].
Acknowledgements We would like to thank all our colleagues in the Centre for Imaging Sciences
for their help. The work was funded by the EPSRC, the MRC and the Arthritis Research Campaign.
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Part II
Statistical & Physiological Models
Statistical Atlases
Abstract This chapter discusses the general concept of statistical atlases built from
medical images. A statistical atlas is a quantitative reflection of normal variability
in anatomy, function, pathology, or other imaging measurements, and it allows
us to establish a baseline against which abnormal images are to be compared for
diagnostic or treatment planning purposes. Constructing a statistical atlas relies on a
fundamental building block, namely deformable registration, which maps imaging
data from many individuals to a common coordinate system, so that statistics of
normal variability, as well as abnormal deviations from it, can be performed. 3D
and 4D registration methods are discussed. This chapter also discusses the statistical
analyses applied to co-registered normative images, and finally briefly touches upon
use of machine learning for detection of imaging patterns that distinctly deviate
from the normative range to allow for individualized classification.
1 Introduction
Medical images are now used routinely in a large number of diagnostic and prog-
nostic evaluations. Their widespread use has opened up tremendous opportunities
for studying the structure and physiology of the human body, as well as the ways in
which structure and function are affected by a variety of diseases and disorders.
C. Davatzikos ()
Department of Radiology, University of Pennsylvania, 3600 Market Street,
Suite 380, Philadelphia, PA 19104, USA
e-mail: [email protected]
R. Verma
Department of Radiology, University of Pennsylvania, PA, USA
D. Shen
Department of Radiology, University of North Carolina, NC, USA
Fig. 1 A statistical atlas of the spatial distribution of gray mattr (GM) in a population of elderly
healthy individuals. Hot colors indicate brain regions with the highest frequency/volume of GM in
the population. A new individual’s spatial distribution of GM can be contrasted against this atlas,
to identify regions of potentially abnormal brain atrophy
Although earlier studies typically involved a few dozens of images each, many
current clinical research studies involve hundreds, and thousands of participants,
often with multiple scans each. Large databases are therefore constructed rapidly,
incorporating rich information of structure and function in normal and diseased
states. Analysis of such a wealth of information is becoming increasingly difficult,
without the availability of advanced statistical image analysis methods.
In order to be able to integrate images from different individuals, modalities,
time-points, and conditions, the concept of a statistical atlas has been introduced
and used extensively in the medical image analysis literature, especially in the fields
of computational anatomy and statistical parametric mapping of brain functional
images [8, 14, 23, 28, 30, 82, 84]. images over certain populations. For example,
a statistical atlas of the typical regional distribution of gray and white matter
(GM, WM) in the brain can be constructed by spatially normalizing a number
of brain images of healthy individuals into the stereotaxic space, and measuring
the average and standard deviation of the amount of GM and WM in each brain
region (Fig. 1). This atlas can also become more specific, for example to the age,
sex, and other characteristics of the underlying population. Similarly, a statistical
atlas of cardiac structure and function can provide the average myocardial wall
thickness at different locations, its change over time within the cardiac cycle, and
its statistical variation over a number of healthy individuals or of patients with a
specific cardiac pathology. Another representative example could be an atlas of the
spatial distribution of prostate cancer [98], which can be constructed from a number
of patients undergoing prostatectomy, in order to guide biopsy procedures aiming
to sample prostate regions that tend to present higher incidence of prostate cancer
(e.g. Fig. 2).
Statistical atlases are quantitative analogs to the knowledge acquired by a
radiologist during clinical training, in that they learn patterns from large number of
scans, and represent anatomical or functional variability in a group of individuals.
The two most common ways in which atlases are used are the following:
Statistical Atlases 127
Fig. 2 A statistical atlas of the spatial distribution of prostate cancer obtained from co-registered
prostatectomy specimens. Brighter green indicates areas of higher cancer incidence. This atlas can
potentially be used to guide biopsy procedures aiming to obtain tissue from regions more likely to
host cancer
Image analysis methods have been studied in the literature during the past 15
years [3, 6, 12, 22, 26, 38, 46, 47, 50, 60, 65, 67, 69, 76, 77, 81]. One very promising
approach for morphometric analysis is based on shape transformations that maps
one template of anatomy (e.g. a typical brain, spinal, cardiac, or prostate image) to
an image of interest. The resulting transformation measures the detailed differences
between the two anatomies under consideration. So far, many methods have been
proposed in the literature for obtaining the shape transformations, typically based
on a method called deformable image registration.
128 C. Davatzikos et al.
extracted from the images via an image analysis algorithm, or simply drawn
manually, and are then used to drive a 3D deformable registration method, which
effectively interpolates feature correspondence in the remainder of the image.
Feature-based methods pay more attention to the biological relevance of the
shape matching procedure, since they only use anatomically distinct features to
determine the shape transformation, whereas image matching methods seek the
transformations that maximize the similarity of images, with little warranty that the
implied correspondences have anatomical meaning. However, the latter approaches
take advantage of the full dataset, and not only of a relatively sparse subset of
features.
Deformable registration using attribute vectors: A method that has been pre-
viously developed by our group attempts to integrate the advantages of various
methods and at the same time to overcome some of their limitations, by developing
an attribute vector as a morphological signature of each point, to allow the selection
of the distinctive points for hierarchically guiding the image registration procedure
[71, 73, 74, 95]. This is the method called Hierarchical Attribute Matching Mech-
anism for Elastic Registration (HAMMER). HAMMER is a hierarchical warping
mechanism that has three key characteristics.
First, it places emphasis on determining anatomical correspondences, which in
turn drive the 3D warping procedure. In particular, feature extraction methods have
been used for determining a number of parameters from the images, to characterize
at least some key anatomical features as distinctively as possible. In [73], geometric
moment invariants (GMIs) were particularly used as a means for achieving this goal.
GMIs are quantities that are constructed from images that are first segmented into
GM, WM and CSF, or any other set of tissues of interest. They are determined from
the image content around each voxel, and they quantify the anatomy in the vicinity
of that voxel. GMIs of different tissues and different orders are collected into a long
attribute vector for representing each voxel in an image. Ideally, attribute vectors are
made as distinctive as possible for each voxel, so that anatomical matching across
individual brains can be automatically determined during the image registration
procedure. Fig. 3 shows a color-coded image of the degree of similarity between the
GMI-based attribute vector of a point on the anterior horn of the left ventricle and
the attribute vectors of every other point in the image. The GMI attribute vector of
this point, as well as of many other points in the brain, is reasonably distinctive, as
shown in Fig. 3. We have also explored more distinctive attribute vectors, aiming
at constructing even more reliable and distinctive morphological signatures for
every voxel in the image. Toward this end, wavelet coefficients [95], multiple-scale
histogram features [72], local descriptor features [92], or combinations of various
local features [92] were computed for hierarchical characterization of images of
multi-scale neighborhoods centered on each voxel [94, 95].
Second, HAMMER addresses a fundamental problem encountered in high-
dimensional image matching. In particular, the cost function being optimized
typically has many local minima, which trap an iterative optimization procedure into
solutions that correspond to poor matches between the template and the individual.
This is partly due to the ambiguity in finding the point correspondences. For
130 C. Davatzikos et al.
Fig. 3 The point marked by a cross has a relatively distinctive GMI-based attribute vector. The
color-coded image on the right shows the degree of similarity between the attribute vector of the
marked point and the attribute vector of every other point in the brain. 1 is maximum similarity
and 0 is minimum similarity
Fig. 4 Results using the HAMMER warping algorithm. (A) 4 representative sections from MR
images of the BLSA database (B) Representative sections from the image formed by averaging
150 images warped by HAMMER to match the template shown in (C). (D1-D4) 3D renderings of
a representative case, its warped configuration using HAMMER, the template, and the average of
150 warped images, respectively. The anatomical detail seen in (B) and (D4) is indicative of the
registration accuracy
transformation during each time point, and then examine longitudinal changes in
the shape transformations. This approach is valid in theory, but limited in practice.
This is because the independent atlas warping for each longitudinal scan typically
leads to jittery longitudinal measurements, particularly for small structures such
as the hippocampus of the brain, due to inconsistent atlas warping across different
scans in a series [75]. Although smoothened estimates of longitudinal changes can
be obtained by smoothing or regressing over the measurements along the temporal
dimension, post hoc smoothed measurements will, in general, deviate significantly
from the actual image data, unless smoothing is performed concurrently with
atlas warping and by taking into account the image features. It is worth noting
that the issue of longitudinal measurement robustness is particularly important in
measuring the progression of a normal older adult into mild cognitive impairment,
which makes it possible to have the ability to detect subtle morphological changes
well before severe cognitive decline appears.
In order to achieve longitudinally stable measurements, we have developed
4-dimensional image analysis techniques, such as a 4D extension of HAMMER
[75]. In this approach [75], all serial scans are jointly considered as a single
4D scan, and the optimal 4D deformation is determined, thus avoid inconsistent
atlas warping across different serial scans. The 4D warping approach of [75]
simultaneously establishes longitudinal correspondences in the individual as well
as correspondences between the template and the individual. This is different from
the 3D warping methods, which aim at establishing only the inter-subject corre-
spondences between the template and the individual in a single time-point. Specif-
ically, 4D-HAMMER uses a fully automatic 4-dimensional atlas matching method
that constrains the smoothness in both spatial and temporal domains during the
132 C. Davatzikos et al.
hierarchical atlas matching procedure, thereby producing smooth and accurate esti-
mations of structural changes over time. Most importantly, morphological features
and matches guiding this deformation process are determined via 4D image analysis,
which significantly reduces noise and improves robustness in detecting anatomical
correspondence. Put simply, image features that are consistently recognized in
all time-points guide the warping procedure, whereas spurious features (such as
noisy edges) that appear inconsistently at different time-points are eliminated. We
have validated this approach against manually-defined brain ROI volumes by very
well trained experts on serial scans [75], and we determined that it produces not
only smoother and more stable measurements of longitudinal atrophy, but also
significantly more accurate measurements, as demonstrated in [75].
Evaluation: The plethora of automated methods for deformable image registra-
tion has necessitated the evaluation of their relative merits. To this end, evaluation
criteria and metrics using large image populations have been proposed by using
richly annotated image databases, computer simulated data, and increasing the
number and types of evaluation criteria [13]. However, the traditional deformable
simulation methods, such as the use of analytic deformation fields or the displace-
ment of landmarks followed by some form of interpolation [6], are often unable
to construct rich (complex) and/or realistic deformations of anatomical organs. To
deal with this limitation, several methods have been developed to automatically sim-
ulate realistic inter-individual, intra-individual, and longitudinal deformations, for
validation of atlas-based segmentation, registration, and longitudinal measurement
algorithms [10, 96].
The inter-individual deformations can be simulated by a statistical approach,
from the high-deformation fields of a number of examples (training samples).
In [96], Wavelet-Packet Transform (WPT) of the training deformations and their
Jacobians, in conjunction with a Markov Random Field (MRF) spatial regulariza-
tion, were used to capture both coarse and fine characteristics of the training defor-
mations in a statistical fashion. Simulated deformations can then be constructed
by randomly sampling the resultant statistical distribution in an unconstrained or a
landmark-constrained fashion. In particular, the training sample deformations could
be generated by first extensively labeling and landmarking a number of images
[5], and then applying a high-dimensional warping algorithm constrained by these
manual labels and landmarks. Such adequately constrained warping algorithms are
likely to generate deformations that are close to a gold standard, and therefore
appropriate for training.
The intra-individual brain deformations can be generated to reflect the structural
changes of an individual brain at different time points, i.e., tissue atrophy/growth of
a selected structure or within a selected region of a brain. In particular, the method
proposed in [51] can be used to simulate the atrophy and growth, i.e., generating a
deformation field by minimizing the difference between its Jacobian determinants
and the desired ones, subject to some smoothness constraints on the deformation
field. The desired Jacobian determinants describe the desired volumetric changes of
different tissues or different regions. Moreover, by using the labeled mesh and the
Statistical Atlases 133
FEM solver [10], the realistic longitudinal atrophy in brain structures can be also
generated, to mimic the patterns of change obtained from a cohort of 19 real controls
and 27 probable Alzheimer’s disease patients.
Section 2 describes the process of spatial normalization, which brings images in the
same coordinate frame. These can now be incorporated into a statistical atlas for
group analysis as will be discussed next.
One of the most common applications of statistical atlases is to be able to compare
two groups. These groups could be groups of patients with a specific disease and a
group of healthy controls, or groups of subjects divided on the basis of age, gender
or some other physical characteristic. Prior to performing any group-analysis, the
images of the subjects to be used are spatially normalized to a subject chosen to
be the template. The method adopted for spatial normalization and group-based
analysis depends completely on the type of data (scalar or high-dimensional) used
for representing the subjects.
Fig. 5 Regions of difference between schizophrenia patients and healthy controls using voxel-
wise application of linear statistics
While the general linear model (GLM) has been used effectively for the statistical
analysis of the scalar map representation of the subjects, with the increasing use
of multi-parametric or multi-modality images, GLM with Gaussian smoothing does
not suffice for several reasons. The simple spatial filtering and subsequent linear
statistics are not a valid approach for the multi-parametric data such as tensors
and multi-modality data as the high-dimensional, non-linear data at each voxel
are typically distributed along sub-manifolds of the embedding space. In tensors,
this embedding space could be in R6 , if single voxel data is to be considered. In
multi-modality data, the dimension of the embedding space will be the number of
Statistical Atlases 135
Fig. 6 Manifold structure of tensors. The gray surface represents the non-linear manifold fitted
through the tensors or any high dimensional structure represented as ellipses. The green line
represents the Euclidean distance between tensors treated as elements of R6 and the red line
represents the geodesic distance along the manifold that will be used for all tensor manipulations
modalities combined to represent the data. Fig. 6 demonstrates this concept, for
the case of tensors, but instead of ellipses, any high-dimensional structure could
be used to emulate the voxel-wise structure of multi-modality data. The filtering
and the subsequent statistics need to be performed on this underlying manifold.
In addition, to the underlying structure of the data, another reason for the lack of
feasibility of the GLM for this data is that the shape and size of a region of interest,
such as a region of growth or abnormal morphological characteristics, is not known
in advance; the way in which a disease process is likely to affect the local tissue
structure of the brain is highly unlikely to follow a Gaussian spatial profile of a
certain pre-defined size. Thus the two main challenges that we need to address in
order to form statistical atlases of this higher dimensional data and follow it with
group analysis are: 1) determining the true underlying structure of the data in the
form of a non-linear manifold and 2) estimating the statistical distribution of the
data on that manifold.
In order to address these two issues, more sophisticated image analysis methods
need to be developed that determine the often non-linear relationships among
different scans and therefore lead to the identification of subtle imaging phenotypes.
In relation to tensors, methods based upon Riemannian symmetric spaces [37, 58]
rely upon the assumption that the tensors around a given voxel from various subjects
belong to a principal geodesic (sub)-manifold and that these tensors obey a normal
distribution on that sub-manifold. The basic principle of these methods is sound,
namely that statistical analysis of high dimensional data must be restricted to an
appropriate manifold. However, there is no guarantee that the representations of the
tensors on this sub-manifold will have normal distributions, and most importantly,
restricting the analysis on the manifold of positive definite symmetric tensors is of
little help in hypothesis testing studies, since the tensors measured at a given voxel or
neighborhood, from a particular set of brains, typically lie on a much more restricted
sub-manifold of the space of symmetric positive definite matrices. For example,
if all voxels in a neighborhood around the voxel under consideration belong to
a particular fiber tract, then the tract geometry will itself impose an additional
nonlinear structure on the sub-space of the tensors at those voxels from all subjects.
Some of these issues were alleviated by the development of a manifold-based
statistical analysis framework which focuses on approximating/learning the local
structure of the manifold along which tensor/higher-dimensional measurements
136 C. Davatzikos et al.
from various individuals are distributed. The learned features belonged to a low-
dimensional linear manifold parameterizing the higher-dimensional tensor manifold
and were subsequently used for group-wise statistical analysis. The filtering and
subsequent statistical analysis are then performed along the manifold, rather than in
the embedding space.
The two frameworks that are discussed below are from the perspective of
whether: 1) the manifold is explicitly determined (Sect. 3.3) or 2) the data distri-
bution is determined by implicitly incorporating the underlying structure of the data
(Sect. 3.4). While explained in the context of tensors they are applicable to high
dimensional muli-parametric data.
In the above discussion involving manifold learning and kernel based methods,
although the data at each voxel were tensors, the frameworks can easily lend
themself to higher dimensional data as it derived from multi-modality data. The
difference would be the manifold learned and the nature of the embedding space.
Fig. 8 An individual is compared against a statistical atlas of normal elderly individuals, in order
to determine whether the pattern of brain atrophy is typical of a normal elderly or not. The figure
displays a z-score map, i.e. a voxel-by-voxel evaluation of the individual’s gray matter volume
against the statistical atlas. A pattern of fronto-temporal atrophy (blue regions) indicates AD-like
pathology
One of the motivating factors behind these developments is the complex and
spatio-temporally distributed nature of the changes that many diseases cause,
particularly in the brain and the heart. For example, in Alzheimer’s Disease, the
anatomical structures that carry most discriminative power are likely to depend on
the stage of the disease, as the disease progressively spreads throughout various
brain regions [7], but also on age and other demographic and genetic factors [61],
since disease is to be distinguished from complex and progressively changing back-
ground normal variations in anatomy and function that may depend on demographic
and/or genetic background. Moreover, Alzheimer’s disease might cause changes
of the image characteristics beyond those measured by volumetrics, such as for
example brightening or darkening of an MR image due to demyelination, deposition
of minerals, or other macro- or micro-structural changes caused by disease. Vascular
disease also causes well-known MR signal changes, for example in the white matter
of the brain (e.g. brightening of T2 -weighted signal). It is thus becoming clear that
multiple modalities and multiple anatomical regions must be considered jointly in
a (possibly nonlinear) multi-variate classification fashion, in order to achieve the
desirable diagnostic power. Moreover, regions that are relatively less affected by
disease should also be considered along with known to be affected regions (which,
for the example of Alzheimer’s Disease might include primarily temporal lobe
structures, in relatively early disease stages), since differential atrophy or image
intensity changes between these regions are likely to further amplify diagnostic
accuracy and discrimination from a background of normal variation. Certain cardiac
diseases also have subtle and spatio-temporally complex patterns of structural and
functional change. For example, arrhythmogenic right ventricular disease involves
spatial patterns of structural and physiological change that are not always easy to
distinguish from normal inter-individual variability.
A fundamental challenge faced by high-dimensional pattern classification meth-
ods in medical imaging is the curse of dimensionality, i.e. the fact that imaging
measurements have vastly larger dimensionality than the number of sample avail-
140 C. Davatzikos et al.
able in the typical study. Extraction, selection, and reduction of all spatio-temporal
information included in a medical scan to a small number of features that optimally
distinguishes between two or more groups is an open problem. Some approaches
have employed global dimensionality reduction methods, such as principal or
independent component analysis [32, 63], before feeding the reduced features into a
pattern classifier.
A more localized approach has been developed in our laboratory, and is termed
COMPARE (Classification of Mosphological Patterns using Adaptive Regional
Elements). This approach was described in [57] and examines spatio-temporal
patterns of regional brain atrophy, by hierarchically decomposing a an image into
images of different scales, each of which capturing structural and/or functional
characteristics of interest at a different degree of spatial resolution. The most
important parameters are then selected and used in conjunction with a nonlinear
pattern classification technique to form a hyper-surface, the high-dimensional
analog to a surface, which is constructed in a way that it optimally separates two
groups of interest, for example normal controls and patients of a particular disease.
Effectively, that approach defines a nonlinear combination of a large number of
image-derived measurements from the entire anatomy of interest, each taken at
a different scale that typically depends on the size of the respective anatomical
structure and the size of the region that is most affected by the disease. This
nonlinear combination of volumetric measurements is the best way, according to the
respective optimality criteria, to distinguish between two groups, and therefore to
perform diagnosis via classification of a new scan into patients or normal controls. In
[27] excellent separation was obtained by high-dimensional nonlinear classification
applied to a population of healthy controls and MCI patients that were not separable
using the commonly used volumetric measurements of the hippocampus and the
entorhinal cortex, further indicating that appropriate increase of dimensionality
helps separate otherwise unseparable data.
In summary, the availability of large numbers of medical image datasets has
necessitated the development and validation of image analysis tools that capture the
range of variation of image-derived structural and functional characteristics, over
populations of patients and healthy subjects. A new generation of techniques for
deformable registration, statistical analysis, and pattern classification has appeared
in the literature over the past decade, aiming to help identify anatomical and
functional differences across different groups, but also to classify individual scans
against baseline statistical atlases of normal and diseased populations. These new
tools are gradually being adopted in clinical studies.
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Statistical Atlases 145
Anatomy is the science that studies the structure and the relationship in space of
different organs and tissues in living systems. Before the renaissance, anatomical
descriptions were mainly based on animal models and the physiology was more
philosophical than scientific. Modern anatomy really began with the authorized
dissection of human cadavers, giving birth to the “De humani corporis fabrica”
published by in 1543 by Vesale (1514-1564), and was strongly pushed by the
progresses in surgery, as exemplified by the “Universal anatomy of the human body”
(1561-62) of the great surgeon Ambroise Paré (1509-1590). During the following
centuries, many progresses were done in anatomy thanks to new observation tools
like microscopy and histology, going down to the level of cells in the 19th and
20th centuries. However, in-vivo and in-situ imaging is radically renewing the field
since the 1980ies. An ever growing number of imaging modalities allows observing
both the anatomy and the function at many spatial scales (from cells to the whole
body) and at multiple time scales: milliseconds (e.g. beating heart), years (growth
or aging), or even ages (evolution of species). Moreover, the non-invasive aspect
allows repeating the observations on multiple subjects. This has a strong impact on
the goals of the anatomy which are changing from the description of a representative
individual to the description of the structure and organization of organs at the
population level. The huge amount of information generated also raises the need
for computerized methods to extract and structure information. This led in the last
10 to 20 years to the gradual evolution of descriptive atlases into interactive and
generative models, allowing the simulation of new observations. Typical examples
are given for the brain by the MNI 305 [25] and ICBM 152 [46] templates that are
the basis of the Brain Web MRI simulation engine [20]. In the orthopedic domain,
one may cite the “bone morphing” method [34,63] that allows to simulate the shape
of bones.
The combination of these new observation means and of the computerized
methods is at the heart of computational anatomy, an emerging discipline at the
interface of geometry, statistics and image analysis which aims at developing
algorithms to model and analyze the biological shape of tissues and organs. The goal
is not only to estimate representative organ anatomies across diseases, populations,
species or ages but also to model the organ development across time (growth or
aging) and to establish their variability. Another goal is to correlate this variability
information with other functional, genetic or structural information (e.g. fiber
bundles extracted from diffusion tensor images). From an applicative point of
view, a first objective is to understand and to model how life is functioning at the
population level, for instance by classifying pathologies from structural deviations
(taxonomy) and by integrating individual measures at the population level to relate
anatomy and function. For instance, the goal of spatial normalization of subjects in
neuroscience is to map all the anatomies into a common reference system. A second
application objective is to provide better quantitative and objective measures to
detect, understand and correct dysfunctions at the individual level in order to help
therapy planning (before), control (during) and follow-up (after).
The method is generally to map some generic (atlas-based) knowledge to
patients-specific data through atlas-patient registration. In the case of observations
of the same subject, many geometrical and physically based registration meth-
ods were proposed to faithfully model and recover the deformations. However,
in the case of different subjects, the absence of physical models relating the
anatomies leads to a reliance on statistics to learn the geometrical relationship from
Statistical Computing on Non-Linear Spaces for Computational Anatomy 149
Computing on simple manifolds like the 3D sphere or a flat torus (for instance
an image with opposite boundary points identified) might seems easy as we can
see the geometrical properties (e.g. invariance by rotation or translation) and
imagine tricks to alleviate the different problems. However, when it comes to
slightly more complex manifolds like tensors, rigid body or affine transformations,
without even thinking to infinite dimensional manifolds like spaces of surfaces or
diffeomorphisms, computational tricks are much more difficult to find and have to
be determined on a case by case basis. The goal of this section is to exemplify
with the development of basic but generic statistical tools that the work specific to
150 X. Pennec and P. Fillard
each manifold can be limited the determination of a few computational tools derived
from a chosen Riemannian metric. These tools will then constitute the basic atoms
to build more complex generic algorithms in Sect. 3.
In the geometric framework, one has to separate the topological and differential
properties of the manifold from the metric ones. The first ones determine the local
structure of a manifold M by specifying neighboring points and tangent vectors,
which allows to differentiate smooth functions on the manifold. The topology
also impacts the global structure as it determines if there exists a connected path
between two points. However, we need an additional structure to quantify how far
away two connected points are: a distance. By restricting to distances which are
compatible with the differential structure, we enter into the realm of Riemannian
geometry. A Riemannian metric is defined by a continuous collection of scalar
products h : j : ip (or equivalently quadratic norms k:kp ) on each tangent space
Tp M at point p of the manifold. Thus, if we consider a curve on the manifold,
we can compute at each point its instantaneous speed vector (this operation only
involves the differential structure) and its norm to obtain the instantaneous speed
(the Riemannian metric is needed for this operation). To compute the length of
the curve, this value is integrated as usual along the curve. The distance between
two points of a connected Riemannian manifold is the minimum length among
the curves joining these points. The curves realizing this minimum are called
geodesics. The calculus of variations shows that geodesics are the solutions of a
system of second order differential equations depending on the Riemannian metric.
In the following, we assume that the manifold is geodesically complete, i.e. that all
geodesics can be indefinitely extended. This means that the manifold has neither
boundary nor any singular point that we can reach in a finite time. As an important
consequence, the Hopf-Rinow-De Rham theorem states that there always exists at
least one minimizing geodesic between any two points of the manifold (i.e. whose
length is the distance between the two points).
Let p be a point of the manifold that we consider as a local reference and Ev a vector
of the tangent space Tp M at that point. From the theory of second order differential
equations, we know that there exists one and only one geodesic
.p;Ev/ .t/ starting
from that point with this tangent vector. This allows to wrap the tangent space onto
the manifold, or equivalently to develop the manifold in the tangent space along
the geodesics (think of rolling a sphere along its tangent plane at a given point), by
mapping to each vector Ev 2 Tp M the point q of the manifold that is reached after
Statistical Computing on Non-Linear Spaces for Computational Anatomy 151
Tp M
p 0
w p
v
pq
γ
u κ
t q
q M
Fig. 1 Left: The tangent planes at points p and q of the sphere S2 are different: the vectors v and
w of Tp M cannot be compared to the vectors t and u of Tq M . Thus, it is natural to define the
scalar product on each tangent plane. Right: The geodesics starting at x are straight lines in the
exponential map and the distance along them is conserved
The exponential and logarithmic maps (from now on Exp and Log maps) are
obviously different for each manifold and for each metric. Thus they have to be
determined and implemented on a case by case basis. Example for rotations, rigid
body transformations can be found for the left invariant metric in [60], and examples
152 X. Pennec and P. Fillard
for tensors in [4, 58]. Exponential charts constitute very powerful atomic functions
in terms of implementation on which we will be able to express practically all
the geometric operations: the implementation of Logp and Expq is the basis of
programming on Riemannian manifolds, as we will see in the following.
In a Euclidean space, the exponential charts are nothing but one orthonormal
coordinates system translated at each point: we have in this case ! D Log .q/ D
pq p
q p and Expp .Ev/ D pCEv. This example is more than a simple coincidence. In fact,
most of the usual operations using additions and subtractions may be reinterpreted
in a Riemannian framework using the notion of bi-point, an antecedent of vector
introduced during the 19th Century. Indeed, vectors are defined as equivalent classes
of bi-points in a Euclidean space. This is possible because we have a canonical way
(the translation) to compare what happens at two different points. In a Riemannian
manifold, we can still compare things locally (by parallel transportation), but not
any more globally. This means that each “vector” has to remember at which point
of the manifold it is attached, which comes back to a bi-point.
A second way to see the vector ! is as a vector of the tangent space at point p.
pq
Such a vector may be identified to a point on the manifold using the exponential
map q D Expp . ! Conversely, the logarithmic map may be used to map almost
pq/.
any bi-point .p; q/ into a vector ! D Log .q/ of T M . This reinterpretation of
pq p p
addition and subtraction using logarithmic and exponential maps is very powerful
to generalize algorithms working on vector spaces to algorithms on Riemannian
manifolds, as illustrated in Table 1 and the in following sections.
Let us take an example with positive definite symmetric matrices, called tensors in
medical image analysis. They are used for instance to encode the covariance matrix
of the Brownian motion (diffusion) of water in Diffusion Tensor Imaging (DTI)
[8, 40] or to encode the joint variability at different places (Green function) in shape
analysis (see [29, 30, 31] and Sect. 4). They are also widely used in image analysis
to guide the segmentation, grouping and motion analysis [16, 47, 73, 74].
Statistical Computing on Non-Linear Spaces for Computational Anatomy 153
The main problem is that the tensor space is a manifold that is not a vector
space with the usual additive structure. Indeed, the positive definiteness constraint
delimits a convex half-cone in the vector space of symmetric matrices. Thus, convex
operations (like the mean) are stable in this space but problems arise with more
complex operations. For instance, there is inevitably a point in the image where
the time step is not small enough when smoothing fields of tensors with gradient
descents, and this results into negative eigenvalues.
To answer that problem, we proposed in [58] to endow the space of tensors with
a Riemannian metric invariant by any change of the underlying space coordinates,
i.e. invariant under the action of affine transformations on covariance matrices. A
few mathematical developments showed that the Exp, Log and distance maps were
given with quite simple formulas involving the matrix logarithm exp and log:
Exp† .W / D †1=2 exp †1=2 W †1=2 †1=2
Log† .ƒ/ D †1=2 log †1=2 ƒ†1=2 †1=2
dist2 .†; ƒ/ D Tr log.†1=2 ƒ†1=2 /2
matrices, the expression of the Exp, Log and distance maps for the Log-Euclidean
metric is easily determined:
These formulas look more complex than for the affine invariant metric because
they involve the differential of the matrix exponential and logarithm in order to
transport tangent vectors from one space to another [59]. However, they are in fact
nothing but the transport of the addition and subtraction through the exponential
of symmetric matrices. In practice, the log-Euclidean framework consist in taking
the logarithm of the tensor data, computing like usual in the Euclidean space of
symmetric matrices, and coming back at the end to the tensor space using the
exponential [3, 5].
From a theoretical point of view, geodesics through the identity are the same
for both log-Euclidean and affine-invariant metrics, but this is not true any more
in general at other points of the tensor manifold [4]. A careful comparison of both
metrics in practical applications [3, 5] showed that there was very few differences
on the results (of the order of 1%) on real DTI images, but that the log-Euclidean
computations where 4 to 10 times faster. For other types of applications, like
adaptive re-meshing [53], the anisotropy of the tensors can be much larger, which
may lead to larger differences. In any case, initializing the iterative optimizations of
affine-invariant algorithms with the log-Euclidean result drastically speeds-up the
convergence. Important application example of this tensor computing framework
were provided in [27,28] with a statistically grounded estimation and regularization
of DTI images. The white matter tractography that was allowed by these methods in
clinical DTI images with very poor signal to noise ratios could lead to new clinical
indications of DTI, for instance in the spinal chord [23].
The previous section showed how to derive the atomic Exp and Log maps from a
Riemannian metric. We now summarize in this section how one generalizes on this
basis many important statistical notions, like the mean, covariance and Principal
Component Analysis (PCA), as well as many image processing algorithms like
interpolation, diffusion and restoration of missing data (extrapolation). For details
about the theory of statistics on Riemannian manifolds in itself, we refer the reader
to [56, 57] and reference therein. Manifold-valued image processing is detailed in
[58] with the example of tensors.
Statistical Computing on Non-Linear Spaces for Computational Anatomy 155
written respectively in the continuous and discrete forms. One can generalize the
variance
R to a dispersion at order ˛ by changing the L2 with an ˛-norm: ˛ .p/ D
. dist.p; q/˛ dP .p//1=˛ . The minimizers are called the central Karcher values at
order ˛. For instance, the median is obtained for ˛ D 1 and the modes for ˛ D 0,
exactly like in the vector case. It is worth noticing that the median and the modes
are not unique in general in the vector space, and that even the mean may not
exists (e.g. for heavy tailed distribution). In Riemannian manifolds, the existence
and uniqueness of all central Karcher values is generally not ensured as they are
obtained through a minimization procedure. However, for a finite number of discrete
samples at a finite distance of each other, which is the practical case in statistics, a
mean value always exists and it is unique as soon as the distribution is sufficiently
peaked [37, 39].
Local minima may be characterized as particular critical points of the cost func-
tion: at Karcher mean points, the gradient of the variance should be null. However,
the distance is continuous but not differentiable at cut locus points where several
minimizing geodesic meets. For instance, the distance from a point of the sphere to
its antipodal point is maximal, but decrease continuously everywhere around it. One
can show [56, 57] that the variance it differentiable at all points where the cut locus
! R ! P
has a null measure and has gradient: r 2 .q/ D 2 qp dP .p/ D 2 n n
!
qp
i D1 i
respectively in the continuous (probabilistic) and discrete (statistical) formulations.
In practice, this gradient is well defined for all distributions that have a pdf since
the cut locus has a null measure. For discrete samples, the gradient exists if there is
156 X. Pennec and P. Fillard
no sample lying exactly on the cut-locus of the current test point. Thus, we end up
with the implicit characterization of Karcher mean points as exponential barycenters
which was presented in Table 1.
To practically compute the mean value, we proposed in [60] for rigid body
transformations and in [56, 57] for the general Riemannian case to use a Gauss-
Newton gradient descent algorithm. It essentially alternates the computation of
the barycenter in the exponential chart centered at the current estimation of the
mean value, and a re-centering step of the chart at the point of the manifold that
corresponds to the computed barycenter
P (geodesic marching step). This gives the
t C1 n !
Newton iteration: pN D ExppNt n i D1 pN pi . One can actually show that its
1 t
Once the mean point is determined, using the exponential chart at the mean point is
particularly interesting as the random feature is represented by a random vector with
null mean in a star-shaped domain. With this representation, there is no difficulty to
define the covariance matrix:
Z
1 X ! !T
n
! !T
†D N pq
pq: N dP .q/ D pq N i
N i :pq
n i D1
and potentially higher order moments. This covariance matrix can then be used to
defined the Mahalanobis distance between a random and a deterministic feature:
!T .1/
!
.p;†/
N .q/ D pqN † pq. N Interestingly, the expected Mahalanobis distance of a
random element is independent of the distribution and is equal to the dimension of
the manifold, as in the vector case. This statistical distance can be used as a basis to
generalize some statistical tests such as the mahalanobis D 2 test [57].
To analyze the results of a set of measurements in a Euclidean space, one often
performs a principal component analysis (PCA). A generalization to Riemannian
manifolds called Principal Geodesic Analysis (PGA) was proposed in [32] to
analyze shapes based on the medial axis representations (M-reps). The basic idea
is to find a low dimensional sub-manifold generated by some geodesic subspaces
that best explain the measurements (i.e. such that the squared Riemannian distance
from the measurements to that sub-manifold is minimized). Another point of view
is to assume that the measurements are generated by a low dimensional Gaussian
model. Estimating the model parameters amounts to a covariance analysis in order
to find the k-dimensional subspace that best explains the variance. In a Euclidean
space, these two definitions correspond thanks to Pythagoras’s theorem. However, in
the Riemannian setting, geodesic subspaces are generally not orthogonal due to the
Statistical Computing on Non-Linear Spaces for Computational Anatomy 157
curvature. Thus, the two notions differ: while the Riemannian covariance analysis
(tangent PCA) can easily be performed in the tangent space of the mean, finding
Riemannian sub-manifolds turns out to become a very difficult problem. As a matter
of fact, the solution retained by [32] was finally to rely on the covariance analysis.
When the distribution is unimodal and sufficiently peaked, we believe that
covariance analysis is anyway much better suited. However, for many problems,
the goal is rather to find a sub-manifold on which measurements are more or less
uniformly distributed. This is the case for instance for features sampled on a surface
or points sampled along a trajectory (time sequences). While the one dimensional
case can be tackled by regression [21], the problem for higher dimensional sub-
manifolds remains quite open. Some solutions may come from manifold embedding
techniques as exemplified for instance in [17].
problem is still valid, but instead of a closed-form solution, we have once again a
Gauss-Newton iterative gradient descent algorithm to reach the filtered value:
Z
pO t C1 .x/ D K.u/ LogpOt .x/ .p.x C u// d u:
Rn
We can also use anisotropic and non-stationary kernels K.x; u/. For instance, it
can be modulated by the norm of the derivative of the field in the direction u. We
should notice that for a manifold-value field p.x/, the directional derivatives @u p.x/
is a tangent vector of Tp.x/ M which can be practically approximated using finite
158 X. Pennec and P. Fillard
“differences” in the exponential chart: @u p.x/ ' Logp.x/ .p.x C u// C O.kuk2 /.
However, to measure the norm of this vector, we have to use the Riemannian metric
at that point: k@u pkp .
Z Z
1X
d
1
Reg.p/ D krp.x/k2p.x/ dx D k@xi p.x/k2p.x/ dx:
2 2 i D1
X 1
p t C1 .x/ D Exppt .x/ "p t .x/ with p.x/ / Logp.x/ .p.x C u//
kuk2
u2V
In order to filter within homogeneous regions but not across their boundaries,
an idea is to penalize the smoothing in the directions where the derivatives are
important [35, 61]. This can be realized directly in the discrete implementation of
the Laplacian by weighting the directional Laplacian by a decreasing function of
P norm k@u pkp of the gradient in that direction.
the For instance, we used u p D
u c.k@u pkp / u p with c.x/ D exp x 2
= 2
in [58]. As the convergence of
Statistical Computing on Non-Linear Spaces for Computational Anatomy 159
this scheme is not guaranteed (anisotropic regularization “forces” may not derive
from a well-posed energy), the problem may be reformulated as the optimization
of a -function of the Riemannian
R norm
of the spatial
gradient (a kind of robust
M-estimator): Reg .p/ D 12 krp.x/kp.x/ dx. By choosing an adequate
-function, one can give to the regularization an isotropic or anisotropic behavior
[7]. The main difference with a classical Euclidean calculation is that we have to
take the curvature into account by using the Laplace-Beltrami operator, and by
measuring the length of directional derivatives using the Riemannian metric at the
right point [26]. Using ‰.x/ D 0 .x/=x, we get:
Pd
rReg .p/ D ‰.krpkp /p i D1 @xi ‰.krpkp /@xi p:
The pure diffusion reduces the noise in the data but also the amount of information.
Moreover, the total diffusion time that controls the amount of smoothing is difficult
to estimate. At an infinite diffusion time, the field will be completely homogeneous.
Thus, it is more interesting to consider the data as noisy observations and the
regularization as a prior on the spatial regularity of the field. Usually, one assumes
a Gaussian noise independent at each position, which leads to a least-squares
criterion through a maximum likelihood approach. For a dense data field q.x/, the
similarity
R criterion that is added to the regularization criterion is simply S i m.p/ D
2
dist .p.x/ ; q.x// dx. The only difference here is that it uses the Riemannian
distance. It simply adds a linear (geodesic) spring rp dist2 .p; q/ D 2 ! to
pq
the global gradient to prevent the regularization from pulling to far away from the
original data.
For sparse measures, using directly the maximum likelihood on the observed data
leads to deal with Dirac (mass) distributions in the derivatives, which is a problem
for the numerical implementation. One solution is to consider the Dirac distribution
as the limit of the Gaussian function G when goes to zero, which leads to the
P !
regularized derivative [58]: rS i m.x/ D 2 niD1 G .x xi / p.x/pi .
Now that we have the methodology to work with geometric features, let us see how
it can be used to model the anatomy. A first interesting example was proposed by
Jonathan Boisvert [12, 13] with a 3D articulated model of the spine. The model
160 X. Pennec and P. Fillard
Fig. 2 First (left) and second (right) modes of variation of the statistical spine model depicted at -3,
0 (mean) and 3 times its standard deviation. Images courtesy of Jonathan Boisvert, Polytechnique
School of Montreal, Canada
gathers the relative configurations of the vertebrae along the spinal chord (the
parameters are the rigid transforms that superpose neighboring vertebrae) rather
than the position and orientation of each vertebra in a global reference frame. As
small local motions at one point of the spine may have a large impact of the position
at another point, this local representation is better capturing information that may get
unnoticed in a global reference frame. However, this requires making statistics on
geometric objects (rigid body transformation parameters) rather than on just points.
The statistical model of the spine was established in a population of 307 untreated
scoliotic patients. Each vertebra was reconstructed in 3D from anatomical land-
marks in bi-planar radiographies. Posture during data acquisition was normalized
but individual factors such as the age, sex or type of scoliotic curve were not
taken into account. Thus, the statistics capture the anatomical variability inherent
to the pathology but also the growth stage. The Fréchet mean and the generalized
covariance of the articulated model was then computed. As there are 102 degrees of
freedom (5 lumbar and 12 thoracic vertebrae), the analysis of the covariance matrix
could hardly be performed by hand. Thus, the most meaningful modes of variation
were extracted using a PCA on the tangent plane.
A visual inspection reveals that the first modes had clinical meanings and were
explaining curve patterns that are routinely used in different clinical classifications
of scoliosis (see [11, 14] for details). For instance, the first mode appears to be
associated with the patient growth with a mild thoracic curve (King’s type II or
III depending on the amplitude of the mode) and the second could be described
as a double thoraco-lumbar curve (King’s type I), see Fig. 2. A more quantitative
analysis showed that there is a statistically significant link between the 4 principal
modes and King’s classes, although each class is generally linked to a combination
of modes rather than only one mode [11].
Statistical Computing on Non-Linear Spaces for Computational Anatomy 161
1
http://www.loni.ucla.edu/~khayashi/Public/medial_surface/
162 X. Pennec and P. Fillard
Fig. 3 Measuring variability tensors along the Sylvian Fissure. Left: Covariance matrices
(ellipsoids at one standard deviation) are overlaid at regularly sampled spatial positions along the
mean sulci. Middle: Tensors selected by our tensor picking operation. Right: Tensors reconstructed
by linear interpolation in-between them. Notice that only 5 tensors in that case nicely represent the
variability of the entire sulcus
Fig. 4 Variability tensor extrapolation. Left: The 366 tensors retained for our model. Right: Result
of the extrapolation. Each point of this average brain shape contains a variability tensor
Fig. 5 Map of anatomical correlations. The tip of the superior temporal sulcus (marked A) was
picked as a reference point. The map indicates regions which are spotted as correlated with this
reference position (hot colors mean correlation). The most correlated points include the parietal
sulci (marked B and C), a very interesting neuroscience finding
n > !
1 X xi xN xi xN †xx †xy
TCM.x; y/ D D :
n 1 i D1 yi yN yi yN †txy †yy
5 Challenges
We have shown in this chapter that the choice of a Riemannian metric and the
implementation of a few tools derived from it, namely the Exp and Log maps,
provide the bases for building a consistent algorithmic framework to compute on
manifolds. In particular, we showed that one can compute consistent statistics, per-
form interpolation, filtering, isotropic and anisotropic regularization and restoration
of missing data.
We also showed that powerful computational models of the anatomy could
be built thanks to this Riemannian computing framework. For instance, Sect. 4.1
demonstrates that using a proper non-linear model of the spine allows to find a good
164 X. Pennec and P. Fillard
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Building Patient-Specific Physical
and Physiological Computational Models
from Medical Images
1 Introduction
Computational models of the human body [3] aim at reproducing the geometrical,
physical and physiological properties of human organs and systems at various scales
(see Fig. 1). This is an emerging and rapidly progressing area of research that
is driven by a better understanding of the physical and physiological processes
involved but also by more efficient computational tools (either software or hardware)
for their realistic numerical simulation. The purpose of this paper is to show how
medical imaging plays a growing role in the development of those models. Indeed,
medical imaging provides macroscopic observations of the human anatomy and its
function for a wide number of patients. It can serve to personalize those computa-
tional models, i.e. to choose a specific set of parameters that best corresponds to the
studied patient.
Before entering the issue of creating patient specific models, it is useful to
structure those models into a hierarchy of three main levels [16], the knowledge
Geometrical Scal
e Morphology
Surface Statistical
Modeling
Shape
Volume
Analysis
Physical Scal
e Kinematics Statistical
Modeling Deformation
Temperature
Electro-magnetism Analysis
of the lower level being required for the implementation of the upper level. The
first level is mainly geometrical and addresses the construction of digital static
descriptions of the anatomy, often based on medical imagery. The techniques
for segmenting and reconstructing anatomical and pathological structures from
medical images have been developed for the past 15 years and have brought many
advances in several medical fields including computer-aided diagnosis, therapy
planning, image-guided interventions, drug delivery, etc. An distinctive achievement
of computational anatomy has been carried out by the “Visible Human Project” [1]
which provided the first digital multimodal anatomical representation of the full
human body.
A second level of modeling describes the physical properties of the human body,
involving for instance the biomechanical behavior of various tissues, organs, vessels,
muscles or bone structures [22].
A third level of modeling describes the functions of the major biological
systems [24, 38] (e.g. cardiovascular [5, 44], respiratory [25], digestive, hor-
monal, muscular, central or peripheral nervous system, etc.) or some pathological
metabolism (e.g. evolution of inflammatory or cancerous lesions [48], formation
of vessel stenoses [7, 42], etc.). Such physiological models often include reactive
mechanisms while physical models only provide a passive description of tissues
and structures.
There is an additional dimension associated with each level: the scale at which the
anatomical, physical or physiological structure is described. With the development
of new imaging modalities, it is now possible to observe the shape or function
of most structures at the macroscopic (tissue), microscopic (cellular) levels and
Building Patient-Specific Physical and Physiological Computational Models. . . 171
Interpretation
(diagnosis)
Prediction of
evolution
Medical Geometry Computational
Images Statistics Models Therapy
and Physics of planning
Signals Physiology human body
Identification Therapy
(personalization) simulation
Fig. 2 This diagram shows how computational models can be coupled with medical images and
signals to build personalized models and use them in clinical applications [4]
even in such cases to reveal the metabolic activity at the nanoscopic (molecular)
scale. Coupled with those multiscale observations are new generations of multiscale
computational models [24, 38]
Furthermore, each model is specified by a number of parameters (e.g. material
stiffness or electrical conductivity for a physical model) and a related task consists
in finding a set of those parameters that produces the best agreement between
the simulated processes (deformation, activation,...) and the observed ones. The
techniques consisting in finding the patient-specific parameters of a dynamic model
typically require to solve an inverse problem and are sometimes called “data
assimilation” techniques in the field of oceanography or climatology. As illustrated
in Fig. 2, the personalization of a model from medical images or signals is often a
requirement for using its predictive power in clinical applications such as therapy
planning or simulation. The personalized models may also be used as advanced
image processing tools that can provide a decision support system with additional
physical or physical parameters relevant for establishing a diagnosis.
Finally, the ability to recover patient-specific parameters leads to the variability
study of those parameters across a given population. Thus, statistical modeling of
those computational models can be seen as an orthogonal modeling activity that
aims for instance at finding the local or global similarities and dissimilarities of a
structure or a function between two populations [18,34,49]. Statistical findings may
also be used to calibrate, refine or constrain [11] a given model. At the basis of
this activity is the growing availability of large databases of subjects and patients
including biomedical signals and images as well as genetic information.
In the next sections, following the proposed hierarchy, we describe a number
of practical cases involving the personalization of computational models before
proposing some perspectives and challenges for future research.
172 H. Delingette and N. Ayache
The brain shift that occurs during a neuro-surgical intervention is the main source
of intra-operative localization inaccuracies of pathologies (cerebral tumors,: : :).
Indeed, a neurosurgeon establishes the surgical plan based on a pre-operative MR
image: any non-rigid motion of the brain between the pre-operative and the intra-
operative configuration may lead to an error in the localization of the target. To
model the brain motion after opening the dura, a number of authors [17, 32] have
made the hypothesis that the loss of cerebro-spinal fluid causes a pressure field along
the gravity direction (Archimedes principle). Furthermore, anatomical constraints
(falx cerebri, skull) of the deformation field can be enforced with a biomechanical
model of the brain discretized as a tetrahedral mesh since the relevant anatomical
information can be extracted from MR images and enforced on the mesh.
This clinical problem has motivated the study of the biomechanical behavior of
the brain. For instance, Miller [33] has proposed a rheological model for swine
brains valid for large displacements. However, in most cases, authors have relied
on linear elastic models to extrapolate displacement fields [17, 47] from the cortex
surface. Similarly, partial validation of brain shift models has been carried out [10]
with a linear elastic model by comparing computed displacements with those
observed from intra-operative MR images.
The fairly good predictive power of those simplified models show that a quasi-
incompressible (Poisson ratio close to 0:5) linear elastic model is a good choice
for simulating the small displacements induced by the brain shift. This is a
Building Patient-Specific Physical and Physiological Computational Models. . . 173
sensible result since any non-linear material can be approximated as a linear elastic
material for sufficiently small displacements. Another important point that makes
the personalization of those biomechanical models less difficult is the fact they
are often used to predict displacements from given imposed displacements. In such
cases, the knowledge of the Young Modulus is irrelevant and only the Poisson ratio
and the boundary conditions must be chosen properly.
Surgery simulation aims at reproducing the visual and haptic senses experienced
by a surgeon during a surgical procedure, through the use of computer and
robotics systems. The medical scope of this technology is linked with the develop-
ment of minimally invasive techniques especially videoscopic surgery (endoscopy,
laparoscopy,...) and possibly telesurgery.
By creating patient-specific models, surgery simulation allows surgeons to verify,
optimize and rehearse the surgical strategy of a procedure on a given patient.
However, an important issue for patient-specific soft-tissue models is the esti-
mation of their material properties. Such parameters may be the Young Modulus
and Poisson ratios for linear elastic materials or other stiffness parameters for
general hyperelastic materials. There are three different sources of rheological data
to estimate those parameters: ex-vivo testing where a sample of a tissue is positioned
inside a testing rig [39]; in-vivo testing where a specific force and position sensing
device is introduced inside the abdomen to perform indentation [8,37]; Image-based
elastometry from ultrasound, Magnetic Resonance Elastometry [26, 31] or CT-scan
imaging.
There is no consensus on which method is best suited to recover meaningful
material parameters, each one having its limitation. For instance ex-vivo testing
may not be relevant because of the swelling or drying of the tissue. In-vivo
experiments should also be considered with caution because the response may be
location-dependent (linked to specific boundary conditions or non-homogeneity
of the material) and the influence of the loading tool caliper on the deformation
may not be well understood. Finally elastometry commonly assumes that the tissue
undergoes small displacements and need to be thoroughly calibrated.
Thus, when assessing the mechanical parameters of the liver, several authors have
reported widely varying parameters [15]. It is especially difficult in the case of the
liver because it undergoes large displacements and its perfusion affects deeply its
rheology (the liver receives one fifth of the total blood flow at any time). In fact,
trying to estimate the liver Young Modulus is prone to large errors because the
liver response largely depends on the speed at which the pressure was applied. One
can expect to obtain meaningful material parameters only if this material is highly
viscoelastic such as the one proposed by Kerdork et al. [27].
174 H. Delingette and N. Ayache
Fig. 3 (Left) View of the simulated hepatic resection involving linear-elastic materials (from [12,
13, 15] and [20, 21]); (Right) A force feedback system suited for surgery simulation
To model the active properties of living tissues and the dynamic nature of normal or
pathological evolving processes, it is necessary to introduce physiological models
of the human body. We illustrate the personalization of those models with two
examples related to the modeling of the electro-mechanical activity of the heart
and the growth of brain tumors.
Building Patient-Specific Physical and Physiological Computational Models. . . 175
where u is the action potential averaged within a volume element of the cardiac
tissue, z is the repolarization variable, D is the electrical conductivity tensor, " is
a numerical constant, k controls the electrical reaction and a controls the action
potential duration.
The electrical activity can be synchronized with the actual ECG (electro-
cardiogram) of the patient and creates a mechanical contraction followed by an
active relaxation which are modeled by a set of partial differential equations
initially proposed by Bestel, Clément and Sorine [6]. The average direction of
the myocardium fibers is also integrated into this model (for instance through
the conductivity tensor D), since it plays an important role in the anisotropic
propagation of both the electrical and mechanical excitations.
This electromechanical model of the heart includes several parameters related
to the heart anatomy (fiber orientation), electrophysiology (electrical conductivity),
blood flow (preload and afterload) or cardiac mechanics (passive stiffness, contrac-
tility). It was shown in [44] that this model could be interactively adjusted to the
actual geometrical, mechanical or electrical properties of patient’s heart through the
use of conventional or tagged MR images and some in vivo electrophysiological
measurements.
However it is important to make the personalization as automatic as possible in
order to predict in the most objective way the effect of a therapy or the evolution of
a pathology [45, 46]. This parameter estimation is typically an inverse problem that
can be formulated as the minimization of a functional measuring the discrepancy
between simulated and observed quantities: the “best” set of parameters specific
to a given patient observation is the one that minimizes the functional. Not all
parameters can be identified however since several combinations of parameters may
lead to the same simulation. For instance, in Eq. (1), the speed of the depolarization
propagation is governed by the product between the conductivity and the reaction
term: D k.
1
cf. CardioSense3D URL http://www-sop.inria.fr/CardioSense3D/
176 H. Delingette and N. Ayache
Fig. 4 (a) Isochrone map of the epicardium measured on a canine heart. The location of the
infarted zone is shown; (b) Simulated isochrones after the estimation of global and regional
parameters; (c) Map of the apparent conductivity, the conductivity being constant for each region.
There exists a good correlation between regions of low conductivity and infarcted regions [36]
of material points are known from the analysis of time series of medical images.
A common difficulty in those approaches lies in the large size of the state vector and
associated covariance matrices due to the addition of the parameters to be estimated.
Fig. 5 (Top) Overview of the evolution model of cancerous cells which takes into account the
anisotropic diffusion along white matter fibers; (Bottom) Result of the tumor growth simulation
on a brain slice; (a) Initial MR T2 image of the patient with lines of constant tumor density; (b)
View of the corresponding MR T2 slice (after rigid registration) six months later; (c) Lines of
constant tumor density predicted by the tumor growth model [9] after 6 months of evolution. (d)
and (e) Patient specific tumor growth modeling in coronal and saggital views. Thick white contours
correspond to the segmented initial tumor front while the thin white contours are the segmented
front 270 days later. Thick black contours are the simulated front after optimizing the diffusion
coefficients : dw D 0:55mm2 =day, dg D 2:7 103 mm2 =day (from [28])
Building Patient-Specific Physical and Physiological Computational Models. . . 179
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Constructing a Patient-Specific Model Heart
from CT Data
Abstract The goal of our work is to predict the patterns of blood flow in a model
of the human heart using the Immersed Boundary method. In this method, fluid is
moved by forces associated with the deformation of flexible boundaries which are
immersed in, and interacting with, the fluid. In the present work the boundary is
comprised of the muscular walls and valve leaflets of the heart. The method benefits
by having an anatomically correct model of the heart. This report describes the
construction of a model based on CT data from a particular individual, opening up
the possibility of simulating interventions in an individual for clinical purposes.
1 Introduction
We wish to compute blood flow in the chambers of a model of the human heart.
For spatial scales on the order of the sizes of the chambers of the heart or the
great vessels, the motion of blood is well-described by the Navier-Stokes equations.
Solution of the Navier-Stokes equations requires specifying conditions on the
boundary. This can be a challenging requirement in the computation of blood flow
within the chambers of the heart. The valve leaflets comprise an important part of the
boundary, and the motion of those leaflets cannot be specified in advance. The valve
leaflets and the surrounding fluid (blood) form a coupled system; the motion of the
leaflets and the motion of the blood must be computed simultaneously. Although
less obviously so, this is equally true for the motion of the heart walls.
We have developed a numerical method, the Immersed Boundary (IB) method,
which simultaneously computes the motion of a fluid and the motion of an elastic
boundary immersed in, and interacting with, that fluid. In this method, the fluid is
represented by Eulerian velocities and pressures which are stored on a regular three-
dimensional computational lattice. The boundary is represented by elastic structures
which are free to move continuously in the space sampled by the computational
lattice. The essence of the method is to replace the elastic boundary by the forces
which result from its deformations. These forces are applied to the lattice in the
neighborhood of the elastic boundary with the aid of a numerical approximation to
the Dirac delta function. The fluid moves under the action of this body force field.
The numerical delta function is then used again, to interpolate the newly computed
lattice velocities to the locations of the boundary, and then the boundary is moved
at the interpolated velocity to a new location (this is the no-slip condition). The
process of calculating forces, computing fluid motion and moving the boundary is
repeated cyclically in a time-stepping procedure with a suitably chosen time step.
Neither the fluid motion nor the boundary motion is an input: both motions are
outputs. The inputs are physical properties of the fluid, the elastic properties of the
boundary (which may be time-dependent), and the initial geometry of the boundary.
A systematic description of the IB method can be found in [4], and its application
to the heart is illustrated in [2].
The myocardial muscle fibers supply the force which moves the heart and the
blood. Computation of blood flow within the chambers of the heart by the IB method
would benefit by the availability of an anatomically correct model of the cardiac
muscle fibers. We have previously described a somewhat idealized model of the fiber
anatomy of the heart [1], strongly influenced by the dissections of Thomas [8]. In
the idealized model the heart at end-systole was comprised of a collection of conical
surfaces; muscle fibers were represented by geodesic paths on these surfaces, each
geodesic beginning on one valve ring and ending on a (possibly different) valve
ring. Representing muscle fibers by geodesics was motivated by the observations of
Streeter, et al. [6]. The use of conical surfaces makes computation of the geodesics
straightforward, since a conical surface can be unrolled onto a plane, but it also
gives rise to some unnatural anatomical shapes, most notably in the neighborhood
of the apex and in the neighborhood of the valve rings. Since the flow patterns in
Constructing a Patient-Specific Model Heart from CT Data 185
Fig. 1 CT data from a patient with congestive heart failure visualized using the Osirix DICOM
viewer. The middle and right panels show the segmentation of the ascending aorta (enlarged)
the chambers of the heart are influenced by the shapes of the chambers, it would be
unrealistic to use the conical-surface model to study the blood flow in any particular
human.
A major (and ambitious) goal of our research is to provide a tool that would
permit a cardiologist to replicate a patient’s disease state in a computer model and
to study how a proposed intervention, such as surgery, changes the behavior of
the model, as a guide to how that intervention might change the behavior of the
patient’s heart. A vital component of such a tool would be an accurate model of the
patient’s cardiac anatomy, that is, a patient-specific heart model. In the following we
describe the techniques by which we produce a computer model of the heart based
on measurements from a particular individual.
The starting point of our construction is a computed tomography (CT) data set from
a patient with congestive heart failure, obtained by Arthur E. Stillman and Randolph
M. Setser at the Cleveland Clinic. A sample plane slice of this data set is shown
in the left panel of Fig. 1. The data set consists of about 300 such slices, 0.5 mm
apart. Cross-sections of the heart and the nearby great vessels from this data set are
segmented by hand. The right panel of Fig. 1 shows a sample segmentation of the
ascending aorta.
For technical reasons, the IB method requires that neighboring points on the
boundary be spaced apart no more than 1=2 of the computational lattice meshwidth
in order for the boundary not to leak. Consequently, the cross-section perimeters
produced by segmentation are re-discretized so that interpoint distances are slightly
less than 1=2 of the intended lattice meshwidth and are uniform around the
perimeter. All subsequent references here to discretized boundaries should be
understood to mean boundaries re-discretized in this way.
Figure 2(upper) shows oblique views of two neighboring cross-sections of the
ascending aorta just below the aortic arch. The aortic surface between these two
perimeters can be defined by triangulation. We find a good triangulation by the
following heuristic procedure. On each perimeter choose any point to be the first
186 D.M. McQueen et al.
Fig. 2 Upper panel: oblique view of two neighboring cross-sections of the ascending aorta just
below the aortic arch; Middle panel: set of edges having minimal aggregate length joining points of
the discretized cross-sections; Lower panel: triangulation of the surface between the cross-sections
point and then compute the aggregate arclength to each subsequent point. The
perimeter is periodic, so the last point is also the first point. Normalize so that
the arclength from first point to last point is 1.0. Logically, the points from both
perimeters could be thought of as coexisting on a line segment of length 1.0. We are
going to connect points of one perimeter to points of the other, and it is convenient to
maintain a pointer on each perimeter to the “current point”, which is the last point on
that perimeter which has been connected to another point. Identify either perimeter
as perimeter one and the other perimeter as perimeter two. Connect the current point
of perimeter one to each point of perimeter two which has an arclength greater than
that of the current point of perimeter two and which also has an arclength less than
or equal to the arclength of the next point on perimeter one (or arclength D 1.0
if the current point of perimeter one is its last point). With each new connection,
the current point of perimeter two is incremented. After making these connections,
interchange perimeter identities, so the perimeter which had identity one now has
identity two, and vice-versa. The cycle of connecting points and interchanging
identities continues until the two last points are connected. These connections define
the edges of a triangulation whose other edges lie on the perimeters. The aggregate
length of the inter-perimeter edges depends on which points are chosen as the first
points. We test all possible pairs of first points and choose the pair which results in
the shortest aggregate length of the inter-perimeter edges. Figure 2(middle) shows
this set of inter-perimeter edges for the perimeters in Fig. 2(upper). Figure 2(lower)
shows the resulting surface triangulation.
Applying this procedure to the entire data set results in triangulated surfaces for
the major anatomical structures at end-systole: aorta and pulmonary artery; superior
and inferior vena cava and pulmonary veins; right atrium; left atrium and appendage;
right ventricle; left ventricular endocardium; left ventricular epicardium; the epi-
cardium of the entire heart. The valves are produced by a procedure described
later. In addition, we require a surface in the left ventricle, midway between the
endocardium and epicardium. For each level at which there are both endocardial and
epicardial cross-sections, a midwall cross-section can be constructed by averaging
Constructing a Patient-Specific Model Heart from CT Data 187
+90 DEG
ENDOCARDIAL SURFACE
EPICARDIAL SURFACE
-90 DEG
Fig. 3 Left panel: left ventricular endocardial, midwall and epicardial triangulated surfaces based
on CT data. Right panel: fiber-angle distribution in the LV wall. Continuous curve is predicted by
the asymptotic theory of Peskin [3], and vertical bars represent the observations of Streeter, et al.
(ref. [7], Fig. 4, curve a) plotted with a tolerance of ˙10o . Horizontal axis is radial distance through
the wall with midwall at zero and epicardial and endocardial surfaces as indicated. Vertical axis is
angle between cardiac fibers and a plane perpendicular to the axis of the left ventricle
along line segments connecting the two cross-sections, drawn normal to the
endocardial cross-section. In all cases the region of the apex is approximated by
the plane of the most apical cross-section of the data set. Figure 3(L) shows the
three surfaces (endocardial, midwall, epicardial) of the left ventricle (LV) with the
front and rear clipped away to improve visibility.
The model heart is comprised of three types of structures in each of which fibers are
constructed using variations on the same general theme: geodesics on surfaces. The
three types of structure are: thick-walled (the LV), thin-walled (all other chambers
and the great vessels), and valvular.
At the present time the technology for directly imaging cardiac muscle fibers (e.g.,
diffusion tensor MRI) is not sufficiently developed for our purposes. Instead, we
approximate the muscle fibers in the left ventricle using a method motivated again
by the observations of Streeter, et al. [6] and by an asymptotic analysis of Peskin [3].
From measurements on the hearts of macaques, and treating the left ventricle as a
nest of ellipsoidal surfaces of revolution, Streeter observed that muscle fibers in
the left ventricle follow trajectories that are approximately geodesic paths on those
188 D.M. McQueen et al.
surfaces. Using an asymptotic approach, also treating the wall of the left ventricle
as a nest of surfaces (but not necessarily ellipsoids) of revolution, Peskin was able
to derive the relation between the angle made by the geodesics as a function of their
distance from the midwall surface. The angle is measured relative to the latitude
lines of an appropriate coordinate system constructed on the surface of revolution.
Figure 3(R) (redrawn from [3]) shows the relation between angle and distance from
the midwall surface.
We treat the midwall surface shown in Fig. 3(L) as if it were a surface of
revolution, even though it is not. A coordinate system is constructed on this surface
consisting of geodesic curves which radiate out from the apex and terminate at the
upper cross-sections of the data set, above the mitral or aortic valve ring. These
coordinates can be thought of as lines of longitude. Lines of latitude are constructed
by joining points of equal arclength measured from the apex along the lines of
longitude. It is an interesting theorem of differential geometry that the latitudes and
longitudes so constructed form an orthogonal net, even when the surface on which
the above construction is done is not a surface of revolution. Because the midwall
surface is not in fact a surface of revolution, some of these longitude lines intersect.
When a pair of longitude lines intersects, the longer of the longitudes is terminated
at the intersection. This insures that when following a line of constant latitude there
is a monotonic change in longitude.
Following Streeter’s observation, and the theoretical curve of Fig. 3(R), muscle
fibers are parallel to the lines of latitude on the midwall surface. We construct
families of model fibers by computing geodesic paths on the CT scan midwall
surface, starting at locations equally spaced on, and initially parallel to, a line of
constant latitude. Geodesics paths are computed in both directions (increasing lon-
gitude and decreasing longitude), terminating whenever a valve ring is encountered.
When a geodesic crosses a longitude line, its angle with respect to the latitude
line is calculated, and the intersection point is projected toward the epicardial or
endocardial surface by the distance given by the theoretical curve of Fig. 3(R). In
this way model muscle fibers fill the space between the epicardial and endocardial
surfaces, and have an angular distribution through the wall which matches the
observed distribution.
How are geodesics constructed? Recall that the surface is triangulated. Each
triangle in such a structure “knows” which triangles are its neighbors. Each triangle
shares each of its edges either with another triangle or with nothing (in the case of
edges on the upper end of the CT scan). No triangle shares any two of its edges with
the same other triangle. It is straightforward to construct a map that indicates the
other triangles with which any triangle shares edges. A triangle is a plane figure,
so on each triangle a local coordinate system may be constructed having one unit
vector normal to the plane of the triangle and two unit tangent vectors in the plane of
the triangle. If a line is drawn from a point within any triangle in a known direction
in the plane of the triangle, its intersection with one of the edges of the triangle
is easily calculated. From these considerations geodesic curves on the surface are
constructed as follows: draw a straight line or ray emanating from a point on a
latitude line in one direction along the latitude line. Call the triangle containing the
Constructing a Patient-Specific Model Heart from CT Data 189
starting point “the current triangle”. The drawn ray, straight and in the plane of the
triangle, is a geodesic of the triangle by definition. Calculate the intersection point of
the drawn ray with an edge of the current triangle (there can be only one such point).
Determine which triangle shares that edge with the current triangle, and call that
triangle “the next triangle”. The vector in the direction of the drawn ray intersecting
the edge can be decomposed into two components, along the edge and normal to the
edge within the current triangle, and then recomposed along the edge and normal
to the edge within the next triangle. The component along the edge is unchanged
since the edge is shared; the component which was normal to the edge within the
current triangle retains its magnitude but changes its direction to be normal to the
edge within the next triangle. The ray drawn in the next triangle line has a known
starting location (on the edge) and a known direction. Rename the next triangle as
the current triangle, and repeat the drawing process just described. The result is a
piecewise linear geodesic path on a triangulated surface. Note that the path is not
necessarily the globally shortest path between the endpoints, but is the shortest path
given the particular starting direction, which is sufficient for a geodesic path.
Figure 4 (upper row) shows the lines of longitude on the midwall surface (left
panel), and a family of midwall-surface geodesics starting on a latitude line near the
apex (right panel). Notice that even though geodesics are initially perpendicular to
longitude lines (near the apex), they become more longitudinal as they rise (toward
the base). Figure 4 (middle row, left panel) shows several families of geodesics
on the midwall surface, each family arising from one of a set of regularly spaced
latitude lines.
We now have a midwall surface covered by geodesic fibers. The density of
coverage can be increased (or decreased) by starting more (or fewer) geodesics
on any particular latitude line, or by having more (or fewer) latitude lines from
which geodesics are launched. Choosing an appropriate density of coverage is
discussed later. During the process of construction the angle any geodesic makes
when it intersects any longitude line can be tracked. The major requirement is a
table which lists the coordinates of the end points of the longitude line segments
crossing any triangle on the midwall surface. The interior of the LV wall can now be
populated with muscle fibers as follows. Recall that Fig. 3(R) shows fiber angle as a
function of depth. Simply inverting this gives depth as a function of fiber angle.
For each intersection of a geodesic with a longitude line, the intersection point
can be “inflated” along the normal to the midwall surface triangle by an amount
given by its angle with respect to the latitude line. For this purpose the distance in
Fig. 3(R) is taken to be the fraction of the maximum possible distance along the
normal. Since every surface is defined as a set of triangles, this inflation process
requires finding the intersection of a midwall-triangle normal with an epicardial
or endocardial surface triangle. There are several thousand such triangles, and
hundreds of intersection points on each of several thousand geodesics. A brute force
search for intersections of normals and triangles would be quite time-consuming. To
improve efficiency we construct a table which lists the endocardial and epicardial
surface triangles intersected by a normal at the centroid of each midwall surface
triangle. For a normal starting at some other point (not the centroid), this table
190 D.M. McQueen et al.
indicates the triangle which is probably intersected by the normal, and, if not, is
a reasonable place from which to start searching for the intersected triangle. (Recall
that each triangle knows its neighbors; a nearest neighbor flooding type of search
proves to be effective here.) Fig. 4 (middle row, right panel) shows the muscle fibers
resulting from inflating the geodesics shown to its left. Figure 4 (lower row) shows
thin cross-sections through the entire collection of geodesics on the midwall surface
(left panel) and the entire collection of inflated fibers in the LV wall (right panel).
Constructing a Patient-Specific Model Heart from CT Data 191
Fig. 5 Triangulated right ventricular surface, three different points of view. The right panel uses
the same point of view as in Fig. 4
All the other chambers of the heart are treated as thin-walled surfaces covered with
geodesics using the same general approach as used in the midwall surface of the LV.
For each chamber the particular geodesics selected are intended to represent fibers
observed experimentally. Figure 5 shows the triangulated surface resulting from
segmentation of the right ventricle (RV). Figure 6 shows the computed geodesics
on the model RV surface. There are two families: first, fibers which radiate out
from the RV apex (“lines of longitude”) and second, fibers which are approximately
orthogonal to the first on the septal surface. These particular families were suggested
by the dissections of Thomas [8].
Figure 7 shows the triangulated surfaces of the model atria. There are three atrial
surfaces in the model: left atrium, right atrium and a combined atrial surface which
serves to hold the two atrial chambers together. The left atrial surface includes
the appendage; the right atrial surface does not. The combined atrial surface is
constructed by joining the left and right surfaces with bridging surfaces consisting
of a small number of triangles (that is, the combined atrial surface is not the result of
another segmentation). All atrial surfaces are considered to be thin-walled. Geodesic
paths are constructed on each of these three surfaces. The resultant muscle fibers are
shown in Fig. 8. Two families of fibers are used here, one to represent the pectinate
muscles and one to represent the interatrial band.
It is our intention initially to use the great vessels as a means to anchor the model
heart, that is, points on the great vessel walls will be connected to fixed points
in space with springs of appropriate stiffness, as if the vessels were surrounded
and constrained by the tissues of the body. Hence, it is unnecessary to construct
paths which represent fibers in the vessels. It is sufficient to represent the vessels as
surfaces triangulated finely enough that there are no leaks. Triangles with edges
192 D.M. McQueen et al.
Fig. 6 Computed geodesics on the model RV surface. Left panel: family 1, radiating from the
apex (longitude lines). Middle panel: family 2, perpendicular to a longitude line on the septum.
Right panel: both families
Fig. 7 Triangulated surfaces of the model atria. Left panel: right atrium; Middle panel: left atrium;
Right panel: combined left and right atrium
Fig. 8 Muscle fibers of the model atria. Left panel: right atrium; Middle panel: left atrium; Right
panel: combined left and right atrium
Constructing a Patient-Specific Model Heart from CT Data 193
Fig. 9 Model great vessels. Left panel is a top view in which extensions of the left and right
pulmonary artery branches to the edges of the computational domain are clearly shown; right panel
is a front view in which the aorta is to viewer’s left of the pulmonary trunk, the superior vena cava
is to viewer’s left of the aorta, and the inferior vena cava is at the bottom
3.4 Valves
The CT data set from which we are constructing the model does not include any of
the four valves. The valves we intend to use, initially, are modified versions of the
valves used in the conical surface model. Figure 10 shows these (modified) valves.
The mitral valve consists of fibers lying on a surface which smoothly interpolates
between a line joining the tips of the papillary muscles and a circle in the plane
of the valve ring. This is a surface of the type described in [1] which interpolates
between two ellipses at different heights. The line joining the tips of the papillary
muscles is an ellipse of eccentricity 1.0, and the circle in the plane of the valve
ring is an ellipse of eccentricity 0.0. Fibers fan out from each papillary tip and
contribute to each leaflet. Where fibers from different papillary tips cross, a fabric
which constitutes the leaflet is formed. Between the papillary tip and the leaflet,
each fiber forms one of the chordae tendineae. The construction of the tricuspid
valve is similar, except that there are three papillary tips and three leaflets. Again,
fibers from each papillary tip fan out to contribute to the two leaflets nearest the
tip. Where fibers from different tips cross, a leaflet fabric is formed. Between the
194 D.M. McQueen et al.
tip and the leaflet, each fiber is one of the chordae. Each valve ring in the model is
constructed as the intersection of a plane with an appropriate triangulated surface.
The triangulation is left unchanged, but whenever a geodesic curve on a triangulated
surface intersects a valve ring, the geodesic is terminated at the point of intersection.
It is in the nature of the data set and the segmentation that the valve rings on any
triangulated surface are unlikely to be perfectly circular. Collars are inserted in order
to join the circular parts of the model valves with the non-circular valve rings. These
collars are visible in Fig. 10.
The model aortic and pulmonic valves result from the solution of a partial
differential equation which describes the equilibrium of a single family of fibers
supporting a hydrostatic pressure load [5]. As in the case of the inflow valves, the
outflow valve rings are not circular, and collars are inserted. The collars for the
outflow valves are significantly smaller than those for the inflow valves. Except for
the collars, the shapes of the aortic and pulmonic valves are identical. In the current
construction the diameter of the pulmonic valve is approximately 11% smaller than
that of the aortic valve.
All the valves shown in Fig. 10 are in their closed configurations. Nonetheless
there is a small gap between neighboring leaflets in each valve. This gap is required
in order for the valves to open. In the IB method, the velocity of any boundary point
is interpolated from the velocities stored on the surrounding computational lattice.
Any two boundary points with identical locations would therefore have the same
velocity and would always stay together. If there were no gap between valve leaflets,
points on neighboring leaflets would move with the same velocity and the leaflets
Constructing a Patient-Specific Model Heart from CT Data 195
Fig. 11 Left panel: entire heart model; Right panel: interior of heart model
would be unable to open. The gap must be sufficiently large that neighboring leaflets
can separate on opening, but not so large that the closed valve leaks. In practice, the
leaflet gap that works best is found by trial and error.
Figure 11(Left) shows the entire model heart composed of all the pieces described
above. The left and right ventricles are contained in an investment layer composed
of longitudinal fibers radiating from the apex of the model heart. At this point in the
construction the great vessels all have open ends. In our earlier (conical surface)
model, the great vessels were capped off, and sources or sinks as appropriate
were inserted within the caps to represent the portions of the circulatory system
not modeled in detail. Although such caps have been constructed for the model
described here, we are currently investigating other approaches for treating inflow
and outflow, such as connecting the great vessels to circulation models (e.g.
windkessels) on the boundaries of the domain. Figure 11(Right) shows the interior
of the heart model by clipping away portions of the heart wall.
We have previously remarked that the IB method requires neighboring points on the
boundary to be spaced apart 1=2 the meshwidth of the computational lattice in order
for the boundary to not leak. The meaning of this spacing requirement is clear for a
closed 2D curve. In three dimensions the situation is more complicated. It is easy to
196 D.M. McQueen et al.
imagine, in 3D, that every point is within 1=2 meshwidth of some other point and
that there are gaping holes in the structure through which fluid could pass.
We have adopted a strategy based on flooding (our favorite technique) for
determining if a 3D structure is leak-proof on some target computational lattice
resolution, that is, whether the boundary has been discretized appropriately not to
leak in a particular computational lattice.
Flooding is a method for estimating the enclosed area within a curve (in 2D) or
volume within a surface (in 3D). It is most easily described for the 2D setting and the
extrapolation to 3D is obvious. Consider a closed 2D discretized curve. Construct
a Cartesian grid covering a rectangular domain which includes the 2D curve. Mark
with a 1 the corner points of every grid cell containing any point of the curve, mark
with a 1 the grid points on the edges of the grid, and unmark (with a 0) all other grid
points. The marks on the grid in the immediate neighborhood of the 2D curve form a
fat stair-step representation of the 2D curve. To begin flooding, locate an unmarked
grid point in the interior of the 2D curve, mark that point with a 1 and place the
coordinates of that grid point on a queue. Repeat the following process until all the
items in the queue have been examined:
(1) Examine the grid points which are neighbors of the grid point at the head of
the queue (at most 8 neighbors in 2D). Each neighbor which is found to be unmarked
is then marked and added to the tail of the queue.
(2) Advance the head pointer to the next grid point on the queue.
This process finishes when the head pointer advances beyond the tail of the queue.
The portion of the grid interior to the 2D curve will be marked (i.e., the interior of
the 2D curve will have been “flooded”) and the number of items placed on the queue
is the number of grid points in the interior of the 2D curve. If each such grid point
is treated as the lower left-hand corner of a grid cell, the number of such grid points
estimates the area enclosed by the 2D curve.
A difficulty arises if the distance between neighboring points on the curve is large
compared with the grid meshwidth. In this case there will be a gap in the stair-step
representation of the 2D curve, and the flooding will not be confined to the interior
of the curve, but will leak into the exterior, encompassing virtually the entire grid.
A remedy for this difficulty would be to interpolate points onto the boundary at
a density appropriate for the grid resolution. For our present purposes we wish to
consider a fixed discretization of the boundary and to use the onset of leaking when
the grid is made finer as an indicator of when that discretization of the boundary is
leak-proof.
Consider the following 1D model problem in which
’|’ indicates the locations of lines in the grid
’*’ indicates boundary points
nr how fine the flooding grid is w.r.t. the target grid
nr=1 means flooding grid is same resolution as target grid
In the picture below boundary points are spaced at 1=2 of the target grid
meshwidth (nr D 1). This is the spacing of boundary points which the IB method
sees as leak-proof. The flooding grid is initialized by marking the grid on either
side of a boundary point. Notice that in all 3 cases (nr D 1, 2, 3) there is a sufficient
Constructing a Patient-Specific Model Heart from CT Data 197
density of boundary points that every grid line ends up being marked, even though
there is not a boundary point between every pair of neighboring grid lines.
nr=1 | * * | * * | * * |
nr=2 | * | * | * | * | * | * |
nr=3 | * | | * | * | | * | * | | * |
nr=1 | * * | * | * * |
nr=2 | * | * | * | | * | * |
nr=3 | * | | * | * | | | * | | * |
Acknowledgements The authors are grateful to Arthur E. Stillman, M.D., Ph.D., and Randolph
M. Setser, D.Sc. of The Cleveland Clinic Foundation, Cleveland, Ohio for providing the CT images
on which this work was based. We are also deeply grateful to “Mr. C.”, the patient whose heart was
imaged.
We thank Nikos Paragios for organizing the collaboration between the Cleveland Clinic,
Siemens Corporate Research and NYU that made possible the present work.
References
1. D. M. McQueen and C. S. Peskin. A three-dimensional computer model of the human heart for
studying cardiac fluid dynamics. Computer Graphics, 34:56–60, 2000.
2. D. M. McQueen and C. S. Peskin. Heart simulation by an immersed boundary method with for-
mal second-order accuracy and reduced numerical viscosity. In H. Aref and J. Phillips, editors,
Mechanics for a New Millennium, Proceedings of the International Conference on Theoretical
and Applied Mechanics (ICTAM) 2000, pages 429–444. Kluwer Academic Publishers, 2001.
3. C. S. Peskin. Fiber-architecture of the left ventricular wall: an asymptotic analysis. Commun.
Pure and Appl. Math., 42:79–113, 1989.
4. C. S. Peskin. The immersed boundary method. Acta Numerica, 11:479–517, 2002.
5. C. S. Peskin and D. M. McQueen. Mechanical equilibrium determines the fractal fiber
architecture of the aortic heart valve leaflets. Am J. Physiol, 266:H319–H328, 1994.
6. D. D. Streeter, W. E. Powers, A. Ross, and F. Torrent-Guasp. Three-dimensional fiber orientation
in the mammalian left ventricular wall. In J. Baan, A. Noordergraaf, and J. Raines, editors,
Cardiovascular System Dynamics, pages 73–84. MIT Press, 1978.
7. D. D. Streeter, H. M. Spotnitz, D. P. Patel, J. Ross, and E. H. Sonnenblick. Fiber orientation in
the canine left ventricle during diastole and systole. Circ. Res., 24:339–347, 1969.
8. C. E. Thomas. The muscular architecture of the ventricles of hog and dog hearts. Am. J. Anat.,
101:17–57, 1957.
Image-based haemodynamics simulation
in intracranial aneurysms
A.G. Radaelli
CISTIB Centre for Computational Imaging & Modelling in Biomedicine, Universitat Pompeu
Fabra, c/ Tanger 122-140, E08018 Barcelona, Spain
H. Bogunović
CISTIB Centre for Computational Imaging & Modelling in Biomedicine, University of Sheffield,
c/ Tanger 122-140, E08018 Barcelona, Spain
M.C. Villa-Uriol • A.F. Frangi ()
CISTIB Centre for Computational Imaging & Modelling in Biomedicine, University of Sheffield,
Sir Frederick Mappin Building, Sheffield, S1 3JD, UK
e-mail: [email protected]
J.R. Cebral
Center for Computational Fluid Dynamics, School of Physics, Astronomy and Computational
Sciences, George Mason University, Planetary Hall, Room 103A, 4400 University Drive,
MSN 3F3, Fairfax, VA 22030, USA
1 Introduction
(LDV) or Particle Image Velocimetry (PIV) are then applied to visualize and
measure the velocity field [59, 60]. A detailed measurement is however quite time
consuming and is generally not achievable close to the wall, thus hampering the
calculation of important haemodynamical variables such as WSS. In addition, the
manufacturing process is not trivial for small arteries and small aneurysms and
would be impractical for a systematic patient-specific analysis.
Instead, image-based haemodynamics simulation may represent an attractive
tool to provide a description of patient-specific haemodynamical variables with
compelling detail. The basic principle of this technique is to obtain accurate
patient-specific vascular models from medical images and apply CFD techniques
to reconstruct the time-resolved blood velocity and pressure fields starting from
flow and/or pressure conditions prescribed at the boundaries of the vascular
domain. The availability of high-resolution scanners, fast modeling algorithms
and powerful computational resources has been key to the widespread adoption
of image-based haemodynamics simulation techniques in biomedical research. In
the next sections, the fundamental components of an image-based haemodynamics
simulation workflow will be illustrated. The significance of assumptions, approxi-
mations and modeling parameters will be considered and efforts in the validation
of the simulation results will be discussed. Current application of state-of-the-art
technologies for the understanding of aneurysm rupture will be further addressed
and directions for future research and development will conclude the chapter.
2 Workflow overview
At present, there are no standard guidelines for the evaluation of image quality
for haemodynamics simulation. This often requires a certain familiarity with the
flow realization across the vessels of the Circle of Willis, an understanding of
the geometrical features prone to affect blood flow and a basic knowledge of the
main components of the processing pipeline. It is generally accepted that 3DRA
images provide both higher resolution ( 0:15mm) and better contrast between
the signal intensity of vascular lumen and background when compared to CTA
and MRA. On the other hand, 3DRA images have been reported to occasionally
present artefacts leading to the underestimation of aneurysm dimensions in specific
locations of the Circle of Willis [35] or to the appearance of pseudo stenosis of
parent vessels [20, 32]. Due to the profound influence of parent vasculature on
aneurysmal haemodynamics, the absence of artefacts has to be ensured not only
in the aneurysm but also for all the vessels influencing the realization of the
aneurysm haemodynamics. While providing important information on the aneurysm
environment in the brain, CTA images offer instead lower resolution ( 0:4mm)
and the ranges of intensities of vessels and bone overlap. These conditions may
limit an accurate segmentation of both small aneurysms and vessels crossing the
skull base, where vascular and bone structures are very close. Similar resolution
is achieved with TOF MRA, which has the disadvantage of sensitivity to metal
implants such as endo vascular devices. In addition, progressive saturation may
occur as the spins penetrate into the imaging volume and for disturbed or slow
flow. The result is the appearance of signal voids in the vascular lumen or blurred
regions across the vascular boundaries, at bifurcations and inside aneurysms,
where complex flow patterns may be expected. Despite these limitations, MRA is
potentially the most suited imaging technique for haemodynamics simulation as it
can derive all the necessary boundary conditions from a single non-invasive imaging
session by combining TOF and PC MRA acquisitions.
For adapt to the topological changes common in the cerebral vasculature, the
segmentation of cerebral vessels may be performed using the geometric deformable
model technique within the level set framework [45]. This technique describes the
evolution of a surface model within the image domain that deforms under the
action of internal (curvature and smoothness) and external (image gradient and
204 A.G. Radaelli et al.
other features) forces to recover the unknown shape of the vessels. The surface is
represented implicitly as a zero level set of a distance transform image whose size
corresponds to the original medical image. Information on image gradient drives
the evolution of the model towards the locus of maximum intensity variation across
the vascular boundaries [9]. Due to limited resolution and/or image artefacts, the
gradient information may be discontinuous or weak across the vascular boundaries,
thus leading to boundary leakage. To overcome this limitation, the Geodesic Active
Regions (GAR) [48] technique combines image gradient maps with statistical
region-based information. The region-based information is presented in the form
of a probability image map, that contains the probability of each image voxels to
belong to a certain region (or tissue) R. The estimated probability value can be
interpreted as a conditional probability, P .x 2 R j f.x//, where x is a point in
the image domain and f.x/ is the feature vector used to characterize the tissue
at the point x. The regional descriptors k for each region are then based on the
corresponding probability map. The equation that drives the evolution of the surface
is expressed as:
where ˆ is an implicit function whose zero level set at any time t of the evolution
represents the vascular surface, kout and ki n are the descriptors of the inner and outer
tissues with respect to the vascular lumen, Km is the mean curvature of the surface, "
is a parameter that controls the contribution of the curvature to the evolution, while
and control the influence of region-based and boundary information, respectively.
We have proposed to create features as vectors of differential invariants [64] up
to the second order, which are computed at multiple scales to provide a richer
description of the different tissues [30]. These feature vectors are expected to be able
to differentiate between tissues that cover overlapping image intensity ranges but
present different shapes, such as vascular and bone tissues in CTA images. The set of
feature vectors belonging to a specific region are first learned in a supervised fashion
and then the probability of each image voxel to belong to a particular tissue is
estimated using a non-parametric technique. Such approach is particularly suitable
for multimodal vessel segmentation as for each modality the vectors of features
corresponding to each tissue can be learned from its own training set. Additionally,
the initialization process does not require user intervention since it can be obtained
by thresholding the probability map corresponding to the vessel region.
The generation of numerical grids for flow simulation requires a watertight descrip-
tion of the vascular surface. This can be obtained by automatically applying the
method of the marching cubes (or tetrahedra) [6] to the distance transform image
obtained from the segmentation process. A sequence of global and local operations
Image-based haemodynamics simulation in intracranial aneurysms 205
Fig. 2 Mesh processing steps. (a) initial model extracted using the marching tetrahedra technique;
(b) smooth model after the application of the Taubin smoothing technique and a gross clipping to
discard unwanted vessels; (c) final model after mesh optimization, editing, clipping and extrusion
Fig. 3 (a) Surface grid with increased mesh resolution in correspondence to a small branching
vessel near the aneurysm neck. (b) Detail of the corresponding volumetric grid
This approach allows to construct complex arterial networks and to investigate the
haemodynamics environment of aneurysms that are fed by vessels typically captured
in separate 3DRA images.
The process of generation of a finite element grid for CFD simulation typically
starts with the generation of a higher quality surface grid. Although mesh processing
operations lead to an appropriate representation of the vascular surface, the quality
and the size distribution of the triangulation is not adequate for CFD simulation.
New surface grids can be generated starting from an analytical representation of the
surface or directly from the surface triangulation obtained after mesh processing.
In the former case, the analytical representation of the surface can be obtained
using parametric patches or implicit functions of global support [50]. Our approach
instead adopts an advancing front method that places newly created points on the
original surface triangulation by linear or quadratic interpolation [41]. This process
provides elements of higher quality and a more uniform distribution of the element
size across the model. This surface mesh is then employed as a support for the
generation of tetrahedral elements inside the anatomical model using the advancing
front method [42]. Other approaches include Delaunay and octree meshing, but we
refer to the literature for further details on the progress in this field [47].
The distribution of element sizes is typically prescribed to obtain a minimum
number of elements across the smallest vessel. Adaptive background grids can also
be used and interactively specified to increase the mesh resolution in regions where
the anatomical model has a large surface curvature. The number of tetrahedral
elements in our models typically varies from 1:5 to 4 millions (average element
size of 0:1 to 0:15mm). Details of the surface and volumetric grids generated with
our approach are provided in Fig. 3.
Image-based haemodynamics simulation in intracranial aneurysms 207
The numerical solution of the equations governing the fluid flow requires the
specification of the fluid behavior at the boundaries of the computational domain,
that account for the unmodeled part of the vascular network. The assumption of
non-moving walls implies that the value of the velocity at the surface nodes is null.
Physiological boundary conditions are instead derived for the inlets and outlets of
the model. These can be obtained from 2D PC MRA images for the main branches
of the Circle of Willis, especially if contributing to the realization of the flow in
the aneurysm. Flow rate curves are obtained at each location across one cardiac
cycle, but due to resolution constraints the technique does not offer an adequate
description of the velocity profile. The flow rate curves are therefore decomposed
into their Fourier modes and the velocity profile is analytically computed from the
Womersley solution [62].
It must be noted that patient-specific flow rate measurements are seldom available
and reference data obtained from normal volunteers are instead employed. Ford
[21] suggested that the use of reference waveforms may be appropriate, although
the time-average flow rate should be scaled to coincide with the patient’s measured
one. If time-averaged flow rates are not available, an approach could be to scale
the reference waveforms by a factor depending on vascular dimensions or so that
the time-average flow rate corresponds to physiological shear stress values. In the
case reference waveforms are also not available, which is the typical scenario for
small outflow branches, traction free (zero-pressure) boundary conditions may be
applied, assuming that the flow division among the arterial branches is determined
by the geometry of the anatomical model. As flow divisions are actually determined
by the impedance of the distal arterial tree, more sophisticated strategies have been
proposed to integrate vascular bed models of the brain [15] or 1D models of the
whole cardiovascular system [3] into the simulation model.
Blood is a suspension of particles (e.g. red/white cells and platelets) immersed into
an aqueous fluid (plasma). However, in medium and large sized vessels (diameter
> 1mm) blood may be considered a homogenous, incompressible, viscous fluid
with constant density. Blood flow is here governed by the Navier-Stokes equations
for incompressible fluids. Starting from an initial condition at t D 0, these equations
require the solution of a system of partial differential equations (PDE) for t > 0,
that express the conservation of mass and linear momentum, respectively, as
r vD0 (2)
@v
C v rv D rp C r C f (3)
@t
208 A.G. Radaelli et al.
the grid. Thus, as the finite number of equations is subsequently turned into a linear
system Au D b, this has the implication that the stiffness matrix A is sparse and
that smaller memory requirements and more efficient solutions can be achieved.
Similar considerations can be extended to the FV method. In addition, clearly for
both methods the finer the grid the more accurate the solution, but also the higher
the computational costs. Higher accuracy could also be achieved by increasing the
degree of the polynomial basis as in the spectral elements method [49].
For advance the solution in time, the two main approaches involve either an
implicit or an explicit time integration of the Navier-Stokes equations. Implicit
schemes involve an update of the solution at each time tn considering also the
unknowns at the new time tnC1 , such as for the backward Euler or the Crank-
Nicholson schemes, and typically guarantee stability regardless the time step size.
Implicit schemes involve the iterative solution of a linear system of equations, which
is not required for explicit schemes, where the update at tnC1 is directly obtained
from the values of v; p at tn . On the other hand, explicit schemes, such as the forward
Euler method, are subject to a stability condition, which imposes limits to the time
step size. More details on the numerical solution of the Navier-Stokes equations can
be found in [43, 65, 71]. Novel techniques that are gaining ground in computational
haemodynamics include spectral/hp element methods [56] and Lattice-Boltzmann
methods [28].
The solution of the Navier-Stokes equations provides the values of the velocity and
pressure fields at the nodes of the computational grid for all the time steps. A number
of techniques may be adopted to investigate the blood flow structure across the
vascular domain and to reduce the large amount of data to a set of meaningful
quantities describing both the blood flow patterns and the fluid stresses on the
vascular wall. In the first case, typical visualization techniques involve the extraction
of particle trajectories and velocity streamlines (Fig. 4(a)), or the projection of
the three-dimensional vectorial field onto 2D cut planes placed within the vascular
domain (Fig. 4(b)).
The visualization of fluid stresses on the surface requires post-processing oper-
ations applied to the CFD solution. In particular, WSS represents the viscous
frictional force of blood that acts parallel to the vessel wall. The OSI instead
measures the degree of angular deviation of the shear stress force with respect to the
mean shear stress during a cardiac cycle. The WSS is represented by a 3D vector
field lying on tangential planes to the vascular surface at each node and at each time.
The WSS magnitude is commonly time-averaged over a cardiac cycle to investigate
210 A.G. Radaelli et al.
its distribution across the aneurysm region. The equations used for the calculation
of time-averaged WSS ./ N and OSI have the form:
Z Z
N D dt D ndt (4)
!
1 j N j
OSI D 1 (5)
2 j j
where is the strain rate tensor and n is the surface normal. Surface color maps of
time-averaged WSS and the OSI are shown in Fig. 4(c) and (d), respectively.
3 Sensitivity analysis
Blood is a non-Newtonian fluid that circulates in vessels with distensible walls and
in a patient-specific pulsatile regime that may change over time. Sensitivity analysis
aims at both assessing the variability of the simulation to assumptions, approx-
imations and uncertainties in the modeling process and at potentially providing
confidence intervals to the simulation output. Our groups have recently conducted
a sensitivity analysis in four models of intracranial aneurysms [12] selected from
a database of 40 anatomical models obtained from CTA and 3DRA images. The
results showed that a qualitative characterization of the intra-aneurysmal flow
patterns is robust to variations to the mean input flow, the outflow division, the
viscosity model or to the grid resolution, while it strongly depends on the geometry
of the parent vessel and on the shape and neck size of the aneurysm. Conversely, an
accurate quantification of the intra-aneurysmal flow patterns and haemodynamical
forces may require the availability of patient-specific flow boundary conditions and
the use of a non-Newtonian rheology model. Without patient-specific information,
it was concluded that sensitivity analyzes should be routinely performed and that
a major effort should be paid to obtain accurate geometrical models. Similar
observations were reported in [10, 11, 68].
Image-based haemodynamics simulation in intracranial aneurysms 211
Fig. 5 Maps of WSS for different distributions of wall displacement at some time points over the
cardiac cycle
Wall compliance has been indicated as an important factor altering the local
haemodynamics. In [18], we have introduced a method based on 2D non-rigid
registration to estimate the wall motion of aneurysm dome and neighboring vessels
from dynamic biplane Digital Subtraction Angiography (DSA). The method was
extended in [46] by post-processing the recovered motion in the Fourier domain
and further applied to cases providing higher acquisition frame rate. Wall motion
curves were compared to blood pressure waveforms confirming that the measured
values corresponded to real displacement. Wall compliance was then integrated
in flow simulations by imposing the measured wall displacement directly to the
3D mesh, thus circumventing the difficulties in estimating personalized elasticity
properties in a fluid-solid interaction approach. Due to the two-dimensional nature
of DSA images, some motion patterns were imposed to the flow simulations and
compared to a rigid wall condition. It was observed that the area of the aneurysm
under elevated WSS with respect to the average WSS in the proximal parent
vessel, the contribution to the total shear force of this region, and the shear force
concentration factor were relatively unaffected by the wall motion. In addition,
changing the amplitude of the wall motion or imposing differential rather than
uniform deformations (Fig. 5) did not have a considerable effect on these variables,
although the impact of the real three-dimensional displacement field (including
the possible angular movement of parent arteries) should be considered in further
studies.
212 A.G. Radaelli et al.
Fig. 6 Conventional (top row) and virtual (bottom row) angiograms during the filling phase of an
aneurysm
4 Validation
The introduction of blood flow simulation technology into routine clinical practice
will eventually require its validation against ground truth in vivo flow measurements.
Due to the absence of in vivo ground truth data, some authors have compared
simulations results with experimental flow measurements in anatomically realistic
replicas [22], while others have confronted their ability to reproduce the gross
haemodynamical features observed during routine clinical examinations. In particu-
lar, Cebral [14] compared the flow structure described by signal isointensity surfaces
in TOF MRA images used in [55] with high flow velocity isosurfaces extracted from
haemodynamics simulation data obtained starting from the same MRA images,
finding good agreement in the aneurysmal inflow region. In two separate works,
Ford [23] and Calamante [8] presented a strategy to simulate the transport of the
contrast agent from the cerebral vessels through to an intracranial aneurysm and
generate visualizations similar to conventional angiography. This technique is called
virtual angiography and allows to qualitatively compare simulation results with
high frame rate angiographic images routinely acquired during treatment. We have
recently applied this technique to assess the reliability of haemodynamics simulation
in three aneurysm models extracted from 3DRA images [16]. The approximated
time-dependent velocity fields were used to simulate the transport of a contrast
agent by solving the transport (or advection-diffusion) equation using an implicit
finite element formulation on unstructured grids. Virtual angiograms were then
constructed by volume rendering of the simulated contrast concentration field.
As depicted in Fig. 6, the virtual angiograms showed good agreement with the
conventional angiograms. Analogous size and orientation of the inflow jet, regions
of flow impaction, major intra-aneurysmal vortices and regions of outflow were
observed in both the conventional and virtual angiograms. Similar conclusions were
drawn by Ford [23], thus supporting the ability of patient-specific image-based
computational models to realistically reproduce the major intra-aneurysmal flow
structures observed with conventional angiography.
Image-based haemodynamics simulation in intracranial aneurysms 213
may be used to offer accurate flow boundary conditions, for the validation of
simulation techniques or directly for diagnostic purposes. Image-based haemody-
namics simulation could then be used in combination with in vivo measurements
to offer prognostic information. Among our current interests is to progress in the
implementation of effective techniques to simulate blood flow around endo vascular
devices [4] and to further integrate models of blood clotting and tissue perfusion to
study the association between haemodynamics and treatment failure.
Among the new ventures ahead of investigators working in the field, we could
also cite the integration of haemodynamics information with imaging data capturing
cellular activities. This process has the potential to enable both the investigation of
the correlation between haemodynamics and biomarkers expressed at the cellular
level and the integration of image-based haemodynamics simulation with predictive
models developed within the framework of the STEP (A Strategy Towards the
Europhysiome) roadmap initiative [1, 2].
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Image-based haemodynamics simulation in intracranial aneurysms 217
1 Introduction
1
Objects of interest can be for instance points, lines, surfaces or volumes.
Atlas-based Segmentation 223
Determinist atlases. First attempts of atlas construction of the human brain are
based on a single subject. This type of atlas is called single-subject based atlas or
determinist atlas. It often corresponds to a reference system or volume image that
has been selected among a data set to be representative of the objects to segment in
other images (average size, shapes or intensity).
In medicine, the pioneer atlas reference system is the Talairach atlas [97] that
was proposed to identify deep brain structures in stereotaxic coordinates. The first
determinist digital atlas was proposed by the Visible Human Project of the National
Library of Medicine [72]. The goal of this project was the creation of complete
and detailed three-dimensional anatomical representations of the normal male and
female human bodies. These representations were obtained from the acquisition of
transverse CT, MR and cryosection high resolution images of representative male
and female cadavers. Also derived from a digitized cryosectioned human brain, the
Karolinska Institute and Hospital, Stockholm, created a Computerized Brain Atlas
(CBA) that was designed for display and analysis of tomographic brain images. The
atlas includes the brain surface, the ventricular system and about 400 structures and
all Brodmann areas [46, 99].
But the large majority of the determinist atlases are created directly from imaging
acquisition. For instance, the digital brain atlas developed by the Harvard Medical
School [58] is based on a 3D MR digitized atlas of the human brain to visualize
spatially complex structures. Also, the digital brain phantom from McConell Brain
Imaging Center [21] is based on 27 high-resolution scans of the same individual.
Its average resulted in a high-resolution (1mm isotropic voxels) brain atlas with
an increased signal-to-noise ratio. This template is the reference data within the
BrainWeb simulator [68]. Bajcsy et al. in [9, 11] created an artificial CT anatomical
volume based on the stained slices of a dead soldier brain of a 31 year old normal
male (from the so-called Yakovlev Collection).
Statistical atlases. Atlases based on a single-subject are however not represen-
tative of the diversity human anatomy. To better characterize the variability of the
anatomical structures, atlases have been constructed based on a population. This
second type of atlases is called population-based or statistical atlas. Such atlases
are in continuous evolution since new images can be easily incorporated. Moreover,
the population that a statistical atlas represents can be easily subdivided into groups
according to specific criteria (age, sex, handedness, etc.). Initial population-based
atlases were based in Talairach space [51, 111] Later, to compensate for implicit
limitations of Talairach space based atlases such as poor resolution across slices
(from 3 to 4 mm), population-based atlases from MR images were proposed.
A composite MRI data set was constructed by Evans et al. [39] from several
hundreds of normal subjects (239 males and 66 females of 23:4 ˙ 4:1 years old).
All the scans were first individually registered into the Talairach coordinate system.
Then, they were intensity normalized and, finally, all the scans were averaged voxel-
by-voxel and probabilistic maps for brain tissue were created. The same procedure
224 M. Bach Cuadra et al.
for constructing an average brain was used later by the International Consortium for
Brain Mapping (ICBM) to 152 brains [60]. Recently, disease-based atlases [38, 67]
have been created. They represent subgroups of some disease instead of using a
healthy group of subjects. Such atlases provide the way to examine the history and
evolution (due to natural disease evolution or reaction to clinical treatment) of a
specific disease.
Important questions arise when generating population-based atlases such as the
selection of a reference space or the registration method for the data alignment.
Many researchers have proposed new strategies to create unbiased average templates
and multi-subject registration as in [12, 23, 31, 47, 54, 63, 80, 118].
As conclusion, the term atlas is rather used in the literature to designate a
reference image generally composed of an intensity image, the intensity atlas and
a labeled image, the labeled atlas). However, as in [2], active shape models [25]
or active appearance models [26] can also be considered as atlases since they bring
spatial prior knowledge in a segmentation process.
In such probabilistic framework, prior probabilities from statistical atlas are easily
incorporated as shown in [41,73,84,103]. Thus, statistical classification approaches
can be considered as atlas-based segmentation approaches when they incorporate
spatial probabilistic information from an atlas. (probably also refer here to previous
chapter on statistical classification).
The most known atlas-based segmentation approach consists to reduce the segmen-
tation problem to an image registration problem (see [85] for a recent survey).
To segment a new image, a dense deformation field that puts the atlas into a
point-to-point spatial correspondence with the target image is first computed. This
transformation is then used to project the labels assigned to structures from the atlas
onto the target image to be segmented. As mentioned above, the atlas is first globally
registered to the volume of interest and in a second step, a more local registration is
applied to compensate for the variability between both images. The main advantage
of this approach is that the dense deformation field, interpolated on the whole image
from the registration of visible image features, permits one to easily estimate, in the
target image, the position of structures with fuzzy or not visible contours. Moreover,
this approach permits one to segment simultaneously several contours of any types
(closed, open, connected or disconnected).
226 M. Bach Cuadra et al.
Fig. 1 Atlas MRI and labeled image from Harvard Medical School [58]. Atlas-based segmentation
results (ventricles, corpus callosum, thalamus, trunk and cerebellum) using a tandem of affine
registration and Demons algorithm as proposed in [5]
demons algorithm [98] - for both tumor growth modeling and atlas matching
deformation. Their solution was called seeded atlas deformation (SAD), as they put
a seed with the same intensity properties as the lesion in the atlas image, and then
computed the non-rigid registration. Other methods [36, 92, 93] locally adapted the
elasticity of the transformation, rather than modeling the deformation induced by
the tumor, in a way that large deformations induced by the tumor can be captured.
Recently, Nowinski et al [74] proposed to use a Talairach registration followed by a
three-dimensional nonlinear tumor deformation based on a geometric assumption,
as in [3, 7], that the tumor compresses its surrounding tissues radially. A more
sophisticated model of lesion growth was proposed by Mohamed et al. [71] based
on 3D biomechanical finite element model.
Our proposed solution [7, 83] improved the SAD: instead of applying the
nonlinear registration algorithm to the whole image, a specific model of tumor
growth inside the tumor area was proposed, which assumed the tumor growth radial
from a single voxel seed. Demons algorithm [98] was used outside the tumor area
and the displacement vector field was regularized by an adaptive Gaussian filter to
avoid possible discontinuities. Note that this method does not apply to infiltrating
tumors or take into account the presence of the edema.
3.1 Methodology
Our approach is called model of lesion growth (MLG), and it works in 4 steps.
First, an affine transformation is applied to the brain atlas in order to globally match
the patient’s volume [27]. Second, the lesion is automatically segmented [57, 107].
Thirth, the atlas is manually seeded with a voxel synthetic lesion placed on the
estimated origin of the patient’s lesion. At this point, the affine registration ensures
that the small displacement assumption is respected in the region of the brain that
is far from the tumor. Meanwhile, the segmentation of the tumor volume and the
manual selection of the tumor seed provides an adequate model for the tumor
and its influence on immediately surrounding tissues. Fourth, the proposed non-
rigid deformation method distinguishes between those two areas fixed from the
segmentation of the lesion. The instantaneous displacement field is computed as:
!
i C1 E i C t !
v i C1 ;
d DD (1)
where t=1, D E i is the current total displacement field. Outside the tumor, the
instantaneous force !v i C1 (velocity) for each demon pointpE at iteration i+1, is
computed as
E i .p// !
!
v i C1 D .g.pE C D E f .p//
E r f .p/
E
!
; (2)
j r g.p/j E i .p//
E 2 C .g.pE C D E f .p//
E 2
Atlas-based Segmentation 229
where f ./ and g./ are the image intensities. Thus, there is a displacement in the
direction of the gradient provided by both a difference in image intensities and a
reference image gradient different from zero. Note that (2) is asymmetrical, that is,
it gives different results depending on which image is chosen as the reference and
which is chosen to be floating. As proposed by Thirion [98], bijectivity is ensured by
computing at each iteration both the direct deformation field (dEdirect , from Eqs. (1)
and (2)) and the inverse deformation field (dEinverse , also from Eqs. (1) and (2) but
replacing f instead of g and viceversa). Then, a residual vector field RE D dEdirect C
dEinverse is equally distributed onto the two deformation fields:
i C1 !
i C1 RE
DE direct D d direct ;
2 (3)
i C1 !
RE
DE inverse D d inverse
i C1
;
2
Inside the tumor, the tumor growth model assumes a radial growth of the tumor
from the tumor seed, i.e.
!
!
v i C1 .p/ DM seed
lesion E D ; (4)
Ni t
!
where ! v
lesion is the instantaneous velocity inside the lesion area, DM seed is the
distance from the corresponding point pE to the seed, and Ni t is the number
of iterations of the deformation algorithm that have to be performed. Then, the
!
i C1
deformation field d lesion is computed similarly as in (2). The bijectivety inside the
lesion area is ensured by forcing dEdirect D dEinverse . This model allows the points
inside the lesion area to converge towards the seed voxel2 , while remaining simple
and allowing any number of iterations to take place outside the tumor volume.
The displacement vector computed at every voxel using either the demons force
(1) or the tumor growth model (4) is regularized by an adaptive Gaussian filter to
avoid possible discontinuities
i C1
E ˛ D DE ˛
D ı G./; (5)
2
Note that the vector field points the origin, and not the destiny, of a voxel.
230 M. Bach Cuadra et al.
Fig. 2 Segmentation results after applying the MLG algorithm. Displayed structures are: tumor
(red), ventricles (green), thalamus (yellow), and central nuclei (blue)
the lesion area. In the region close to the tumor (including the tumor contour) there
are large deformations due to the tumor growth. Then, it is necessary to allow large
elasticity, i.e. should have a small value, typically 0:5 mm. In the rest of the brain,
deformations are smaller, due primarily to inter-patient anatomical variability. So,
a larger proves to be better, as it simulates a more rigid transformation. Previous
studies [3] suggest that a typical to match two healthy brains is about 0:5 mm and
1 mm. In what follows, D 0:8 mm is used. The number of iterations is arbitrarily
fixed to 256 C128 C32 C16 from low to high resolution scale and it stops at the end
of the iterations. The algorithm is implemented in a multiscale way: a first match is
made with downsampled images and the resulting transformation is upsampled to
initialize the next match with finer image resolution.
3.2 Results
The result after applying these steps is a deformed brain atlas in which a tumor
has grown from an initial seed, causing displacement and deformation to the
surrounding tissues. After this, structures and substructures from the brain atlas
may be projected to the patient’s image. This is illustrated in Fig. 2. The need of a
correct estimation of the tumor growth in order to obtain a good final segmentation
of the structures directly displaced and deformed by the lesion is proven in [7]. As
illustrated in Fig. 3, without an explicit model of tumor growth, SAD cannot grow
the small seed until the final tumor size. However, it seems that a good deformation
has been obtained in the rest of the brain. Thus, since we are interested in the
deep brain structures and not in the tumor itself, the need of simulating the lesion
growth could be questionable. Let us then compare the accuracy of the segmentation
results of the ventricles, the thalamus and the central nuclei for both approaches.
The obtained results, Fig. 4 show that the MLG performs clearly better in the case
of the structures near the tumor (thalamus and central nuclei). The most critical
Atlas-based Segmentation 231
Fig. 3 Top and bottom row, without and with model of lesion growth, respectively. First column,
seeded atlas (small seed on top and one voxel seed on bottom). Second column, deformation of
seeded atlas. Third column, deformation field in the tumor area
structure is the central nuclei (MLG in green and SAD in red) since it is initially
placed inside the tumor area. In this case, SAD method fails because the central
nuclei segmentation is placed inside the tumor area. On the contrary, MLG pushes
the central nuclei out of the tumor region and it obtains a better segmentation.
Our proposed method in [7, 83] increases the robustness of previous existing
methods but other limitations arise: the placement of the seed needs expertise
and previous segmentation of the lesion is still necessary. Also, since the Demons
algorithm [98] uses the sum of the mean squared differences of intensities as sim-
ilarity measure, the contrast agent (often present in MR scans of such pathologies)
induced some errors in the deformation field. Recently, we proposed in [6] a Mutual
Information (MI) flow algorithm combined with the same radial growth model
presented here. This approach is in fact very similar to the one presented in [7, 83]
but MI flow algorithm has proven its robustness to intensity inconsistencies between
the atlas and the patient images.
Other limitations persist and they are shared by all voxel-based methods since
they often lead to a compromise between the accuracy of the resulting segmentation
232 M. Bach Cuadra et al.
Fig. 4 Importance of the tumor growth model: without (SAD) and with (MLG) model of lesion
growth, respectively. Segmented structures: ventricles (MLG in blue and SAD in magenta),
thalamus (MLG in cyan and SAD in yellow), and central nuclei (MLG in green and SAD in red)
contour. This active contour is going to segment the tumor of the patient image
during the registration process. Thus, with this model, the pre-segmentation of the
patient image is not anymore required. Contours of the objects of interest selected
in the atlas (the head in green, the brain in yellow, the ventricles in blue and the
tumor in red) are superimposed to all images. Our active contour-based algorithm
permits to select the atlas contours that will drive its registration. In this case, the
registration was performed following the registration of the head contour and the
tumor growth only. The rest of the image just follow the deformation interpolated
from the displacement of the selected contours. Fig. 5(c) shows the segmentation
result obtained after this type of registration and Fig. 5(d) shows the corresponding
deformation field. We can see that the registration of the selected green and red
contours are bringing the yellow and blue contours closer to their target contours.
This object-based registration process points out the spatial dependance that exists
between anatomical structures. Such spatial dependance can be exploited in a
hierarchical atlas as described in Sect. 4.2.
The registration framework we propose allows not only to easily include object-
based registration constraints but also to select different type of segmentation
forces derived from the active contour framework for the registration of different
structures in the atlas. Like the biomechanical methods, this algorithm can also be
seen as a surface-based registration method. Its first difference is that it computes
the deformation based on the image and not on mechanical or biological laws.
This implies that its accuracy does not depend on a good physical modeling of
the tissues. Above all, as mentioned above, its main advantage is that it does
not need a pre segmentation of the patient image. The contours defined in the
atlas evolve following an energy functional specially defined to be minimal when
they have reached the desired object contours, as in the active contour-based
segmentation framework [76]. Unfortunately, the main limitation of the surface to
surface registration algorithm remains. As the deformation is only based on contours
of interest, the probability of registration errors increases more we are far from these
contours. As far as we know, most of the existing methods for registration of images
234 M. Bach Cuadra et al.
with space-occupying tumors are either surface-based [59, 62, 71, 116] or voxel-
based [7, 13, 28, 36, 83, 93] approaches. However, in our opinion it is worth to study
how to combine the advantages of both approaches.
4 Discussion
In this chapter, we saw that the atlas-based segmentation has become a standard
paradigm for exploiting spatial prior knowledge in medical image segmenta-
tion [16]. The labeled atlas aims to delineate objects of interest in the intensity atlas.
The atlas-based segmentation process consists to deform the selected atlas objects
in order to better align them with their corresponding objects in the patient image to
be segmented. To perform this task, we have distinguished two types of approaches
in the literature.
The most known approach reduces the segmentation problem in an image
registration problem [5,10,14,18,22,29,43,53,86,98]. Its main advantage is that the
deformation field computed from the registration of visible contours allows to easily
estimate the position of regions with fuzzy contours or without visible contours, as
for instance the subthalamic nuclei (STN) targeting for Parkinson disease [30, 88].
However, these registration algorithms do not exploit the object-based information
that could be obtained by combining the intensity and the labeled atlas. This object-
based information contains an estimation of the objects position in the patient image,
the description of their shape and texture, and the features of their adjacent regions.
Therefore, usual atlas-based segmentation methods via registration often miss local
constraints to improve the accuracy of the delineation of some objects. Besides,
this technique assumes that a point to point correspondence exists between the atlas
and the image to be segmented. Then, the presence of inconsistencies can generate
registration errors, and consequently segmentation errors, if special schemes are not
used (see Sect. 3).
As mentioned in Sect. 2.2, contours in the labeled atlas can be directly deformed
without need of a geometrical deformation [8, 19, 115]. The contour morphing tech-
nique that has attracted the most attention to date is the active contour segmentation
model [56]. Its advantage is that it can exploit the image information directly linked
to the object to be delineated. Therefore, active contour models are often able to
extract objects where the atlas-based segmentation method by registration fails (see
an example on the cerebellum segmentation in [32]). Moreover, this segmentation
method allows extracting only the objects that are consistent in the image. Thus,
it usually does not need special model to solve the problem of inconsistencies. On
the other hand, this segmentation method is very sensitive to the initial position of
the atlas contour: the closer to the contours to be detected, the more robust the
active contour-based segmentation will be. Besides, this segmentation technique
needs prior shape models to be able to estimate the position of regions with fuzzy
or without visible contours. Note that these shape models are in fact atlases that are
registered with the patient image during the process to incorporate prior knowledge
Atlas-based Segmentation 235
in the active contour segmentation. See [17, 75, 78, 79, 104] for examples of active
contour segmentation of medical images with shape priors.
Biomechanical models such as in [40, 42, 59, 69] can be seen as object-based
registration since they are based on selected image objects. They track key surfaces
of objects, as for instance the cortical surface or the lateral ventricles of the brain, to
propagate then the surface displacements through the entire volume guided by the
prior biomechanical knowledge about the deformability of anatomical structures.
One drawback of this type of object-based registration method, compared to image-
based registration methods as [98] or [86], is that it remains difficult to accurately
estimate all the forces that can interact with the model. The level of accuracy stays
thus highly dependent on the number of surfaces tracked.
Fig. 6 Joint atlas-based registration and segmentation of Neck CT images. Row 1: Intensity Atlas
with surrounded objects of interest (the external contour of the neck in green, the trachea in yellow,
the jaw in red and the vertebra in blue). Row 2: Objects of interest delineated in the patients images.
Rows 3: Corresponding deformation fields
patient image. Here, we did not consider in the registration process the arteria,
muscles and fat (structures inside the gray part of the neck) that do not correspond
between these 2D images.
5 Conclusion
Acknowledgements Our acknowledgment goes to Prof. Reto Meuli from the Radiology Depart-
ment of the Lausanne Hospital (CHUV) and to Dr. Simon Warfield from Harvard Medical School
238 M. Bach Cuadra et al.
for providing the patient images. Also, we thank Prof. Ron Kikinis who has provided us with
the digitized atlas of the Harvard Medical School. This work has been supported by Center for
Biomedical Imaging (CIBM) of the Geneva - Lausanne Universities, the EPFL, and the foundations
Leenaards and Louis-Jeantet, as well as by the Swiss National Science Foundation under grant
number 205320-101621.
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Integration of Topological Constraints
in Medical Image Segmentation
1 Introduction
Support for this research was provided in part by the National Center for Research Resources
(P41-RR14075, R01 RR16594-01A1 and the NCRR BIRN Morphometric Project BIRN002, U24
RR021382), the National Institute for Biomedical Imaging and Bioengineering (R01 EB001550,
R01EB006758), the National Institute for Neurological Disorders and Stroke (R01 NS052585-01)
as well as the Mental Illness and Neuroscience Discovery (MIND) Institute, and is part of the
National Alliance for Medical Image Computing (NAMIC), funded by the National Institutes of
Health through the NIH Roadmap for Medical Research, Grant U54 EB005149.
F. Ségonne () • B. Fischl
Department of Radiology, MGH/Harvard Medical School, Building 149,
13th Street, Charlestown, MA 02129, USA
e-mail: [email protected]; [email protected]
Fig. 1 a) Subcortical structures have a spherical topology. For instance, the shape of the
hippocampus can be continuously deformed onto a sphere. b) The human cerebral cortex is a highly
folded ribbon of gray matter that lies inside the cerebrospinal fluid (the red interface) and outside
the white matter of the brain (the green interface). When the midline connections between the left
and right hemisphere are artificially closed, these two surfaces have the topology of a sphere. c)
Due to the partial volume effect, subject motion, etc : : : , it becomes hard to distinguish opposite
banks of a the gray matter. d) Segmentation algorithms that do not constrain the topology often
produce cortical segmentations with several topological defects (i.e. handles, cavities, disconnected
components). e) A close-up of a topologically-incorrect cortical surface representation
1.2 Motivation
1
The human cerebral cortex is a highly folded ribbon of gray matter (GM) that lies inside the
cerebrospinal fluid (CSF) and outside the white matter (WM) of the brain. Locally, its intrinsic
“unfolded” structure is that of a 2D sheet, several millimeters thick. In the absence of pathology and
assuming that the midline hemispheric connections are artificially closed, each cortical hemisphere
can be considered as a simply-connected 2D sheet of neurons that carries the simple topology of a
sphere - see Fig. 1-b
Integration of Topological Constraints in Medical Image Segmentation 247
1.3 Challenges
Fig. 2 a-b) Two tori that are homeomorphically equivalent. They share the same intrinsic
topology. However, they do not share the same homotopy type as one cannot be continuously
transformed into the other. c) A geometric object with a spherical topology; its Euler-characteristic
is D v e C f D 8 12 C 6 D 2. d) A geometric object with a toroidal topology and an Euler-
characteristic of D v e C f D 16 32 C 16 D 0
Fig. 3 a) a simple closed curve with the topology of a circle. b) One example of a polyhedral
decomposition of the curve using 25 vertices and edges. The corresponding Euler-characteristic
D v e D 0 is that of a circle. c) Another discretization of the same curve using 14 edges and
vertices. Note that the Euler-characteristic is still that of a circle D 0, even though the discrete
representation of the curve self-intersects in the 2D embedding space. d) Close-up
2
In the case of multiple surfaces involving K connected components, the total genus is related to
the total Euler-characteristic by the formula: D 2(K g).
250 F. Ségonne and B. Fischl
Fig. 4 a) 6-, 18- and 26-connectivity. b) The circled voxel is a non-simple point c) Several dual
topological corrections are possible: either cutting the handle (top) or filling the hole (bottom)
ing defect in the background (i.e. the embedding space): a disconnected foreground
component can be interpreted as a background cavity; a foreground cavity is a
disconnected background component; and a handle in a foreground component
defines another handle in the background component. This foreground/background
duality is of crucial importance for all retrospective topology correction techniques,
as it provides a dual methodology to correct a topological defect. For instance, the
presence of a handle in an object could be corrected by either cutting the handle
in the foreground object, or cutting the corresponding handle in the background
object. Cutting the background handle can be interpreted as filling the corresponding
foreground hole (Fig. 4-b,c).
on a 3D voxel grid, is usually the signed distance function of the surface with the
contour being the zero level set of : C D 1 (0).
This type of representation has several advantages. First, no explicit represen-
tation and no parameterization are required. In the theory of active contours, this
has proven to be a huge advantage as implicit representations can naturally change
topology during the deformation of the model. Self- intersections, which are costly
to prevent in parametric deformable models, are avoided and topological changes
are automated. In addition, many fundamental properties of the surface C, such as
its normal or its curvature, are easily computed from the level set function .
However, these models can only represent manifolds of codimension one without
borders, i.e. closed surfaces in R3 . For the purpose of segmenting anatomical
structures, the use of such representations is not a limitation. Another - more
subtle - drawback of implicit representations is that, even though level sets achieve
sub-voxel accuracy, the exact location of the contour depends on the image
resolution. For instance, in the case of two adjacent banks of a sulcus that are
closer than the resolution of the underlying voxel grid (or physically touching), the
finite image resolution and the topological constraint necessitate some voxels to
be labeled as outside voxels (ideally, these voxels should be the ones belonging to
CSF), thus imposing a constraint on the location and accuracy of the surface model
(some recent methods to alleviate this limitation have been proposed in [2, 27]).
So far, we have not specified how implicit representations can ensure that the
topology of the encoded surface is the correct one. Since implicit representations
make use of the underlying 3D voxel grid (through a signed distance function ) to
encode the contour of interest, digital topology (Sect. 2.2-A) can be used to specify
the topology of the contour [28]. The foreground object X is simply defined as the
set of negative grid points (i.e. X D fx 2 R3 j .x/ 0g), and the background
object X as the set of strictly positive grid points (i.e. XN D fx 2 R3 j .x/ > 0g).
Then, given a choice of compatible connectivities, the topology of the contour is
determined unambiguously.
C - From Images to Surfaces: Isocontour Extraction
In the previous section, we described the manner in which topology can be adapted
to the two most common data structures used in medical imaging. The ability to go
from one representation to the next arises as a difficulty. Although it is possible to
generate triangulations from 3D binary digital segmentations, such that the resulting
topology of the surfaces is consistent with the choice of digital topology, it is not
always possible to produce a digital binary representation, whose topology is similar
to that of a given triangulation: digital topology constitutes a discrete approximation
of the continuous space at a finite resolution, while triangulations approximate
continuous surfaces at any level of precision.
The marching cubes (MC) algorithm was first introduced by Lorensen and Cline
in 1987 [34] as a way to generate a polygonal decomposition (e.g. a triangulation)
from a scalar field sampled on a rectilinear grid (e.g. an implicit representation).
Given an isovalue, the MC algorithm quickly extracts a representation of the
isosurface of the scalar field. The MC algorithm first partitions the data into a set
254 F. Ségonne and B. Fischl
of cubic (or rectilinear) cells, the cell vertices being the grid points. Based on the
relative polarity of their scalar value (above or below the isovalue), each vertex is
assigned a binary label, which indicates whether the grid point is inside or outside
the isosurface. Then, each cubic cell is processed sequentially. Patches (i.e. sets
of triangles) that approximate the isosurface (based on tri-linear interpolation) are
produced within each cube, and the polygon patches are naturally joined together to
form the final isosurface representation.
Unfortunately, the standard marching squares or marching cubes algorithm does
not generate topologically consistent tessellations, since the resulting tessellations
may contain tiling and topological inconsistencies (Fig. 5-b). In order to alleviate
this problem, Han et al. [28] have designed a modified connectivity-consistent
marching contour algorithm, by building a specialized case table for each type of
digital topology (Fig. 5-c). Extensive discussion of isocontour extraction algorithms
can be found in the thesis of Han [25]. Note also some new research directions such
as [1].
connectivity of the segmentation; the topological defects present in the volume are
then corrected by introducing some cuts in the connectivity graph (e.g. modifying
the binary labels of some key voxels in the volume).
One of the most inspirational approaches in this domain is certainly the pioneer-
ing work of Shattuck and Leahy [49]. One drawback of their approach is that the
“cuts”, which are necessary to correct the topological defects, can only be oriented
along the Cartesian axes and give rise to “unnatural” topological corrections. Their
method is based on the theory of digital topology but is limited to 6-connectivity
and has not been generalized for any other connectivity rule.
Han et al. developed an algorithm to correct the topology of a binary object
under any digital connectivity [26]. They detect handles by graph analysis, using
successive foreground and background morphological openings to iteratively break
the potential topological defects at the smallest scales. In contrast to the approach
of Shattuck and Leahy, “cuts” are not forced to be oriented along cardinal axes.
However, topological corrections at a specific scale depend on the choice of
filter, either foreground or background morphological filter, which fails to evaluate
simultaneously the effect of two complementary dual solutions (i.e. cutting the
handle or filling the corresponding hole) on the corrected segmentation.
Kriegeskorte and Goeble proposed a region growing method prioritized by
the distance-to-surface of the voxels in order to force the cuts to be located at
the thinnest part of each topological defect [32]. The same process is applied to
the inverse object, offering an alternative solution to each cut. An empirical cost
is then assigned to each solution and the final decision is the one minimizing the
global cost function.
While these methods can be effective, they cannot be used to correct the topology
of arbitrary segmentations, as they make assumptions regarding the topology of
the initial input image. Most frequently, fully-connected volumes are assumed and
cavities are supposed to be removed as a preprocessing step. In addition, they do
not integrate any statistical or geometric information into the topology correction
process. To alleviate these limitations, Ségonne et al. [46, 45] propose a topology
correction approach that is phrased within the theory of Bayesian parameter estima-
tion and integrates statistical information into the topology correction process. In
addition, no assumption is made about the topology of the initial input images.
B - Surface-Based Approaches
Approaches of the other type operate directly on the triangulated surface mesh.
Topological defects are located either as intersections of wavefronts propagating
on the tessellation [24, 29] or as non-homeomorphic regions between the initial
triangulation and a sphere [19, 47, 48].
In [24, 29], a randomly selected vertex is used to initialize a region growing
algorithm, which detects loops (i.e. topological defects) in the triangulation where
wavefronts meet. Topological corrections are obtained through the use of opening
operators on the triangle mesh, resulting in a fast method that depends on the
initially selected vertex. In a similar work, Jaume [29] identifies minimal loops
in the volume by wavefront propagation. This method assumes that the initial
258 F. Ségonne and B. Fischl
thus far to generate multiple solutions and explore the full space of potential
solutions in order to select the best correction of a topological defect.
4 Conclusion
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Monte Carlo Sampling for the Segmentation
of Tubular Structures
C. Florin ()
Corporate Technology, Siemens Corporation, 755 College Rd E, Princeton, NJ 08540,
United States
e-mail: [email protected]
N. Paragios
Center for Visual Computing, Department of Applied Mathematics, Ecole Centrale Paris,
Paris, France
e-mail: [email protected]
J. Williams
CEO at Siemens Healthcare Molecular Imaging, Siemens Healthcare, Nürnberg, DE
e-mail: [email protected]
1 Introduction
Cardio-vascular diseases are the leading cause of death in the western world; there
is a constant demand for improvement of diagnostic tools to detect and measure
anomalies in the coronary tree. Coronary arteries are narrow vessels (between 3
to 5 mms next to the aorta, between 1.5 to 2.5 mms after two branchings). Their
role is to feed the heart muscle with oxygenated blood, and their segmentation
provides a valuable tool for clinicians to diagnose pathologies such as calcifications
and stenoses. Nevertheless, their segmentation is a difficult task because of the low
contrast conditions, bifurcations, intensity distortions produced by pathologies and
scanner artifacts, and the coronaries’ proximity to the heart chambers [26].
path of minimal length between two points, backtracking from one point toward
the other crossing the isosurfaces perpendicularly. To discourage leaking, a local
shape term that constrains the diameter of the vessel was introduced in [22]. One
should also mention the method introduced in [20], where the optimization of a
co-dimension two active contour was presented to segment brain vessels.
Model-based techniques, on the other hand, use prior knowledge and features
to match a model with the input image and extract the vessels. The knowledge
may concern the whole structure, or consist of a local region of the vessel. Along
this direction, vessel template matching techniques (deformable template matcher)
[25] have been investigated. The template model consists of a series of connected
nodes that is deformed to best match the input image. Generalized Cylindrical
models are modified in Extruded Generalized Cylinders in [23] to recover vessels in
angiograms. For highly curved vessels, the local basis used for classical generalized
cylinders may be twisted, and a non-orthogonality issue may occur. This problem is
solved by keeping the vessel cross section orthogonal to the centerline and the two
normal vectors always on the same side of the tangent vector spine as the algorithm
moves along the vessel. In [19], the vessel is modeled by a tubular structure, and
segmented by filtering the image with a multiscalestructural term derived from the
image intensity Hessian matrix [14, 36]. More recently, [30] a vessel likelihood is
obtained from a classifier trained over a bag of multiscale filters. After the likelihood
is computed over the whole image, a tracing algorithm tracks the vessel from a seed
point.
Fig. 1 The feature space is defined by the cross-section center position x D (x1 , x2 , x3), the cross-
section tangential direction ‚ D ( 1 , 2 , 3) and the lumen pixel intensity distribution pvessel
the reason why the authors are driven toward a method that would handle multiple
hypotheses, and keep only the few most probable following [12, 13]. At each step,
a scheme based on particle filtering [8] is used to sample the parameters probability
density function (pdf). To these samples is assign a probability measure (Sect. 2.2)
that is updated at every step with the prior value and the model’s fitness to the new
image features. In Sect. 3, the experimental method is explained and the results are
presented in Sect. 3.3. Finally, Sect. 4 concludes this chapter with a discussion.
To explain our method at a concept level, let us assume that a segment of the
vessel has been detected: a 2D shape on a 3D plane. Similar to region growing and
front propagation techniques, our method aims to segment the vessel in adjacent
planes. To this end, one can consider the hypotheses ! of the vessel being at a
certain location (x), having certain orientation (‚), and referring to certain shape -
an elliptic model is a common choice (ç) - with certain appearance characteristics
(pvessel ).
mechanism that, given prior knowledge, predicts the actual position of the vessel
and a sequential estimate of its corresponding states. To this end, we define:
• a state vector ! composed of x, ‚, ç and pvessel (Eq. (1))
• an iterative process to predict the next state and update the density function, that
can be done using a Bayes sequential estimator and is based on the computation
of the present state ! t pdf of a system, based on observations from time 1 to time
t z1:t : (! t jz1:t ). Assuming that one has access to the prior pdf (! t1 jz1:t1 ),
the posterior pdf (! t jz1:t ) is computed according to the Bayes rule:
X
M
m m
.!t jz1Wt / œ ı !t –! ; (2)
t t
mD1
m m
where each weight œ reflects the importance of the sample ! in the pdf.
t t
m
The samples ! are drawn using the principle of Importance Density [9], of pdf
t
ˇ m m
q ! ˇx1Wt ; zt and it is shown that their weights œ are updated according to
t t
m m m
zt j! ! j!
m m t t t-1
œ /œ : (3)
t t-1 m
q ! j! m t –1 ; zt
t
268 C. Florin et al.
m m
Once a set of samples has been drawn, ! j! t –1 ; zt can be computed out of
t
the observation zt for each sample, and the estimation of the posteriori pdf can be
sequentially updated.
m
This theory is now applied to vessel tracking. Each one of the particles !
t
m
represents a hypothetic state of the vessel; a probability measure p zt j! is
t
m
used to quantify how the image data zt fits the vessel model ! . To this end,
t
we are using the image terms, and in particular the intensities that do correspond
to the vessel in the current cross-section. The vessel’s cross-section is defined by
the hypothetic state vector (see Eq. (1)) with a 3D location, a 3D orientation, a
lumen’s diameter and a pixel intensity distribution model (the multi-Gaussian). The
observed distribution of this set is approximated using a Gaussian mixture model
according to the Expectancy-Maximization principle. Each hypothesis is composed
by the features given in Eq. (1), therefore, the probability measure is essentially
the likelihood of the observation z, given the appearance A model. The following
measures (loosely called probabilities) are normalized so that their sum over all
particles is equal to one. Assuming statistical independence between shape S and
appearance model A, p(zt j! t ) D p(zt jS)p(zt jA).
• Probability measure for shape based on contrast
Given the vessel model (see Eq. (1)), whose parameters are specified by
the particle ! t , a measure of contrast, that we call the ribbon measure R, is
computed:
(
R D 1; int ext
int –ext (4)
RD ; otherwise
int Cext
The probability of the observation given the shape model is then computed:
ˇ – jRj
ˇ R
p z ˇS D e 0 (5)
ˇ – jD.Dp;q /j
ˇ
p z ˇA D e 0
; (7)
When a branching occurs, the particles naturally split up in the two daughter
branches (the case of trifurcation is not studied here), and then track them separately
(see Fig. 2). As branchings are never perfectly balanced, one of them attracts the
majority of the particles after few resampling steps. To avoid the collapse of one of
the modes, two techniques are available: either to increase the number of particles in
the weakest branch, or to treat the two branches separately. The second approach is
preferred in this paper, for the particular context of vessel segmentation; therefore,
after branchings are detected, each modes is treated as an entirely separate new
particle filter. To this end, a simple K-means [10] clustering in the joint space
(position C orientation) of the particles is considered at each iteration. When the
two clusters are well separated (when the distance between the clusters center is
above a certain threshold), the number of particles is doubled and they are equally
dispatched in the two branches. The segmentation goes on, according to Eq. (3), by
treating the two modes as entirely distinct particle filters.
270 C. Florin et al.
Fig. 2 (a) branching points between LCX and LAD for three patients with the particles’ mean
state overlaid, (b) the particles are clustered at each time step. The branching is detected when the
distance between the two clusters center is above a certain threshold
3 Experimental Validation
The algorithm was tested on 34 CT images from different SOMATON scanners and
patients who presented different or no pathologies. A typical voxel resolution is
0.3 mm 0.3 mm 1 mm. Contrast agent was used for all images, with different
concentration and different products. Table 1 summarizes the typical intensity
range for different tissues, as they are found in a CT angiography volume, with
pixels’ value coded on 12 bits. No preprocessing is applied before the segmentation
procedure described in this article.
Regarding the initial configuration, the use of approximatively 1, 000 particles
gave sufficient results for our experiments. We performed a systematic resampling
2
according to the SIR every time the effective sampling size Neff D †i 1=w (where
i
wi is the weight of the ith particle) falls below half the number of particles. The
preference for SIR is motivated by the robustness of the segmentation. The tracking
stops when the sum of image measures at a given iteration falls below a given
threshold.
Monte Carlo Sampling for the Segmentation of Tubular Structures 271
Table 2 Results table showing the number of cases for which branches are incorrectly segmented,
over a dataset of 34 patients, using Particle Filters (PF) and Front Propagation (FP), with respect
to expert ground truth
Acute First Obtuse
vessel name RCA Marg. LAD Septal LCX Marg.
# missed, PF none 5 none 2 none 2
# missed, FP 12 28 16 23 21 26
Our method is compared with Front Propagation, implemented using the Fast
Marching algorithm [5], based on a curvilinear structures detection [36]. The Hes-
sian analysis is used to detect tubular structures; this measure (called “vesselness”
in [15]) is integrated into a potential map on which the Fast Marching algorithm
is run such as in [6]. In few words, Front Propagation computes isosurfaces in a
Riemanian space, whose metric is based on the image: the vesselness measure in
our case. The front propagates faster along the vessel than in other non-tubular
structures. However, in the case of intensity inhomogeneities, this measure drops
and the front either stops or leaks into neighboring structures.
In the synthetic case, the error measure 4 is defined as the symmetric difference
between ground truth G and segmentation S:
2 jG \ S j
D1 :
jGj C jS j
Since ground truth is not available for the real case studies, an expert visually
validates the number of branches correctly segmented and missed.
3.3 Results
The algorithm has been evaluated on 34 patients, and has successfully recovered
all the main arteries (RCA, LAD, LCX) for each patient as shown in Table 2,
while a small portion of visual results are also presented in Fig. 3. The results
in Table 2 corresponds to the number of branches segmented by Particle Filters
and identified by a human expert. For comparison purposes, the same test is
performed using Front Propagation based on the image Hessian matrix [36]. These
results were achieved with a one-click initialization. Allpatients presented some
kind of artery pathologies in one, at least, of their coronary vessels (12 cases with
calcification, 8 stenosis, 4 stent, 2 bypasses), and many present intensity artifacts
(7 stepping, 5 hardening effects). Our approach has successfully segmented both
healthy and unhealthy coronaries without leaking into neighboring structures (over-
segmentation). The method seems to outperform regarding the detection of the main
branchings, while in some cases branching of lower clinical importance at the distal
part of the tree have been missed.
272 C. Florin et al.
4 Conclusion
In this chapter, we have shown that Monte-Carlo sampling and multiple hypotheses
testing can be used for the segmentation of tubular structures. In the context of vas-
cular segmentation, Particle Filters sequentially estimate the pdf of segmentations in
a particular feature space. The case of coronary arteries was considered to validate
such an approach where the ability to handle discontinuities on the structural
(branching) as well as appearance space (calcifications, pathological cases, etc.)
was demonstrated. The main advantage of such methods lies in their capability
to handle intensity inhomogeneitiesfrom pathologies and bifurcations. Experiments
were conducted on several healthy and diseased patients CTA data sets, segmenting
the Left Main Coronary Artery and the Right Coronary Artery Fig. 3.
As a final remark, it may be underlined that particle filters require heavy
computational time in a general context (around an hour for a CT 512 512 300
volumetric image), compared to front propagation. However, in the case of non
linear problems, with missing or corrupt data, particle filters provide a better
segmentation than deterministic methods. In the particular case of coronary arteries
segmentation, due to pathologies, contrast agent heterogeneities and branchings,
the use of non deterministic methods have been proved successful. Therefore, when
time is a constraint, a compromise is to be found to apply deterministic methods
in linear cases and statistical modelization, such as Particle Filtering, in all other
cases.
Monte Carlo Sampling for the Segmentation of Tubular Structures 273
Fig. 3 Segmentation of the Left anterior descending coronary artery and Right coronary artery in
CTA (in red) for four patients ; (a) coronary tree, (b,c,d) Different 3D views super-imposed to the
cardiac volume are presented
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Non-rigid registration using free-form
deformations
1 Introduction
D. Rueckert ()
Department of Computing, Imperial College London, 180 Queen’s Gate,
London SW7 2AZ, UK
e-mail: [email protected]
P. Aljabar
Department of Biomedical Engineering, Division of Imaging Sciences, King’s College
London, Lambeth Wing, St Thomas’ Hospital, London SE1 7EH, UK
e-mail: [email protected]
The goal of image registration is to relate any point in the reference or target image
to the source image, i.e. to find the optimal transformation T W p 7! p0 which
maps any point in the target image IA into its corresponding point in the source
image IB . The transformation T can be separated into two components: A global
component (e.g. a rigid or affine transformation) and a local component. Thus, the
transformation T can be written as:
The global transformation typically accounts for variations in the position, orienta-
tion and scaling between the two images. However, the global transformation cannot
account for any local deformations.
In the late eighties a number of technique for modeling deformations emerged
in the computer graphics community. In particular, Sederberg and Parry developed
free-form deformations (FFD) [57] as a powerful modelling tool for 3D deformable
objects. The basic idea of FFDs is to deform an object by manipulating an
underlying mesh of control points. The resulting deformation controls the shape of
the 3D object and produces a smooth and continuous transformation. In the original
paper by Sederberg and Parry [57] trivariate Bernstein polynomials were used to
interpolate the deformation between control points. A more popular choice is to use
trivariate B-spline tensor products as the deformation function [37, 38]. The use of
FFDs based on B-splines for image registration was first proposed by Rueckert et al.
[53, 54]. Over the last decade the use of FFDs for image registration has attracted
significant interest [36, 45, 50, 51].
Non-rigid registration using free-form deformations 279
X
3 X
3 X
3
Tlocal .p/ D Bl .u/Bm .v/Bn .w/i Cl;j Cm;kCn (2)
lD0 mD0 nD0
where i D b xı c 1; j D b yı c 1; k D b ız c 1; u D xı b xı c; v D yı b yı c;
w D ız b ız c and where Bl represents the l-th basis function of the B-spline [37,38]:
B0 .u/ D .1 u/3 =6
B1 .u/ D .3u3 6u2 C 4/=6
B2 .u/ D .3u3 C 3u2 C 3u C 1/=6
B3 .u/ D u3 =6
In contrast to thin-plate splines [6] or elastic-body splines [23], B-splines are locally
controlled which makes them computationally efficient even for a large number of
control points. In particular, the basis functions of cubic B-splines have a limited
support, i.e. changing control point i;j;k affects the transformation only in the local
neighbourhood of that control point.
The derivative of a coordinate transformation is the matrix of its partial deriva-
tives. In the case of 3D coordinate systems this is always a 3 3 matrix called the
Jacobian matrix and the determinant of this matrix is called the Jacobian determinant
of the transformation, or simply the Jacobian. This determinant measures how
infinitesimal volumes change under the transformation. For this reason, the Jacobian
determinant is the multiplicative factor needed to adjust the differential volume form
when applying the coordinate transformation.
An advantage of B-spline FFDs is the fact the derivatives of the transformation
can be computed analytically. The derivatives of the transformation are often
used in the optimization of the registration and for regularization as well as in
the subsequent analysis of the resulting transformation. The Jacobian matrix of
transformation is defined as:
0 @T .p/ @T .p/ @T .p/ 1
x x x
B @x @y @z
C
B @Ty .p/ @Ty .p/ @Ty .p/ C
J.p/ D B @x C (3)
@ @y @z A
@Tz .p/ @Tz .p/ @Tz .p/
@x @y @z
280 D. Rueckert and P. Aljabar
The determinant of this matrix measures how infinitesimal volumes change under
the transformation and can be used to analyze the local behavior of the transforma-
tion. A positive value of the determinant of the Jacobian matrix can be interpreted
as follows:
8
< > 1 volume expansion
J.p/ D det jJ.p/j D D 1 no volume change (4)
:
< 1 volume contraction
If the value of the determinant changes from positive to negative the transformation
is folding and is no longer a one-to-one transformation. Since the FFD is the tensor
product of independent 1D B-splines, the derivative of the local transformation
Tlocal with respect to x is computed as follows:
1 X X X dBl .u/
3 3 3
@Tlocal .p/
D Bm .v/Bn .w/i Cl;j Cm;kCn (5)
@x ıx mD0 nD0
du
lD0
The remaining derivatives have an analogous form. The computation of the deriva-
tives of the B-spline basis functions Bi itself is straightforward.
The control points ˆ act as parameters of the B-spline FFD and the degree
of non-rigid deformation which can be modelled depends essentially on the
resolution of the mesh of control points ˆ. A large spacing of control points allows
modelling of global non-rigid deformations while a small spacing of control points
allows modelling of highly local non-rigid deformations. At the same time, the
resolution of the control point mesh defines the number of degrees of freedom
and consequently the computational complexity. A common approach uses a multi-
resolution approach for FFDs in which the resolution of the control point mesh
is increased in a coarse to fine fashion (see Fig. 1). An arbitrary FFD based on
B-splines can be refined to an identical deformation with half the control point
spacing along each dimension. In the 1D case, the control point positions 0 of
the refined grid can be computed from the coarse control points [26]:
0 1 0 1
2i C1 D .i C i C1 / and 2i D .i 1 C i C1 C 6i / (6)
2 8
This equation can be easily generalized to 3D by applying the tensor product.
Another possibility is the use of non-uniform FFDs [55]. This can be achieved by
introducing a control point status associated with each control point in the mesh,
marking it either active or passive. Active control points can be modified during
the registration process, whereas passive control points remain fixed. An alternative
approach for FFDs based on non-uniform rational B-splines (NURBS) has been
proposed by Wang and Jiang [64].
Non-rigid registration using free-form deformations 281
Fig. 1 A free-form deformation control point mesh (a) before subdivision (control point spacing
20 mm) and (b) after subdivision (control point spacing 10 mm)
To relate a point in the target image to the source image, one must define a similarity
criterion (or cost function) which measures the degree of alignment between both
images. A popular choice for this are voxel-based similarity measures which use the
image intensities directly and do not require the extraction of any features such as
a landmarks, curves or surfaces. Commonly used voxel-based similarity measures
include the sum of squared differences (SSD) or cross-correlation (CC). However,
these measures make rather strong assumptions about the relationship of the image
intensities in both images which is not suitable for multi-modality registration.
Even in the case of mono-modality registration this assumption is often violated,
e.g. in contrast-enhanced imaging. An alternative voxel-based similarity measure is
mutual information (MI) which was independently proposed by Collignon [16] and
282 D. Rueckert and P. Aljabar
Viola [62]. Mutual information is based on the concept of information theory and
expresses the amount of information in one image A that explains a second image B,
where H.A/; H.B/ denote the marginal entropies of A, B and H.A; B/ denotes
their joint entropy. These entropies can be estimated from the joint histogram of A
and B or using kernel density estimators like Parzen windowing. If both images are
aligned the mutual information is maximised. It has been shown by Studholme [60]
that mutual information itself is not independent of the overlap between two images.
To avoid any dependency on the amount of image overlap, Studholme suggested the
use of normalised mutual information (NMI) as a measure of image alignment:
H.A/ C H.B/
Csimilarity .A; B/ D (8)
H.A; B/
This type of cost function comprises two competing goals: The first term represents
the cost associated with the image similarity Csimilarity in Eqs. (7) or (8) while the
second term penalizes certain transformations and thus constrains the behavior of
the transformation (different penalty functions will be discussed in the next section).
The parameter is a weighting parameter which defines the trade-off between the
alignment of the two images and the penalty function of the transformation. From
a probabilistic point of view, the cost function in Eq. (9) can be explained in a
Bayesian context: The similarity measure can be viewed as a likelihood term which
expresses the probability of a match between source and target image while the
penalty function represents a prior which encodes a-priori knowledge about the
expected transformation.
In the original paper by Rueckert et al. [54] the optimization of the FFD is
carried out is a multi-resolution fashion via a steepest gradient descent optimization
algorithm. More recently, Klein et al. has compared different optimization strategies
for FFDs [35].
Non-rigid registration using free-form deformations 283
Here J.p/ is the determinant of the Jacobian matrix J of the free-form deformation.
As mention previously the Jacobian measures how infinitesimal volumes change
under the transformation. This function therefore penalizes the compression or
expansion of tissues or organs during the registration. It should be noted that the
penalty term above penalizes volume changes over the entire domain, however due
to the integration there may be small regions in the image which show a large
volume change while the majority of regions show no volume change. Other authors
have proposed a rigidity constraint which forces the deformation in certain regions
to be nearly rigid [41], e.g.
Z
Crigidity D jjJ.p/J.p/T 1jjd p (12)
The penalty functions above do not guarantee that the resulting deformation field
is diffeomorphic (smooth and invertible). In order to ensure that the FFD is diffeo-
morphic it is possible to add a penalty function which penalizes non-diffeomorphic
284 D. Rueckert and P. Aljabar
where
(
2
2 if jJ.p/j
A similar penalty function was first proposed by Edwards et al. [25] and effectively
penalises any transformations for which the determinant of the Jacobian falls below
a threshold
. By penalising Jacobians that approach zero, one can prevent the
transformation from collapsing and ensure diffeomorphisms. Note that simply using
a smoothness penalty function would not be sufficient to guarantee a diffeomorphic
transformation, since it is possible for a transformation to be smooth but non-
diffeomorphic.
In general, most registration algorithms make the assumption that similar structures
are present in both images. Therefore it is desirable that the deformation field be
smooth and invertible (so that every point in one image has a corresponding point
in the other). Such smooth, invertible transformations are called diffeomorphisms.
Choi and Lee [13] have derived sufficient conditions for the injectivity of FFDs
which are represented in terms of control point displacements. These sufficient
conditions can be easily tested and can be used to guarantee a diffeomorphic FFD.
Without loss of generality we will assume in the following that the control points are
arranged on a lattice with unit spacing. Let ci;j;k D .xi;j;k ; yi;j;k ; zi;j;k / be
the displacement of control point ci;j;k . Let ıx D max jxi;j;k j, ıy D max jyi;j;k j,
ız D max jzi;j;k j.
Theorem 1. A FFD based on cubic B-splines is locally injective over all the
domain if ıx < K1 , ıy < K1 and ız < K1 .
Choi and Lee [13] have determined a value of K 2:48 so that the maximum
displacement of control points given by the bound K1 is approximately 0.40. This
means that the maximum displacement of control points is determined by the
spacing of control points in the lattice. For example, for a lattice with 20mm control
point spacing the maximum control point displacement is 8mm while for a lattice
with 2.5mm control point spacing the maximum control point displacement is 1mm.
In practice the bounds on the displacements are too small to model any realistic
deformations. To model large deformations one can use a composition of FFDs as
Non-rigid registration using free-form deformations 285
proposed in [30]. For each FFD in this composition, the maximum control point
displacement is limited by theorem 1. This a fundamentally different to the multi-
level FFDs mentioned earlier since the FFDs are concatenated,
3 Applications
X
t
T.p; t/ D Tilocal .p/
i D1
Fig. 2 The short-axis images (top) and the long-axis images (bottom) taken at different times are
registered to their corresponding images taken at time t D 0 (left top and bottom) to recover the
deformation within the myocardium. The short-axis and long-axis images show a virtual tag grid
which has been aligned with the tag pattern at time t D 0. As time progresses, the virtual tag grid
is deformed by the free-form deformation and follows the underlying tag pattern in the images
tag pattern at time t D 0. As time progresses the virtual tag grid is deformed by
the free-form deformation according to the cardiac motion. If the cardiac motion
has been recovered the virtual tag grid will follow the underlying tag pattern in the
images.
A different application of non-rigid registration is the correction of respiratory
motion in contrast-enhanced dynamic MR. Here the motion induced by free
breathing during the acquisition degrades the images. It has been shown that
respiratory motion induces significant deformations of the heart [46]. Non-rigid
registration based on free-form deformations has been used successfully to correct
for this respiratory motion [47].
The non-rigid registration of brain images has led to a variety of applications in the
context of neurological studies in which the transformations between image pairs
are the focus of attention. In longitudinal studies, changes in the brain over time
can be modeled using non-rigid transformations between serially acquired images.
These longitudinal changes can range from the dramatic and complex growth of
the early years to the subtle changes due to neurodegeneration later in life. In
cross-sectional studies, non-rigid registrations between images of different subjects
can be used to characterised inter-subject variability or the differences between an
individual and a reference image. Approaches that focus on the transformations in
288 D. Rueckert and P. Aljabar
Fig. 4 Left: An MRI image of the anatomy of a subject. Right: Overlay of the segmentation for a
group of sub-cortical structures obtained by using atlas-based segmentation and classifier fusion
4 Discussion
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294 D. Rueckert and P. Aljabar
Abstract Different imaging modalities, such as CT, MRI and PET, are based
on different physical principles and capture different and often complementary
information. Many applications in clinical practice benefit from an integrated visu-
alization and combined analysis of such multimodal images. In many applications
it is also necessary to compare images acquired at a different time points, such as
in the analysis of dynamic image sequences or of follow-up studies. Analysis of a
single scene from multiple images assumes that the geometrical correspondence
or registration between these images is known, such that anatomically identical
points can be precisely identified and compared in each of the images. But reliable
automated retrospective fusion or registration of multimodality images based on
intrinsic image features is complicated by their different photometric properties,
by the complexity of the scene and by the large variety of clinical applications.
Maximization of mutual information of corresponding voxel intensities allows for
fully automated registration of multimodality images without need for segmentation
or user intervention, which makes it well suited for routine clinical use in a variety
of applications.
1 Introduction
less automated approaches for image registration have been proposed, one strategy
in particular, namely maximization of mutual information (MMI) of corresponding
voxel intensities, has been very successful in the field of medical image analysis.
Mutual information (MI) is a basic concept from information theory, that is applied
in the context of image registration to measure the amount of information that one
image contains about the other. The MMI registration criterion postulates that MI
is maximal when the images are correctly aligned. MMI has been demonstrated
to be a very general and powerful criterion, that can be applied automatically
and very reliably, without prior segmentation or pre-processing, on a large variety
of applications. This makes the method highly suited for routine use in clinical
practice. In this text, which is a largely based on [21], we focus on the application
of MMI for global affine registration of three-dimensional (3-D) medical image
volumes. MMI has also been applied for other registration problems, such as non-
rigid image matching, 2D/3D image registration and registration of models to
images, or registration in other contexts, such as microscopy, histology, remote
sensing or computer vision.
Images acquired by different scanners or at different time points are usually acquired
independently. Unless specific provisions were made prior to acquisition (e.g. the
use of a stereotactic reference frame), their relative position is generally unknown
and a retrospective registration procedure is required that recovers the registration
transformation from the image content itself. Even when the images are acquired in
the same session without the patient leaving the scanner and can be assumed to be
registered by acquisition, explicit image registration may be required to correct for
inter-scan patient or organ motion. Image registration may be performed manually
by letting a human expert interactively displace one image relative to another,
based on geometric clues provided by anatomical landmarks visible in each of
the images and assisted by visualization software that supplies visual feedback
of image alignment. While such subjective approach may be sufficient to support
clinical decisions in some applications, a more formal and objective registration
measure is required to provide a reliable registration solution in case registration
clues are uncertain or inconsistent. Moreover, for the registration tool to be useful
and successful in clinical practice, automating the registration process as much as
possible is important to minimize the effort and time required by the user.
In many applications, local non-rigid tissue deformations are negligible or
irrelevant and the geometric relationship between the images to be registered
can be modeled by a rigid or affine linear transformation, composed of a 3-D
translation and rotation and possibly also 3-D scaling and skew. The registration
problem then consists of determining the 6 or 12 parameters of the rigid or affine
geometrical transformation that correctly aligns both images. In other applications
it may be needed to correct for local non-rigid image distortions, for instance to
Image registration using mutual information 297
The relationship pAB .a; b/ between a and b and hence their mutual information
I.A; B/ depends on T˛ , i.e. on the registration of the images. The mutual informa-
tion registration criterion postulates that the images are geometrically aligned by the
transformation T˛ for which I.A; B/ is maximal:
4 Implementation
The MMI registration criterion does not require any preprocessing or segmentation
of the images. With each of the images is associated a 3-D coordinate frame in
millimeter units, that takes the pixel size, inter-slice distance and the orientation
of the image axes relative to the patient into account. One of the images to be
registered is selected to be the floating image F from which samples s 2 S are
taken and transformed by the geometric transformation T˛ with parameters ˛ into
the reference image R. S may include all voxels in F or a subset thereof to increase
speed performance.
The MMI method requires the estimation of the joint probability density p.f; r/
of corresponding voxel intensities f and r in the floating and reference image
respectively. This can be obtained from the joint intensity histogram of the region of
overlap of the images. The joint image intensity histogram h˛ .f; r/ of the volume
of overlap s 2 S˛ S of F and R can be constructed by simple binning of the
image intensity pairs .f .s/; r.T˛ .s// for all s 2 S˛ . In order to do this efficiently,
the floating and the reference image intensities are first linearly rescaled to the range
Œ0; nF 1 and Œ0; nR 1 respectively, with nF and nR the number of bins assigned
to the floating and reference image respectively and nF nR being the total number
300 F. Maes et al.
of bins in the joint histogram. Estimations for the marginal and joint image intensity
distributions pF ;˛ .f /, pR;˛ .r/ and pF R;˛ .f; r/ are obtained by normalization of
h˛ .f; r/
h˛ .f; r/
pF R;˛ .f; r/ D P (2)
f;r h˛ .f; r/
X
pF ;˛ .f / D pF R;˛ .f; r/ (3)
r
X
pR;˛ .r/ D pF R;˛ .f; r/ (4)
f
Typically, nF and nR need to be chosen much smaller than the number of differ-
ent values in the original images in order to assure a sufficient number of counts in
each bin. If not, the joint histogram hF R;˛ would be rather sparse with many zero
entries and entries that contain only one or a few counts, such that a small change
in the registration parameters ˛ would lead to many discontinuous changes in the
joint histogram, with non-zero entries becoming zero and vice versa, that propagate
into pF R;˛ . Such abrupt changes in pF R;˛ induce discontinuities and many local
maxima in I.˛/, which deteriorates optimization robustness of the MI measure.
Appropriate values for nF and nR can only be determined by experimentation.
Moreover, T˛ .s/ will in general not coincide with a grid point of R, such that
interpolation of the reference image is needed to obtain the image intensity value
r.T˛ .s//. Zeroth order or nearest neighbor interpolation of R is most efficient,
but is insensitive to translations up to 1 voxel and therefore insufficient to guarantee
subvoxel accuracy. But even when higher order interpolation methods are used, such
as linear, cubic or B-spline interpolation, simple binning of the interpolated intensity
pairs .f .s/; r.T˛ s// leads to discontinuous changes in the joint intensity probability
pF R;˛ .f; r/ and in the marginal probability pR;˛ .r/ for small variations of ˛ when
the interpolated values r.T˛ s/ fall in a different bin. Note that post-processing the
histogram obtained by binning by convolution with a Gaussian or other smoothing
kernel is not sufficient to eliminate these discontinuities.
To avoid the problem of discontinuities induced by intensity binning, two
different solutions have been proposed. The first one involves the use of the Parzen
windowing technique (PW) to estimate the joint probability density p.f; r/ as a
sum of continuous and differentiable kernel functions k.f fi ; r ri / centered
around each interpolated
P voxel sample pair .fi ; ri / and satisfying the partitioning of
unity constraint f;r k.f fi ; r ri / D 1; 8fi ; ri . The function k distributes the
contribution of each sample i over multiple adjacent histogram bins .f; r/, hence
smoothing the histogram and making it a continuous function of the registration
Image registration using mutual information 301
parameters ˛. Different kernel functions can be used for this purpose, such as
linear [18], Gaussian [42] or B-spline [39] functions. An alternative approach
to update the joint histogram in a continuous way for each voxel pair .s; T˛ s/
was proposed in [1, 2, 19]. Instead of interpolating new intensity values in R,
This method, termed partial volume distribution interpolation (PV), distributes the
contribution to the joint histogram of the sample s with intensity f .s/ in F over
the intensity values r of the nearest neighbors of T˛ s on the 3-D grid of R, using
the same weights as for trilinear [19] or higher order [1] interpolation. Each entry
in the joint histogram is then the sum of smoothly varying fractions of 1, such
that the histogram changes smoothly as ˛ is varied. PV interpolation results in a
continuous and a.e. differentiable registration criterion with typically a large basin
of attraction around the correct optimum [19]. However, in case the images to be
registered have identical voxel grids or if their voxel sizes are multiples of each other
in one or more dimensions, PV interpolation may introduce local optima in the MI
measure at grid aligning registration positions [18, 28, 40]. These may deteriorate
registration accuracy in case the true registration solution differs little from a grid-
aligning position, such as when using image registration to recover subvoxel small
displacements for motion correction in dynamic image sequences.
The optimal registration parameters ˛ are found by maximization of I.˛/ for
which different local optimization schemes can be applied, including heuristic
search [36], Powell’s method [19], simplex search [20, 24], gradient descent [39]
or other gradient based optimization methods [20], as well as global optimization
methods [11]. The gradient of MI w.r.t. the registration parameters can be evaluated
numerically using a finite difference scheme as in [33], while analytical expressions
for the gradient of MI w.r.t. the registration parameters have been derived for
PW interpolation in [23, 39] and for PV interpolation in [20]. For high resolution
images subsampling of the floating image can be applied without deteriorating
optimization robustness of the MMI registration criterion [20, 29]. Important speed-
ups can thus be realized by using a multiresolution optimization strategy, starting
with a coarsely sampled image for efficiency and increasing the resolution as the
optimization proceeds for accuracy [36, 39]. Multiple multiresolution strategies,
involving different subsampling factors and number of resolution levels and using
various optimization methods, were compared in [20] for affine and in [15] for non-
rigid registration. A stochastic iterative gradient-based optimization method was
used in [14], estimating the gradient of MI at each iteration from only a small subset
of voxel pairs randomly sampled from the images.
The robustness of the MMI registration algorithm was established in various studies
with respect to implementation issues such as sampling [19, 29, 36], interpola-
tion [19, 26, 28, 39], initial positioning of the images [35, 36] and optimization
302 F. Maes et al.
strategy [20, 39], as well as with respect to partial overlap of the images [36]
and image degradations such as noise, intensity inhomogeneity or geometric
distortion [19].
The accuracy of the MMI registration algorithm has been validated for registra-
tion of CT, MR and PET brain images within the framework of the Retrospective
Registration Evaluation Project (RREP) conducted by Fitzpatrick et al. at Vanderbilt
University [12] and reported in West et al. [44, 45, 46], using as gold standard a
prospective, marker-based registration method. To ensure blindness of the study, the
frame and the fiducial markers were removed from the images by manual editing
prior to retrospective image registration. The transformation differences between
the reference and the submitted transformations were evaluated at different sites
within the brain and the median and maximal error over all sites and all patients
were recorded for each method that participated in the study. The RREP evaluation
showed that the MMI approach achieves subvoxel registration accuracy for both
CT/MR as well as PET/MR registration and performs better than the other methods
in the study, although the number of registration experiments performed was too
small to draw statistically significant conclusions. This was confirmed in other
studies, such as [34].
Because of its reliability and generality and because of its full automation, image
registration by MMI has large potential for routine use in clinical practice in a
variety of applications, involving various organs and imaging modalities (see Fig. 1).
For an extensive survey of MMI registration applications we refer to [30].
6 Discussion
Mutual information does not rely on the intensity values directly to measure
correspondence between different images, but on their relative occurrence in each
of the images separately and co-occurrence in both images combined. As such it
is insensitive to intensity permutations or one-to-one intensity transformations and
is capable of handling positive and negative intensity correlations simultaneously.
Unlike other voxel-based registration criteria, the MI criterion does not make
limiting assumptions about the nature of the relationship between the image
intensities of corresponding voxels in the different modalities, which is highly data
dependent, and does not impose constraints on the image content of the modalities
involved. This explains the success of MMI for multimodal image registration in a
wide range of applications involving various modality combinations, while also for
unimodal registration applications MMI is often preferred [10].
Nevertheless, there are cases in which MMI fails as a registration criterion. Such
failures occur due to insufficient mutual information in the images, ambiguity about
the intensity relationship between both images if this is not spatially invariant, or
inability to reliably estimate MI if the number of image samples is small. The
fundamental assumption of MMI based registration that image intensities in both
images are related to corresponding objects that should be aligned by registration,
Image registration using mutual information 303
Fig. 1 Global affine registration using MMI of CT (top) and MR images (bottom) of the prostate
used for radiotherapy planning. The central part of either image has been shown in overlay over
the other for visual inspection. The CT image is needed for estimating the dose distribution, while
the target volume and organs at risk can be more accurately delineated in the corresponding MR
image. Registration of both images allows to transfer the MR contours into the CT volume, such
that the complementary information of both scans can be combined during planning. Despite the
presence of large local non-rigid deformations of soft tissues such as skin, fat and muscles, the
MMI criterion succeeds at aligning corresponding rigid bony structures in the two images. The
registration can be locally refined if needed by defining a suitable region of interest around the
prostate
304 F. Maes et al.
may be invalid if the information in both images is very different, such as anatomical
information from CT with functional information from PET in non-brain regions
such as the thorax [41]. Because MI is computed from the joint intensity probability
of both images that is estimated by pooling contributions from everywhere in the
image domain, the MMI criterion implicitly assumes that the statistical relationship
between corresponding voxel intensities is identical over the whole area of overlap.
However, the photometric relationship between two multimodal images of the same
scene may not be spatially invariant, for instance if one of the images suffers from
severe intensity inhomogeneity. Also, the MMI registration criterion assumes that
the joint probability distribution of corresponding voxel intensities can be estimated
reliably around the registration solution. In practice, this requires the volume of
overlap at registration to contain a sufficiently large number of voxels. For low
resolution images or if the region of overlap is small, the statistical relationship
between both images needs to be derived from a small number of samples, which is
not robust. In these cases, the computed MI may show multiple local optima around
the correct registration solution or the registered position may not coincide with a
local maximum of MI [29, 38].
Several adaptations of the MI measure have been proposed in order to increase
registration robustness in cases where the joint intensity histogram by itself is
insufficient, such as including gradient information in the registration measure [27],
the use of higher-order mutual information to explicitly take the dependence
of neighboring voxel intensities into account [32], or incorporating additional
information channels with region labeling information in the mutual information
criterion [6, 37].
While 3D affine image registration using MMI is well established and already
used in routine clinical practice, extension of the MMI criterion to non-rigid image
registration is still subject of research. Non-rigid registration involves finding a 3-D
deformation field that maps each point in one image onto the corresponding point
in the other image, displacing each voxel individually to correct for local distortions
between both images up to voxel scale. Regularization of the deformation field is
required to constrain the registration solution space to include only deformation
fields that are physically acceptable and to smoothly extrapolate the registration
solution from sites with salient registration features (e.g. object boundaries) towards
regions where registration clues are absent or ambiguous (e.g. regions with homo-
geneous intensity). Various approaches for multimodal non-rigid image registration
using MMI have been proposed that differ in their regularization of the deformation
field, e.g. using thin plate splines [24] or B-splines [14, 17, 33], elastic [7] or
viscous fluid [5] deformation models. Another distinction can be made regarding the
way the variation of MI with changes in the deformation parameters is computed,
namely globally over the entire image domain [14, 33] or locally within subregions
only [16, 17].
Image registration using mutual information 305
7 Conclusion
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1 Introduction
2.1 Background
The finite element method is a numerical analysis technique for obtaining approx-
imate solutions to a wide variety of engineering problems [29]. The key to this
method is that the domain of problem is divided into small areas or volumes called
elements. The problem is then discretized on an element by element basis and the
resulting equations assembled to form the global solution.
An Example Problem: In this section, we describe an example problem and
outline a possible solution using FEM in an energy minimization framework.
The goal is to estimate a displacement field, u(x, y, z), that is the optimal trade
off between an internal energy function, W(u),1 and an approximating noisy
displacement field, um (x, y, z).
1
Note that although W is defined as function of the strain, e, as e is a function of the displacement,
u, W can also be written as a function of the displacement field, u.
312 P. Yang et al.
We define the optimal solution displacement field, u, as the one that minimizes
functional P(u) in a weighted least squares sense:
Z
P .u/ D .W .u/ C V .u; um // d .vol/
vol
W .u/ D e.u/t C e.u/
V .u; um / D ˛ .um u/ 2
W(u) can be defined using a strain energy function as W D et Ce, where e is local
tissue strain and C, the material stiffness matrix, is a function of the displacement
field (u), spatial position (m), and the tissue’s material properties-Young’s modulus
(E) and Poisson’s Ratio (). V (u, um ) is the external energy term, based on um , an
original displacement estimate, and ˛, the confidence in the match. We will focus
here primarily on the first term, W(u).
Outline of the Solution Procedure:
Step 1: Divide Volume into elements (tetrahedra or hexahedra) to provide the basis
functions for the discretization.
Step 2: Discretize the problem by approximating the displacement field in each
element as a linear combination of displacements at the nodes of each P element.
For a hexahedral element, this discretization can be expressed as: u Ð 81D1 Ni ui ;
where Ni is the interpolation shape function for node i and ui is the displacement at
node i of the element.
Step 3: Write the internal energy equation as the sum of the internal energy for each
element, vel :
X Z
@u X 8
@ .Ni ui / X @Ni
8
D D ui
@xk i D1
@xk i D1
@xk
@u
The derivatives of the displacement field, u, (i.e. @x k
) are linear functions of
the nodal displacements, ui . Since the infinitesimal strain tensor consists of only
sums and differences of partial derivatives, this tensor can also be expressed as a
linear function of the nodal displacements by e D Bu. (See Bathe [7] for nonlinear
extensions of the finite strain deformation case.) Substituting this into equation (1)
yields:
Physical Model Based Recovery of Displacement and Deformations from 3D. . . 313
X Z
X
W .u/ D U et
B CBd .el / U e D
t
U et ŒK e U e
all elements el all elements
where I is the re-indexing function, which takes element Kije and adds it to the
element Kkl , where k and l are the global node numbers of local nodes i and j.2
The internal energy can now be written as W(U ) D U t KU.
Applying External Data Constraints: The rest of the process involves the formula-
tion of the external energy term, which is problem specific. Let’s assume for now
that this term can be posed in quadratic form as V(U ) D (Um U)t A(Um U ).
Once this is in place, the sum of W(U) C V(U) can be minimized, by differentiation
with respect to U, and set to zero. This results in the final equation:
KU D A.AU m U / (3)
Equation (3) can be solved for U using sparse matrix methods.3 Since U represents
the values of u at each node, we can compute the resulting values of the displacement
field u anywhere in the volume by means of the finite element approximation .u
P 8
i D1 Ni ui /.
2
Within an element, the nodes are always numbered from 1 to 8. However this is a local index
(short-hand) to the global node numbers. When the global matrix is assembled, the local indices
(1 to 8) need to be converted back to the global indices (e.g. 1 to n). Ke has dimensions 24 24
and K has dimensions 3n 3n. K14 e
, which is the stiffness between the x-directions of local nodes
1 and 2 would be part of Kkl where k D 3(a 1) C 1 and a is the global index of local node 1 and
l D 3(b 1) C 1, where b is the global index of local node 2. Since nodes appear in more than one
element the final value of Kkl is likely to be the sum of a number of local Kije ’s.
3
In the case of finite deformations, we end up with an expression of the form K(U) D A(Um U)
which is solved iteratively.
314 P. Yang et al.
Fig. 1 Left: The brain and skull are extracted from the preoperative MRI, serving as inputs, along
with the deformed cortical surface, to the FEM volume calculation. The FEM result is the deformed
position of every brain mesh node. This mesh is then resampled into the original image space to
yield a simulated “intraoperative” MRI. The red arrow indicates the region of greatest deformation.
Right: Sample brain mesh with surface node labels. (See Sect. 2.3)
Our approach to brain shift compensation, outlined on the left side of Fig. 1,
employs a 3D biomechanical brain model guided by sparse intraoperative data. The
intraoperative data is acquired by stereo camera images and consists of cortical
surface intensities and features (sulci). We use a game theoretic framework to
overcome the resolution issues associated with stereo imaging and predict the
cortical deformation. The application of this method requires discretizing the
preoperative brain into small elements (right side of Fig. 1) and applying the finite
element method (Sect. 2.2) to determine each element’s displacement.
Image-based Displacement Estimates: In order to obtain accurate quantitative
information from stereo cameras, as with any imaging system, calibration is usually
necessary. However, in many real world situations, accurate calibrations are not
possible [34]. This is especially true in the operating room, where extreme time
and space constraints limit the calibration procedure possibilities. (See [52] for
calibration methods and the use of calibration parameters to project 3D points onto
images.) The resulting inaccurate camera calibrations decrease image resolution and
compound the difficulty of image-derived deformation estimation.
Therefore, in order to track the deforming cortical surface, a framework with
the ability to solve for competing variables (surface displacement field/accurate
camera calibration parameters) is needed. Game theory, the study of multiperson
decision making in a competitive environment [6, 36], can provide this framework.
In a game theoretic formulation, the players are computational modules. In the
context of intraoperative neurosurgical guidance, the players would be 1) Udns ,
the dense displacement field applied to the preoperative cortical surface and 2)
A D ŒA0 ; A1 , the camera calibration parameters for the left (0) and right (1)
Physical Model Based Recovery of Displacement and Deformations from 3D. . . 315
stereo cameras. This analysis therefore updates surface displacement and calibration
parameter estimates at every iteration.
The model for determining these variables, expressed in a game theoretic
formulation is:
C1 Udns ; A D TU Udns C ˛ TF Udns ; A C TI Udns ; A (4)
„ ƒ‚ … „ ƒ‚ … „ ƒ‚ …
smoothness constraint feature matching intensity correlation
C2 Udns ; A D TA .A/ C ˇ TC Udns ; A (5)
„ ƒ‚ … „ ƒ‚ …
fiducial matching reconstructed sulci matching
where C1 , C2 are the cost functions for the dense displacement field and camera
calibration parameters, respectively. These cost functions can be iteratively mini-
mized until they reach equilibrium, representing the algorithm solution [11]. The
constants in these functions, ˛ and ˇ, are chosen using game theoretic constructs
for noncooperative games, in which collusion between players is prevented and the
players can pursue their own interests, which may conflict [6, 11]. The other terms
are presented below.
Displacement Field Determination: The intensity correlation term matches the
stereo image intensities that are backprojected onto the exposed brain surface.
A backprojected image (Fig. 2D) is defined as BiS D Ii .P .Ai ; x//8x 2 S , where S
is the deformed surface, I is an intraoperative stereo image, P is a standard camera
projection function from the surface to the images and i represents the camera
number (0 or 1). This term can be written as TI .Udns ; A/ D NC C B0S ; B1S where
NCC is the normalized cross correlation and is a normalizing constant, ensuring
that all terms have similar orders of magnitude.
A feature matching term measures the distance between 3D sulci on the cortical
surface, C; which are projected into the stereo images, and the intraoperative sulci
outlined in those images, K D ŒK0 ; K1 . The imaged sulci are manually extracted
by an expert user and stored as 2D curves. This term can be expressed by:
Z h i
TF Udns ; A D d K0 ; P A0 ; C C UCdns dS
Z h i
C d K1 ; P A1 ; C C Udns
C
dS ;
where UCdns is the dense displacement field restricted to the sulci and d is a mean
Euclidean distance metric. R
A prior term, TU .Udns / D e kUdns"
kdS, where is a normalizing constant and
"
Udns is the second derivative of the dense displacement field, ensures deformation
smoothness.
316 P. Yang et al.
where B is the entire brain, consisting of all nodes in the brain volume (V) and on
the surface (S) and W (u, m, E, ) is defined in Sect. 2.2.
Equation (6) is subject to three constraints: (1) The first constraint forces the
displacements of the intraoperatively exposed cortical nodes, u.Sic /, in the region
of the
ccraniotomy,
Sc , to exactly equal
the game theoretic results at those nodes,
Udns si . It can be written as u sic D Udns sic ; 8sic 2 S c . Due to this exact
matching, the external energy term of equation (1) is not used. (2) The second
constraint k .sku C u.sku //; rj k > ı; 8sku 2 S u ; rj 2 R, ensures that all nodes
on the brain surface remain some small distance away from the skull (except in
the craniotomy region). Here, sku are brain surface nodes in the region not exposed
during surgery, Su, rj are nodes on the rigid skull surface, R, and ı is an arbitrarily
small constant. Due to the surface connectivity, this constraint also prevents any
nodes from crossing the skull boundary, as this would force other surface nodes
to violate this condition. Rather than forcing some surface nodes to be fixed, this
Physical Model Based Recovery of Displacement and Deformations from 3D. . . 317
Fig. 2 Mean (A) and maximum (B) displacement and algorithm error (˛ D 4, ˇ D 0.83, D 0.1,
D 25). In (C), intraoperative images of Data Set #2 show the misalignment of projected
preoperative sulci (green) with intraoperative sulci positions (black) due to brain shift and camera
calibration errors. Predicted sulci positions, projected with the updated calibration parameters
(yellow), show better alignment. Backprojected intensities (D) are found by projecting each point
on the surface to the left (left column) or right (right column) image and assigning the associated
image intensity value to that point. Red arrows indicate the misalignment between the sulci on the
preoperative surface (green) and those seen in the backprojected image. Sulci on the algorithm-
predicted surface (yellow) are better aligned with the image intensities
model more realistically constrains the anatomy. (3) Finally, the third constraint,
f f f
u.sl / D 0; 8sl 2 S f ; states that the model deformation of the fixed nodes, sl ;
f
within the fixed region, S ; must be zero. The fixed surface region is at the base
of the brain in the inferior occipital lobes. Due to the tough tentorium cerebelli, as
well as their distance from the craniotomy site, these nodes will not move during
surgery. (See right side of Fig. 1.)
The constrained minimization was performed using the finite element analysis
software package ABAQUS (ABAQUS, Inc., Providence, RI). The model inputs
were a tetrahedral brain mesh (created using the automated algorithm suggested in
Stokking [50]), a manually-outlined surface representing the surrounding skull (with
craniotomy), Young’s modulus (66.7 kPa) and Poisson’s ratio (0.48) of brain [30].
The finite element analysis output is the displacement of all brain mesh nodes, which
can be resampled into image space using trilinear interpolation.
Game theoretic cortical surface tracking was used in five separate surgeries for a
total of eight data sets. The algorithm results for all cases are shown in Figs. 2A & B.
In Fig. 2A, the blue bars represent the calculated mean average displacement of the
cortical surface as predicted by the game theoretic algorithm. Mean residual error
of the algorithm (red bars) is calculated by averaging the closest distances between
the predicted surface and sparse cortical surface points touched with a 3D locator
intraoperatively.
Five out of eight of the cases (62.5 %) resulted in a mean algorithm error of less
than 1.0 mm, and the mean error never exceeded 1.70 mm, representing an 81 %
improvement over uncompensated error. Also, for half the cases, the maximum error
was under 1.6 mm (Fig. 2B), representing a 76 % decrease in the maximum errors
318 P. Yang et al.
Fig. 3 A) A slice of the preoperative MRI (left), deformed using either a fixed surface (middle) or
a skull constraint (right). Red and yellow spheres indicate intraoperatively acquired surface points.
The aqua arrow is in the same location on each image. B) One slice of the preoperative (right) and
predicted intraoperative initial (middle) and final (left) MR image. The spheres were acquired by
the neurosurgeon either 2 (red) or 3.25 (yellow) hours into surgery. C) Volume Renderings of the
images in (B)
using the model guidance. Thus, for all eight cases, every part of the surface was
found more accurately using the game theoretic algorithm then by relying on the
preoperative surface. Figures 2C & D illustrate these results using images from a
typical sample case, Data Set #2.
These surface results were then used in conjunction with the biomechanical
model to obtain volumetric deformation. As mentioned above, rather than artificially
fixing the non-exposed surface nodes, the rigid skull was used to constrain the
surface deformation (constraint #2). Figure 3A illustrates this effect on a case
in which a bilateral craniotomy was performed. For this patient, the surface
deformation for each side of the brain was calculated separately, using data sets
2 (left side of brain) and 3 (right side of brain) from Fig. 2, and the modeled
skull contained two craniotomy sections. With a fixed surface, the nodes near the
craniotomy cannot move, even when the deformation becomes large. This effect is
most obvious in the region indicated by the aqua arrow, which is located in the same
relative position on all three images. The deformation decreases sharply to zero
outside the craniotomy region when the surface nodes are fixed. However, when
constrained by the skull, the region indicated by the aqua arrow is allowed to deform
inward as well, resulting in a more natural deformation.
To validate model consistency, volumetric deformation was also calculated for
two data sets (4 & 5) from the same surgery. Figures 3B & C show the calculated
downward surface shift, which is propagated through the volume.
3.1 Background
Acute coronary artery occlusion results in myocardial injury, which will progress
from the endocardium to the epicardium of the heart wall in a wavefront fashion.
A primary goal in the treatment of patients presenting with acute myocardial
Physical Model Based Recovery of Displacement and Deformations from 3D. . . 319
The H and G are the fundamental matrices for the boundary nodes and they are
defined by the elastic material property and shape information. The detail definition
of the H and G can be found in [8]. The displacement at any point can be derived
from known boundary displacements U (qj ) and tractions P (qj ):
X
J
u .ai / D b qj HO U qj
GP (8)
j D1
first consider one data point ai in A. Here we denote the measured displacement
associating with the point ai as uQ .ai /. For
the displacement at the point ai to take on
the value uQ .ai /, the displacements UQ i qj at the boundary nodes must satisfy:
X
J
uQ .ai / D Cij UQ i qj (9)
j D1
where C D GG b 1 H HO . There are many values of U b i qj that are solutions to
Eq. (9). Here we choose the solution in the least-squared sense such that:
0 1
X
J
UQ i .q/ D arg min @ UQ i2 qj A (10)
j D1
Simple linear algebra using the pseudoinverse is used to derive the solution [28]:
0 1
X
J
UQ i .q/ D Cij uQ .ai / = @ Cij2 A (11)
j D1
Now we consider all the data points in A. Here we choose the displacements
U(q) of boundary nodes to minimize the sum of squared differences between the
displacements u(ai ) and uQ .ai / of all the points in the point-set A, such as:
!
X
I
2
U.q/ D arg min i k u .ai / uQ .ai / k (12)
i D1
where i is the weight based on the confidence in the uQ .ai / Then we get:
! !
X
I X
I
U.q/ D i Cij2 UQ i .q/ = i Cij2 (13)
i D1 i D1
Once we know the displacements of all the boundary nodes, the displacements of
any point gl in the dense point-set G can be calculated by:
X
J
U .gl / D Clj U qj (14)
j D1
322 P. Yang et al.
The GRPM extends the Robust Point Matching (RPM) framework [13] to use a
more general metric form that includes curvature information [32]. In particular,
the use of shape information is embedded to guide more precise motion recovery
and points that are mistaken as features or unmatched real feature points are
automatically treated as outliers by the GRPM algorithm during the optimization
annealing process. The objective function of GRPM is:
X
I X
K
E.M / D mi k Œk f .ai / bk k2 C A g.k A .ai / B .bk /k2 /
i D1 kD1
X
I X
K
C k L f k2 C T mi k logmi k
i D1 kD1
X
I X
K
C T0 mi;KC1 log mi;KC1 C T0 mI C1;k logmI C1;k (15)
i D1 kD1
Figure 5 shows the design strategy: 1. Segmentation at the first frame; 2. Extracting
the feature points; 3. Calculating the curvature associated with each feature point;
4. Calculating the surface mesh at the next time frame using the BEM-GRPM; 5. If
the last time frame is reached, stop. Otherwise, repeat the step 4; 6. Calculating the
dense displacement fields; 7. Calculating the strains.
Following steps summarize the scheme of BEM-GRPM framework:
Step 1: Estimate the correspondence matrix M between the points aj and bk The
correspondence matrix M is calculated:
I C1
kf .ai /bk k2 CA g.kA .ai /B .bk /k2 X X
KC1
1
mi k D p e T ; mi k D1; and mi k D1
2T 2
i D1 kD1
(16)
We denote the outlier clusters as aN C1 and bK C1 .
Physical Model Based Recovery of Displacement and Deformations from 3D. . . 323
2 3 Distance
Dense displacement
fields
Curvature
T<Threshold
5
4
Extracted feature points
BEM-GRPM 6
Algorithm
T>=Threshold
7
Segmentation
1
at the first
frame
Elastic
parameters of
myocardium
BEM-based
Radial Circumferential
regularization model
Strains Strains
X
K X
K X
K
b
bi D m i k bk = m i k ; i D mi k (17)
kD1 kD1 kD1
X
I 2
b
f D arg min i f .ai / b i (18)
f i D1
Fig. 6 A 2D slice of 3D radial strains Err (top) and circumferential strains Ecc (bottom) derived
from an in-vivo cardiac MRI data (ED ! ES). Positive values represent thickening and negative
values for shortening. Figure reprinted from [53], ©2007 by permission from Elsevier
We first present the experimental results using the shape-based tracking system.
The key practical application includes the estimation of left ventricular deformation
from 3D C t MR and echocardiographic images. The results from MR images were
compared to displacements found using implanted markers.
Experiments on 3D Canine MR images We test the BEM-GRPM algorithm on
3D cardiac MRI data from the baseline MR images (without post-occlusion) [40].
The node number of the BEM mesh is set to be 20 15 (, z). We track the
myocardium frame-by-frame along the image sequence (from end-diastole (ED) to
end-systole (ES)). The feature points are extracted by using thresholded curvature
in this experiment because MRI has good image quality. The coordinates and the
curvature value of the feature points are normalized in the beginning. We set the
starting temperature T as 4 pixels. In the annealing process, we gradually reduce it
by an annealing rate of 0.9. For each dataset, strains are calculated between end-
diastole (ED) and end-systole (ES). A 2D slice of the 3D-derived radial strains (Err )
and circumferential strains (Ecc ) of one dataset are illustrated in Fig. 6. Note the
normal behavior in the LV, showing positive radial strain (thickening) and negative
circumferential strain (shortening) as we move from ED to ES.
To quantitatively validate the resulting motion trajectories, we use four canine
MRI datasets with implanted markers for point-by-point displacement comparison
(see [42] for more details on the marker implantation and localization). The
mean displacement errors of BEM-GRPM for the four datasets are calculated and
compared to the errors of EFFD-GRPM [32] which uses Extended Free Form
Deformation (EFFD) as the regularization model with the GRPM. The displacement
errors of BEM-GRPM are less than those of EFFD-GRPM as shown in Fig. 7.
Physical Model Based Recovery of Displacement and Deformations from 3D. . . 325
Fig. 7 Absolute
displacement error vs.
implanted markers. The errors
are estimated between ED to
ES for 4 canine MR image
datasets. Blue: the error of
BEM-GRPM; Red: the error
of EFFD-GRPM. Figure
reprinted from [53], ©2007
by permission from Elsevier
Fig. 8 Radial strains Err (top) and circumferential strains Ecc (bottom) derived from a contrast-
enhanced echocardiographic images (ED ! ES). Positive values represent thickening and negative
values for shortening. Figure reprinted from [53], ©2007 by permission from Elsevier
4 Concluding Remarks
We have presented two distinct application areas where biomechanical models are
used to recover information from image sequences ....
326 P. Yang et al.
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Graph-based Deformable Image Registration
The first two authors contributed equally to this work.
A. Sotiras () • C. Davatzikos
Section of Biomedical Image Analysis, Center for Biomedical Image Computing and Analytics,
University of Pennsylvania, Philadelphia, USA
e-mail: [email protected]; [email protected]
Y. Ou
Athinoula A. Martinos Center for Medical Imaging, Massachusetts General Hospital,
Harvard Medical School, Boston, USA
e-mail: [email protected]
N. Paragios
Center for Visual Computing, Department of Applied Mathematics,
Ecole Centrale Paris, Paris, France
e-mail: [email protected]
1 Introduction
In this chapter, we focus on pairwise deformable registration. The two images are
usually termed as source (or moving) and target (or fixed) images, respectively. The
source image is denoted by S W S Rd 7! R, while the target image by T W T
Rd 7! R, d D f2; 3g. S and T denote the image domain for the source and target
images, respectively. The source image undergoes a transformation T W S 7! T .
336 A. Sotiras et al.
Image registration aims to estimate the transformation T such that the two
images get aligned. This is typically achieved by means of an energy minimization
problem:
In discrete optimization settings, the variables take discrete values and the optimiza-
tion is formulated as a discrete labeling problem where one searches to assign a label
to each variable such that the objective function is minimized. Such problems can
be elegantly expressed in the language of discrete Markov Random Field theory.
An MRF is a probabilistic model that can be represented by an undirected graph
G D .V ; E /. The set of vertices V encodes the random variables, which take values
from a discrete set L . The interactions between the variables are encoded by the set
of edges E . The goal is to estimate the optimal label assignment by minimizing an
energy of the form:
X X
EMRF D Up .lp / C Ppq .lp ; lq /: (2)
p2V pq2E
The MRF energy also comprises two terms. The first term is the sum of all unary
potentials Up of the nodes p 2 V . This term typically corresponds to the data term
since the unary terms are usually used to encode data likelihoods. The second term
comprises the pairwise potentials Ppq modeled by the edges connecting nodes p
and q. The pairwise potentials usually act as regularizers penalizing disagreements
in the label assignment of tightly related variables.
Many algorithms have been proposed in order to perform inference in the
case of discrete MRFs. In the works that are presented in this chapter, the fast-
PD1 algorithm [39, 40] has been used to estimate the optimal labeling. The main
1
Fast-PD is available at http://cvc-komodakis.centrale-ponts.fr/.
Graph-based Deformable Image Registration 337
motivation behind this choice is its great computational efficiency. Moreover, the
fast-PD algorithm is appropriate since it can handle a wide-class of MRF models
allowing us to use different smoothness penalty functions and has good optimality
guarantees.
In the continuation of this section, we detail how deformable registration is for-
mulated in terms of Markov Random Fields. First, however, the discrete formulation
requires a decomposition of the continuous problem into discrete entities. This is
described below.
X
k
u.x/ D !i .x/di ; (3)
i D1
X
k
T .x/ D x C !i .x/di : (4)
i D1
points need to be sought. If we take them into consideration, the matching term (see
Eq. (1)) can be rewritten as:
k Z
1X
M .S ı T ; T / D !O i .x/ .S ı T .x/; T .x//d x; (5)
k i D1 S
where !O i are weighting functions similar to the ones in Eq. (4) and denotes a
similarity criterion.
Here, the weightings determine the influence or contribution of an image point x
onto the (local) matching term of individual control points. Only image points in the
vicinity of a control point are considered for the evaluation of the intensity-based
similarity measure with respect to the displacement of this particular control point.
This is in line with the local support that a control point has on the deformation.
The previous is valid when point-wise similarity criteria are considered. When a
criterion based on statistics or information theory is used, a different definition of
!O i is adopted,
(
1; if !i .x/ 0;
!O i .x/ D (6)
0 otherwise:
Thus, in both cases the criterion is evaluated on a patch. The only difference is
that the patch is weighted in the first case. These local evaluations enhance the
robustness of the algorithm to local intensity changes. Moreover, they allow for
computationally efficient schemes.
The regularization term of the deformable registration energy (Eq. (1)) can also
be expressed on the basis of the set of control points as:
k Z
1X
RD !O i .x/ .T .x//d x; (7)
k i D1 S
Having identified the discrete deformation elements of our problem, we need to map
them to MRF entities, i.e., the graph vertices, the edges, the set of labels, and the
potential functions.
Let Gico denote the graph that represents our problem. In this case, the random
variables of interest are the control point displacement updates. Thus, the set of
vertices Vico is used to encode them, i.e., jVico j D jDj D k. Moreover, assigning
Graph-based Deformable Image Registration 339
where Tico;lp denotes the transformation where a control point p has been updated
by lp . Region-based and statistical measures are again encoded in a similar way
based on a local evaluation of the similarity measure.
Conditional independence is assumed between the random variables. As a
consequence, the unary potential that constitutes the matching term can only be an
approximation to the real matching energy. That is because the image deformation,
and thus the local similarity measure, depends on more than one control point
since their influence areas do overlap. Still, the above approximation yields very
accurate registration as deomonstrated by the experimental validation results that
are reported in latter sections (Sect. 2.4, Sect. 3.3 and Sect. 4.3). Furthermore, it
allows an extremely efficient approximation scheme which can be easily adapted
for parallel architectures yielding extremely fast cost evaluations.
Actually, the previous approximation results in a weighted block matching strat-
egy encoded on the unary potentials. The smoothness of the transformation derives
from the explicit regularization constraints encoded by the pairwise potentials and
the implicit smoothness stemming from the interpolation strategy.
The evaluation of the unary potentials for a label l 2 Lico corresponding to
an update d can be efficiently performed as follows. First, a global translation
according to the update d is applied to the whole image, and then the unary
potentials for this label and for all control points are calculated simultaneously. This
results in an one pass through the image to calculate the cost and distribute the local
energies to the control points. The constrained transformation in the unary potentials
is then simply defined as Tico;lp .x/ D Tico .x/ C lp , where Tico .x/ is the current or
initial estimate of the transformation.
The regularization term defined in Eq. (7) could be defined as well in the above
manner. However, this is not very efficient since the penalties need to be computed
on the dense field for every variable and every label. If we consider an elastic-like
regularization, we can employ a very efficient discrete approximation of this term
based on pairwise potentials as:
The explicit control that one has over the creation of the label set L enables us to
impose desirable properties on the obtained solution without further modifying the
discrete registration model. Two interesting properties that can be easily enforced
by adapting appropriately the discrete solution space are diffeomorphisms and
symmetry. Both properties are of particular interest in medical imaging and have
been the focus of the work of many researchers.
Diffeomorphic transformations preserve topology and both they and their inverse
are differentiable. These transformations are of interest in the field of computational
neuroanatomy. Moreover, the resulting deformation fields are, in general, more
physically plausible since foldings, which would disrupt topology, are avoided.
As a consequence, many diffeomorphic registration algorithms have been proposed
[3, 5, 8, 68, 85].
In this discrete setting, it is straightforward to guarantee a diffeomorphic result
through the creation of the label set. By bounding the maximum sampled dis-
placement by 0:4 times the deformation grid spacing, the resulting deformation is
guaranteed to be diffeomorphic [68].
The majority of image registration algorithms are asymmetric. As a consequence,
when interchanging the order of input images, the registration algorithm does not
estimate the inverse transformation. This asymmetry introduces undesirable bias
upon any statistical analysis that follows registration because the registration result
depends on the choice of the target domain. Symmetric algorithms have been
proposed in order to tackle this shortcoming [5, 13, 56, 79, 84].
Symmetry can also be introduced in graph-based deformable registration in a
straightforward manner [77]. This is achieved by estimating two transformations,
T f and T b , that deform both the source and the target images towards a common
domain that is constrained to be equidistant from the two image domains. In order
for this to be true, the transformations, or equivalently the two update deformation
fields, should sum up to zero. If one assumes a transformation model that consists
of two isomoprhic deformation grids, this constraint translates to ensuring that the
displacement updates of corresponding control points in the two grips sum to zero
and can be simply mapped to discrete elements.
The satisfaction of the previous constraint can be easily guaranteed in a discrete
setting by appropriately constructing the label set. More specifically, by letting the
labels index pairs of displacement updates (one for each deformation field) that
f
sum to zero, i.e. lp
fdp ; dbp g. The extension of the unary terms is also
straightforward, while the pairwise potentials and the graph construction are the
same.
Fig. 2 a) In the first row, from left to right, the mean intensity image is depicted for the data set,
after the graph-based symmetric registration method and after [5]. In the second row, from left to
right, the target image is shown as well as a typical deformed image for the graph-based symmetric
registration method and [5]. For all cases, the central slice is depicted. b) Boxplots for the DICE
criterion initially, with the graph-based symmetric registration method and with [5]. On the left,
the results for the WM. On the right, the results for the GM. The figure is reprinted from [77]
(rotation only). The MR brain data set along with manual segmentations was
provided by the Center for Morphometric Analysis at Massachusetts General
Hospital and are available online2. The data set was rescaled and resampled so
that all images have a size equal to 256 256 128 and a physical resolution
of approximately 0:9375 0:9375 1:5000 mm.
This set of experiments is based on intensity-based similarity metrics (for results
using attribute-based similarity metrics, we refer the reader to the next section of this
chapter). The results are compared with a symmetric registration method based on
continuous optimization [5] that is considered to be the state of the art in continuous
deformable registration [38]. Both methods use Normalized Cross Correlation as
the similarity criterion.
A multiresolution scheme was used in order to harness the computational burden.
A three-level image pyramid was considered while a deformation grid of four
different resolutions was employed. The two finest grid resolutions operated on the
finest image resolution. The two coarsest operated on the respective coarse image
representations. The initial grid spacing was set to 40 mm resulting in a deformation
grid of size 7 7 6. The size of the gird was doubled at each finer resolution.
A number of 90 labels, 30 along each principal axis, were used. The maximum
displacement indexed by a label was bounded to 0.4 times the grid spacing. The
pairwise potentials were weighted by a factor of 0.1.
2
http://www.cma.mgh.harvard.edu/ibsr/data.html
Graph-based Deformable Image Registration 343
The qualitative results (sharp mean and deformed image) suggest that both
methods successfully registered the images to the template domain. The results
of [5] seem to have produced more aggressive deformation fields that have resulted
to some unrealistic deformations in the top of the brain and can also be observed
in the borders between white matter (WM) and gray matter (GM). This aggressive
registration has also resulted in slightly more increased DICE coefficients for WM
and GM. However, the results reported for the graph-based registration method were
obtained in 10 min. On the contrary, 1 hour was necessary to register the images
with [7] approximately. This important difference in the computational efficiency
between the two methods can outweigh the slight difference in the quality of the
solution in practice.
attribute vector at each voxel. This similarity ranged from 0 (when the attributes
between two voxels differed infinitely) and 1 (when the attributes between two
voxels were identical). This figure shows that, as one replaced the intensity-based
similarity to (optimal-)attribute-based similarities, even very ordinal voxels under
the blue crosses were distinctively characterized or better localized in the space,
therefore we only needed to search for their corresponding voxels within a much
smaller range in the target image, largely removing matching ambiguities.
Let us detail in the next section how one can introduce Gabor-based attributes in
the case of graph-based deformable registration [62]. More specifically, let us detail
how the Markov Random Field energy (see Eq. (2)) changed in this regard.
The ease with which one can adopt attribute-based similarity criteria in the case
of graph-based formulations for deformable registration is evidence of their high
versatility and modularity. The key elements of the graphical model (i.e., graph
Graph-based Deformable Image Registration 345
Fig. 3 The similarity maps between special/ordinary voxels (labeled by red/blue crosses) in
the source (a.k.a, subject) images and all voxels in the target (a.k.a, template) images. As
correspondences were sought based on voxel similarities (subject to spatial smoothness con-
straints), (optimal-)Gabor-attribute-based similarity maps returned a much smaller search range
for correspondences. This figure is reprinted from [62]
construction, pairwise potentials, inference) need not change. One only needs to
slightly change the definition of the unary potentials.
The unary potentials need only be modified in two regards: i) to evaluate the
similarity criterion over the attribute vectors A./; and ii) to optionally, as
suggested by [62], take into account a spatially-varying weighting parameter ms.x/,
namely “mutual-saliency”, which automatically quantified the confidence of each
voxel x to establish reliable correspondences across images. Therefore, the modified
unary potentials are defined as:
Z
Uico;p .lp / D ms.x/ !O p .x/ .AS ı Tico;lp .x/; AT .x// d x: (10)
S
346 A. Sotiras et al.
Fig. 4 The computational times (in minutes) when combing the MRF registration formulation
with the discrete optimization strategy versus with the traditional gradient descent optimiza-
tion strategy. The discrete optimization strategy on the MRF registration formulation helped
significantly reduce the computational time. AM refers to attribute matching; MS refers to
mutual-saliency weighting, which is a second component in DRAMMS but was not described
in full detail in this section; basically it is a automatically computed weighting for adaptively
utilizing voxels based on how much confidence we have for those voxels to find correspondences
across images. FFD is the free form deformation transformation model as used in the MRF
registration formulation. And DisOpt and GradDes are the discrete optimization and gradient
descent optimization strategies. This figure is reprinted from [62]
Fig. 5 The average Jaccard overlap among all ROIs in all possible pair-wise registrations within
the NIREP database, for different registration tools. Reprinted from [57]
3
DRAMMS is available at http://www.nitrc.org/projects/dramms/.
348 A. Sotiras et al.
Fig. 6 Example registration results between subjects in the multi-site Alzheimer’s Disease
Neuroimaging Initiative (ADNI) database, by different registration methods. Blue arrows point
out regions where the results from various registration methods differ. Reprinted from [57]
1X
n
Mgeo .K ı Tgeo ; ƒ/ D ı.Tgeo .i /; e
i / (11)
n i D1
where ı measures the Euclidean distance between two landmark positions, and
e
i D arg min .Tgeo .i /:j /: (12)
j
Note that the Euclidean position of the landmarks and is denoted in bold.
As far as the regularization term Rgeo is concerned, it aims to preserve the
smoothness of the transformation. More specifically, it aims to locally preserve the
geometric distance between pairs of landmarks:
1 Xn X
n
Rgeo .Tgeo / D k.Tgeo .i / Tgeo .j // .i j /k: (13)
n.n 1/ i D1
j D1; j 6Di
This implies the assumption that a linear registration step that has accounted for
differences in scales has been applied prior to the deformable registration.
An equivalent way of formulating the geometric registration problem consists of
first pairing landmarks 2 K with the most similar in appearance landmarks 2 ƒ
and then pruning the available pairs by keeping only those that are geometrically
consistent as quantified by the regularization term (Eq. (13)). Let us note that, in
both cases, the problem is inherently discrete.
As discussed in the introduction, there are various ways of integrating geometric and
iconic information. The most interesting, and potentially more accurate, is the one
that allows both problems to be solved at the same time through the optimization of
a universal energy that enforces the separate solutions to agree. This is possible by
combining the previous energy terms for the iconic and geometric problem along
with a hybrid term that acts upon the separate solutions:
1X
n
H .Tico ; Tgeo / D kTico .i / Tgeo .i /k: (14)
n i D1
Graph-based Deformable Image Registration 351
Note that we only need to enforce the agreement of the two solutions in the landmark
positions. If we now also consider a connection between control point displacements
D and landmark displacements, the previous relation can be rewritten as:
1X X
n k
H .Tico ; Tgeo / D ki C ugeo .i / i !j .i /dj k; (15)
n i D1 j D1
where ugeo .i / D ei i , i.e. the displacement for the correspondence of the two
e
landmarks i and i . As a principle, we would like this displacement to be ideally
equal to the one that is given as a linear combination of the displacements of the
control points at the position of a landmark. However, we can relax the previous
requirement in order to increase the computational efficiency of the method. If
we apply the triangular inequality and exploit the fact that the coefficients !j are
positive, the coupling constraint is redefined as:
1 XX
n k
H .Tico ; Tgeo / !j .i /kugeo .i / dj k: (16)
n i D1 j D1
Having identified the discrete elements for both geometric and hybrid registration,
let us map them to MRF entities.
The two different though equivalent ways to see the label assignment problem
are depicted in the previous equation. Assigning a label lp can be interpreted as
applying a transformation Tgeo;lp D p C ugeo;lp .p / or stating that the landmark p
corresponds to the lp . Contrary to the iconic case, the set of transformations that can
be applied is specified by the candidate landmarks and is sparse in its nature.
There is a number of ways to define the dissimilarity function %. One approach
would be to consider neighborhood information. That can be easily done by
evaluating the criterion over a patch centered around the landmarks,
Z
Ugeo;p .lp / D %.S ı Tgeo;lp .x/; T .x//d x; (18)
S;p
where S;p denotes a patch around the point p . Another approach is to exploit
attribute-based descriptors and mutual saliency [58] and define the potential as:
ms.p ; lp / si m.p ; lp /
Ugeo;p .lp / D exp : (19)
2 2
where is a scaling factor, estimated as the standard deviation of the mutual saliency
values of all the candidate pairs.
The regularization term defined in Eq. (13) can be encoded by the edge system
Egeo of the graph. In this setting, the regularization term can be expressed as:
In this case, the graph-based formulation will consist of the discrete model for
the iconic and geometric registration along with a coupling penalty (Eq. (16)).
Therefore, the graph that represents the problem comprises Gico and Ggeo along
with a third set of edges Ehyb containing all possible connections between the
iconic random variables and the geometric variables. The pairwise label assignment
penalty on these coupling edges is then defined as:
Phyb;pq .lp ; lq / D !q .p / ugeo;lp .p / .dq C lq / ; (21)
Graph-based Deformable Image Registration 353
Fig. 7 An example
landmark pair (denoted
by red and blue crosses)
detected based on the
Gabor response-based
similarity metric and the
mutual-saliency measure.
(a) Source and (b) target
images. This figure is
re-printed from [58]
where p 2 Vgeo and q 2 Vico , lp 2 Lgeo and lq 2 Lico , and .p; q/ 2 Ehyb . Such
a pairwise term couples the displacements given by the two registration processes
and imposes consistency. To conclude, the coupled registration objective function
is represented by an MRF graph Ghyb D .Vgeo [ Vico ; Egeo [ Eico [ Ehyb / with its
associated unary and pairwise potential functions. This model was presented in [76].
Figure 7 shows a typical landmark pair detected by Gabor response and matched by
the MRF formulation. Many such pairs found by the MRF formulation resulted in a
deformation that was smoother with the MRF regularization rather than without, as
can be seen in Fig. 8.
Table 1 End point error (in millimeters) for the registration of the Synthetic MR Dataset. The grid
spacing is denoted by h. This figure is reprinted from [25]
Iconic (h D 60 mm) Hybrid (h D 60 mm) Iconic (h D 20 mm) Hybrid (h D 20 mm)
# mean std mean std mean std mean std
1 1.33 0.69 1.25 0.59 1.38 1.21 0.98 0.61
2 1.32 0.75 1.18 0.53 2.46 3.21 1.06 0.68
3 1.44 0.97 1.22 0.56 2.05 2.40 1.03 0.67
4 1.40 0.74 1.16 0.50 1.40 1.02 1.08 0.69
5 1.23 0.60 1.15 0.56 1.38 1.01 1.03 0.67
6 1.35 0.74 1.24 0.62 1.58 1.39 1.05 0.71
7 1.16 0.56 1.09 0.50 1.45 1.18 1.05 0.67
8 1.29 0.68 1.23 0.58 1.93 2.61 1.11 0.79
9 1.23 0.62 1.19 0.53 1.72 1.89 1.04 0.71
10 1.54 1.08 1.19 0.58 2.60 3.43 1.05 0.73
all 1.33 0.11 1.19 0.05 1.79 0.45 1.05 0.03
of the registration performance regarding both the dense deformation field accuracy
and the quality of the established landmark correspondences.
The goal of this experiment is to demonstrate the added value from considering
geometric information on top of standard iconic one. Thus, a comparison of the
proposed framework with and without the geometric registration part takes place.
Regarding the results, if we look at the registration accuracy in terms of end point
error (Table 1), we see that the coupled iconic geometric registration method is able
to further improve the results of the iconic one. This is evident, as the end point error
has decreased by taking advantage of the geometric information.
As we expect the hybrid approach to be able to cope with large displacements
better than the pure iconic one, we repeated the experiments by decreasing the
initial control point spacing to 20 mm and thus limiting the maximum amount of
deformation that can be handled. The results are also reported in Table 1. In this
case, we can observe a more significant difference between the performance of
the two proposed approaches. Therefore, we should conclude that the additional
computational cost demanded by the coupled approach can be compensated by the
better quality of the results.
5 Conclusion
Acknowledgements We would like to acknowledge Dr. Ben Glocker, from Imperial College
London, whose work formed the basis of the subsequent works that are presented here.
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Part IV
Clinical Biomarkers
Cardiovascular Informatics
1 Introduction
Cardiovascular disease has long been the leading cause of death in developed
countries, and it is rapidly becoming the number one killer in developing countries
[3]. In 2006, it is estimated that more than 19 million people worldwide experienced
a life-threatening heart attack. In the US alone, 1.4 million people suffer from a heart
attack annually. Of the 140 million Americans between the ages of 35-44, 17.4 %
of males (24.36 million) and 13.6 % of females (19.04 million) have coronary heart
disease. Approximately 50 % of heart attack related deaths occur in people with no
prior symptoms [6]. Hence, sudden heart attacks remain the number one cause
of death in the US. Unpredicted heart attacks account for the majority of the $280
billion burden of cardiovascular diseases.
2 CT Data Analysis
necessarily nearby, pixels in the image. It considers the strengths of all possible
paths between given two pixels, where the strength of a particular path is the weakest
affinity between the successive pairs of pixels along the path. Thus, the strongest
connectedness path between the given two pixels specifies the degree of global
hanging togetherness between the given two pixels. Global object affinity is the
largest of the weakest affinities between the successive pairs of pixels along the
path pcd of all possible paths Pcd from c to d and is given by K (c,d) D maxpcd 2Pcd
fmin1 i m[ (c(i) , c(iC1) )]g.
In our framework, the global object affinity and local pixel affinity are assigned
only if the global class affinity (or discrepancy measure) of c and d belonging to
the neighboring objects’ classes is more (or less) than a predefined value,
(note
that the affinity value has an inverse relationship with the Mahalanobis distance
metric in our formulation). The minimum discrepancy measure J(c,d) D min1 i
b md (c, d), where b is the number of neighboring classes of the target object, gives
the maximum membership value of a pixel pair belonging to a certain class. If J(c,d)
<
, and the class to which the pixel pair belongs is not the target object class, then
the local pixel affinity (c,d) is set to zero, else its local pixel affinity is computed
as described earlier.
Since pericardial fat tissue appears as disjoint sets of pixels distributed all over in
the thoracic cavity, we relax the spatial connectedness constraint in our formulation
to allow scattered tissue classification (Fig. 1). Our segmentation algorithm uses
dynamic statistics of fat tissue for automatic segmentation of the fat tissue. We
Cardiovascular Informatics 369
Fig. 2 Top: (a) Flowchart of an analysis of a contrast-enhanced IVUS sequence. From left to
right - the original sequence, the sequence decimated by gating, the contour-tracking step, and
difference imaging and overlay of results. Bottom: Demonstration of registration between histology
and IVUS. (b) A stained histological image, (c) an IVUS image to which the histology image will
be co-registered by manually defining corresponding landmarks, (d) deformed histology image
based on the landmarks, and (e) the IVUS image highlighting the correspondence. Note the
excellent agreement of our analysis with the histology
estimate the statistics of fat tissue by using a sample region around a seed point,
hence the selection of the seed point is very critical. We obviate the need for manual
seed selection by automatic seed initialization using relationships defined in the
training phase. Thus, instead of applying a space-invariant global threshold value,
our method adapts the threshold value locally in the feature space. In addition to fat
segmentation in CT, this method has also been used for left ventricular segmentation
in MRI [14].
In this section, we introduce a number of techniques for IVUS image analysis [9,
10] which enable the use of difference imaging to detect those changes which occur
in the IVUS imagery due to the perfusion of an intravascularly-injected contrast
agent into the plaque and vessel wall. To determine if a particular physical region of
the frame experiences an increase in echogenicity due to contrast perfusion into the
wall, it is necessary to compare the appearance of that region under IVUS before
and after the introduction of contrast. Since multiple sources of motion are present,
we follow three steps to detect perfusion: motion compensation, image subtraction
and deriving statistics from the resulting difference images (Fig. 2(a)).
370 I.A. Kakadiaris et al.
The goal of two-step motion compensation (frame gating and contour- tracking)
is to provide pixelwise correspondence between a region of interest (e.g., the
plaque) in each frame. Unlike previous efforts utilizing ECG signals, we perform
an appearance-based grouping of frames. By formulating the problem in terms of
multidimensional scaling (MDS), a number of other useful operations may be per-
formed. The MDS transform places points defined only by inter-point proximities
into a metric space such that the proximities are preserved with minimal loss. In our
context, this allows the creation of a frame-similarity space which may be employed
as a concise visual and numerical summary of an entire frame sequence. Clustering
this space allows sets of frames with various similarity properties to be extracted
efficiently. We begin by taking our n-frame sequence and creating a square matrix
D in which each entry di,j represents the dissimilarity between frames i and j. As
normalized cross-correlation returns values in the range [1, C1], we clamp these
values to [0, C1] and subtract them from one. This results in a matrix with zero
along the diagonal and values on the range [0, 1] everywhere else. Next, we let
A be the matrix where ai;j D – 12 di;j 2
and let Cn D In n1 1n 1Tn ; where In is the
n n identity matrix and 1n is the unit vector of length n. Let B D Cn ACn . We
let œ1 œn and v1 , . . . , vn be the eigenvalues and associated eigenvectors
of B, and p be the number
of positive eigenvalues. By forming the matrix Y D
p p
œ1 v1 ; : : : ; œp vp , we obtain a p-dimensional point cloud in which each frame
is represented in space by a single point. The distance between any two points i and
j in Y approximates the dissimilarity between those frames as represented in D. We
use randomly-initialized k-means with multiple runs to converge to a lowest-error
clustering [9, 10].
To eliminate residual motion artifacts after frame gating, a more precise contour
tracking operation is performed to provide pixel-wise correspondence. Two contours
are drawn which define the inner and outer boundaries. Initialization for a single
contour comes in the form of a manually-drawn contour on the first frame. Contours
are found for all frames after the first by pairwise matching. Our method follows a
two-step approach to complete the process: a rigid alignment step followed by an
elastic refinement step. In the rigid step, starting with static-image contour x, the
following rigid transformations are modeled to match the contour to the moving
image: ˙x translation, ˙y translation, ˙ rotation, and ˙ dilation. Then, we proceed
using a gradient ascent. In the elastic step, given the contour x0 , which is itself a
rigid transformation of the initial contour x, we deform x0 elastically in order for it
to better conform to the image features associated spatially with x. The output of this
elastic matching step is a refined contour, x00 . We define a contour energy function
for any contour, and by manipulating x0 we seek to maximize the energy function
to produce x00 . Lastly, if information about of the regions on the inside and outside
of the contour is known, it is possible to use histogram statistics to influence the
deforming contour.
Given tracked contour pairs for each image in our gated IVUS sequence, the
region between the contours is resampled from image space into a rectangular region
space. Difference imaging is accomplished by subtracting the pre-injection baseline
from all region images in the gated sequence. As the same baseline is subtracted
Cardiovascular Informatics 371
from both the pre- and post-injection frames, it is simpler to determine which
deviations from the baseline occur as a result of the contrast injection and which are
the result of noise unrelated to the presence of contrast. To quantify enhancement in
the difference-imaged regions of interest after they have been mapped back to the
IVUS image space, we consider the set of pixels in the region of interest which are
flagged as enhanced. Averaging the grey levels of these enhanced pixels, we obtain
the average enhancement per enhanced pixel (AEPEP) statistic. Each frame in our
gated sequence will have one associated AEPEP value; due to noise, pre-injection
frames will have some positive value but, if enhancement occurs, the post-injection
value will be greater.
4 Results
5 Discussion
6 Conclusion
Our long term goal is to develop a new risk assessment scoring index for a patient’s
risk of a cardiovascular event. If these scores are to be used as markers of subclinical
disease, they should provide the best representation of subclinical information.
Cardiovascular Informatics 373
This requires optimal use of all available data. Currently used tools do not use the
wealth of information present in the images. In this chapter, we presented novel
methods to mine information from CT and IVUS data to obtain pericardial fat
measurements and to image extra-luminal perfusion due to blood flow through the
vasa vasorum. The results we obtained are encouraging, and show the possibility of
these methods being used in clinical settings.
Acknowledgment We would like to thank all members of the Ultimate IVUS team for their
valuable assistance. This work was supported in part by NSF Grant IIS-0431144 and an NSF
Graduate Research Fellowship (SMO). Any opinions, findings, and conclusions or recommenda-
tions expressed in this material are those of the authors and do not necessarily reflect the views of
the NSF.
References
13. A. Pednekar and I.A. Kakadiaris. Image segmentation based on fuzzy connectedness using
dynamic weights. IEEE Trans. Image Processing, 15(6):1555–1562, 2006.
14. A. Pednekar, U. Kurkure, I. A. Kakadiaris, R. Muthupillai, and S. Flamm. Left ventricular
segmentation in MR using hierarchical multi-class multi-feature fuzzy connectedness. In Proc.
Medical Image Computing and Computer Assisted Intervention, Rennes, Saint-Malo, France,
2004. Springer.
15. D. Rueckert et al. Nonrigid registration using free-form deformations: application to breast
MR images. IEEE Trans. on Medical Imaging, 18:712–721, 1999.
16. R. Taguchi et al. Pericardial fat accumulation in men as a risk factor for coronary artery disease.
Atherosclerosis, 157(1):203–9, 2001.
17. M. Vavuranakis, I. Kakadiaris, S. O’Malley, T. Papaioannou, E. Sanidas, S. Carlier,
M. Naghavi, and C. Stefanadis. Contrast enhanced intravascular ultrasound for the detection
of vulnerable plaques: a combined morphology and activity-based assessment of plaque
vulnerability. Expert Review of Cardiovascular Therapy, 5:917-915, 2007.
18. M. Vavuranakis, I.A. Kakadiaris, S. M. O’Malley, T. G. Papaioannou, E. A. Sanidas,
M. Naghavi, S. Carlier, D. Tousoulis, and C. Stefanadis. A new method for assessment of
plaque vulnerability based on vasa vasorum imaging, by using contrast-enhanced intravascular
ultrasound and differential image analysis. Int. Journal of Cardiology, 2008 (In Press).
Rheumatoid Arthritis Quantification
using Appearance Models
a b
Bare areas
Synovia
Effusion Joint space
narrowing
Bare areas
Synovitis
Erosion
"Pannus"
Fig. 1 A joint affected by synovitis and succeeding RA exhibiting joint space narrowing and
erosive destructions in the bare area
1 Introduction
The radiographic surrogates associated with the progression of RA are joint space
narrowing (JSN) which reflects an impairment of the cartilage and erosions, the
destructions of the bony structure. The precise quantification of these markers is a
decisive factor during treatment and during clinical multi-center trials. While ultra-
sound and magnetic resonance imaging are used to monitor synovitis, radiography
is the standard modality for long-term RA progression monitoring [34]. Scoring
of radiographic joint space width and erosions are accepted imaging biomarkers to
assess the progression of RA during therapy.
Several manual scoring systems [21, 27] have been published and refined over
the last 30 years. They use a discrete scale of categories to integrate the status
of multiple joints. They are time consuming, require specialized training, and
suffer from significant inter-and intra-reader variation [35]. This limits long-term
assessment of disease progression, as well as the feasibility and discriminative
power of multi-center studies.
The availability of digital image acquisition systems has prompted the devel-
opment of new, increasingly automatic, quantitative measurement methods for
radiographic features such as bone axes, bone density, or joint space width. In one
study [1] an interactive joint space measurement method for rheumatoid arthritis of
the finger joints gave highly reproducible results, thus increasing the study power
while remaining consistent with traditional scoring.
Another interactive approach [25, 26], where points had to be placed manually in
the metacarpophalangeal joint (MCP), achieved a considerably high reproducibility
rating. In [8, 10] the diagnostic performance of a computer based scoring method
was also found to surpass traditional scoring. These methods are restricted to angle-
and distance measurements, include manual annotation on the image as part of the
measurement procedure, and integrate only a limited degree of automation with user
input. In [30] different methods for the measurement of the joint space width with
various states of automation were compared. In [24] initial experiences with a fully
automatic joint space width measurement method for RA were reported.
In a number of recent clinical studies [2, 3, 15, 22] erosions proved to provide
more discriminative information on disease progression with respect to the treat-
ment as opposed to the joint space width. The manual assessment of erosions in
the traditional scoring frame work impedes the precise follow-up quantification and
suffers from the afore-mentioned limitations.
378 G. Langs et al.
Appearance models are used to solve three different problems during the
disease assessment:
• Detection of the anatomical structures of interest in the radiography data.
• Consistent identification of individual positions in the anatomy over time
for a single patient (pathology tracking), and localization of corresponding
positions between patients.
• Analysis and measurement of the deviation from a healthy training popu-
lation: the residual error after appearance model matching can be used to
indicate pathologies if the training population is sufficiently representative.
The joint space widths are measured between the detected contours and the
location information covered by the model landmarks (i.e. the definition of the
joint region on the bone). Erosions and their extent are determined by a boosted
classifier ensemble that analyses texture features extracted from the bone contour
region. It results in a label for each contour point describing the extension of erosive
destructions. Furthermore erosions can be marked by the residual appearance
model fitting error [20]. For both measures the model landmarks serve to establish
correspondences across individuals, e.g. in order to define the joint space width
measurement region and to track changes during follow-up assessment of one
individual.
As a first step before segmenting the individual bone contours, a coarse estimate of
the joint positions is necessary to provide the ASMs with a reliable initialization.
The repetitive appearance and the variability of the hand positioning during
acquisition is beyond the capture range of the ASMs that delineate the bone
contours. Local linear mappings (LLMs) are trained to detect the positions of 12
joints (Fingertips, metacarpophalangeal joint metacarpophalangeal joints (MCP)
and carpo metacarpal joints (CMC) of Fingers 2,3,4, and 5). They have been used
for hand gesture recognition [23] and perform well on salient structures. In the case
of radiographs they model dependencies between local image texture and landmark
positions, and give reliable results for the initial detection of the hand, its orientation
and the positions of the individual bones for the ASM initialization [17]. For each of
the 12 joints a cascade of LLMs is trained on a series of increasingly small texture
patches. The initial estimate is based on features extracted from a configuration
of 12 overlapping windows on the radiograph. Subsequent iterations are based on
features extracted locally at the current joint position estimate. The deformation of
the configuration is constrained by a statistical shape model. In Fig. 2 an overview
of this estimation is shown, a detailed explanation is given in [17, 19].
Based on coarse joint position estimates active shape model (ASM) driven snakes
[18, 19] delineate the bone contours and identify regions relevant to analysis. ASM
driven snakes (ASMdS) segment the bones in a two-phase process: first they rely
on a statistical shape model (ASM) to obtain a stable contour estimate, this is
followed by an active contour approach, that controls the statistical model constraint
in a gradual manner and adapts to deviations from the training population, while
retaining the landmark identities.
380 G. Langs et al.
True position
1. Initial coarse localization based on a single 2. Fine localization of individual positions based on a clique of
model appearance models, connected by a joint shape model
ASMs [6] are statistical landmark based models that represent the variation of shape
and local gray values of a training set of examples in a compact manner. Although
they provide very reliable estimates, the accuracy of ASMs with respect to the
true image structure or contour is limited because of the shape model constraint
that is based on a finite training population. This is a drawback if fine details
that possibly deviate from the training population have to be analyzed, and the
ASM training set stems from bones with no deviations from normal anatomy,
Rheumatoid Arthritis Quantification using Appearance Models 381
e.g. because the variability of local pathological changes cannot be modeled with
a reasonable training set size and evades the representative power of a linear
model. A similar issue was addressed in [7]. ASM driven snakes overcome this
constraint by gradually decreasing the influence of the model constraint. They refine
the contour estimate obtained by ASM and fit slight deviations from the normal
training anatomy. However, they retain the location information captured by the
model landmarks. The result is a dense delineation of the bone contour, and known
positions of the landmarks on this contour.
The ASM search results in landmark estimates xASM D (x1 , . . . ,xn ). These
landmarks are interpolated by a spline which is sampled at smaller intervals: c D
(c1 , . . . ,cd ). Gray level profiles pi with length m are extracted from the image
orthogonally to the interpolated contour. They build a matrix P D [p1 , . . . ,pd ].
Figure 3 shows the original positions of the grey level extraction points for a contour
section of a proximal phalanx, and the set of extracted profiles P(x, y) for the entire
bone contour. The spline interpolation in between the ASM landmarks is positioned
at points s1 D (x, y)iD1, : : : ,d : (x, y)i D (i, m/ 2) in P(x, y), and can serve as initialization
for a search with an active contour in P. As in the standard active contour search,
we minimize an energy functional
Z1
1 ˇˇ 0 ˇˇ2 ˇ ˇ2
ED ˛ s .s/ C ˇ ˇs00 .s/ˇ C Eext .s.s// ds (1)
2
0
where the first term is the internal energy Eint capturing elasticity and rigidity
properties of the curve, and the second term is the external energy Eext . Their
influence is determined by the factors ˛ and ˇ. The external energy Eext is derived
from the image and usually drags the contour towards high gradient edges in the
data. In our case the local texture model of the ASM is taken advantage of by
deriving Eext from the image in the following way: the mean grey-level profiles
corresponding to the landmarks in the ASM: g1 ASM , . . . , gn ASM are interpolated
in order to derive an ordered set g1 , . . . , gd . Thus, for every column in P a
corresponding grey level profile gi is generated approximating the mean appearance
in the training set from the model grey value profiles. The identification between gi
and pi is defined by the landmarks on the fitted ASM. Then
Eext D
jrPj P ? G (2)
where P * G denotes the column wise convolution of pi with the corre- sponding
mean grey value profile gi . Thus, with a high value for the lowest energy is
obtained if the snake follows a path corresponding to a maximal similarity of the
382 G. Langs et al.
External energy
External energy
Fig. 4 ASM driven snakes; alternating: section of the grey value profiles extracted along the
contour after ASM search, the resulting Eext and the snake result
The joint space width can be measured straightforwardly after the bone segmenta-
tion. Since the development over time or joint space narrowing (JSN) is clinically
relevant, the precision of the measurement is of prime importance. To measure the
joint space width of the metacarpal phalangeal joint (MCP) ASM landmarks in
the proximal region of the proximal phalanx (PP) and in the distal region of the
metacarpal (MC) identify the measurement region. They are depicted in Fig. 5. For
each point on an interpolation of the landmarks the minimum distance to the MC
bone is measured, the mean value of these measurements within the region is defined
as the JSW. In Fig. 5 an example of the resulting measurements for 2 MCP joints is
depicted. The vertical lines indicate the closest neighbor on the MC for every point
in the measurement region on the PP contour. In contrast to approaches that rely
on measuring gradients along a line that passes through the joint region this method
takes advantage of a model fitted to the entire bone, hence improving stability in case
of possible ambiguous local texture or centre line orientation in the joint region.
After bone contours have been delineated, the task of detecting erosions on the
bone contour can be formulated as a classification of contour points into the classes
healthy bone contour, i.e. Non-Erosion and contour affected by RA, i.e. Erosion.
The result is a continuous value that captures the amount of affected bone contour.
For this, texture features are extracted from a sequence of rectangular patches along
384 G. Langs et al.
the bone contour. The dimensionality of the feature vector is reduced by feature
selection [16] and the classification is accomplished by an AdaBoost classifier [11]
for each point on the contour. In order to account for the high variability of erosions
[32] two classes are referred to, Erosion I or pre-erosions and Erosion II, that
differ in their appearance. Class II erosions are unequivocal erosions exhibiting all
radiographic signs, while Class I erosions lack one or more of these features, and
appear as an unsharpening of bone architecture (Fig. 6).
7.1 Detection
For each point ci 2 cfinal on the bone contour, the bone texture is extracted in
the form of a rectangular patch pi with borders parallel and orthogonal to the
bone contour normal vector ni at the position si . This results in a set of patches
(pi )iD1, : : : ,n for a bone, each corresponding to a single contour point (Fig. 6). Erosion
detection performs a classification on these patches and assigns them one of the two
classes Erosion or Non Erosion.
For the patches pi texture features comprising gradient, gradient orientation, and
grey value deviation on a grid of 10 sub-patches are extracted. Before a classifier
is trained, the number of features is decreased by a feature selection procedure that
is based on an iterative re-weighting scheme similar to AdaBoost [16]. The point-
wise classification of the bone contour is accomplished by an AdaBoost classifier
working with linear discriminant analysis as a weak learner. Each weak learner is
trained on a sub-set of example patches and features. Thereby the variability of
erosion appearance can be accounted for. The classification of the contour points
Rheumatoid Arthritis Quantification using Appearance Models 385
is achieved by a voting of 4 classifiers. For each of the erosion classes type 1 and
type 2, two classifiers are trained: one on the entire body bone contour Ci f and one
in the joint region Ci j . The combined classifier is defined by C D C2 j C2 f C C1 j C1 f
Ĉ1 f Ĉ2 f , where Ĉ is the indicator function of C > t. The inputs for the classifiers are
the features extracted from a single patch, the output is the class label No-Erosion vs.
Erosion. The voting results in a value indicating the presence of erosive destructions.
For each contour point a classifier response is calculated, and thereby the extent and
the location of the erosions are determined.
7.2 Visualization
In addition to the numerical value associated to each contour point, a more specific
visualization of the deviation of erosion appearance from normal anatomy is
necessary to allow the clinician to approve the results. This can be achieved by a
generic appearance model in a straightforward fashion. To visualize the deviation of
the observed local bone appearance from healthy bone texture a model is built from
healthy training regions on bones and the best fit of the model is compared to the
texture along the bone contour [20]. The appearance of healthy patches is modeled
by Gaussian mixture models (GMMs) [4]. These models are generative models, and
are able to synthesize data examples, which are plausible with regard to the training
data. During the visualization the generative model of an intact bone contour is used
to determine the deviation of erosion appearance from intact bone texture.
The GMM of patch appearance is a generative model. That is, it can simulate
bone appearance that is plausible with regard to the training population of bone
texture patches. By fitting a model to a patch, i.e., by reconstructing it, the algorithm
determines the closest estimate of the patch appearance within the constraints
imposed by the statistical model, i.e., the distribution of model parameters in the
training set. The residual error, the difference between the actual appearance and
the reconstruction by the model provides information about the local texture and its
difference from the learned distribution. Showing this residual in the radiograph in
addition to the labels C from the classifier, provides the musculoskeletal radiologist
not only with location information but also with an estimate about the deviation
of the bone contour texture from healthy bone. Note that the mere residual error
could also be used for the detection of erosions. However, experiments indicate, that
the discriminative power is not sufficient for classification, in particular in the case
of pre-erosions. For the high variation of erosion appearances a classifier utilizing
texture as described above is necessary.
386 G. Langs et al.
In this section we report experimental results on several data sets of hand radio-
graphs with mild to moderate rheumatoid arthritis. More detailed evaluations are
reported in [19, 20, 24]. A comparative study of different approaches to semior
fully-automatically measure the joint space width is reported in [30].
Contour delineation: The effect of ASM driven snakes is important, if small local
deviations from the training population are to be expected. For meta-carpal and
proximal phalangeal bones and a varying ratio between
and , and elasticity
parameter ˛, a minimum median error is reached by ASM driven snakes for
intermediate values. In Fig. 8, the median contour error is plotted. For standard
ASMs the mean/median error is 2.41/2.03px. The mean ASMdS error reaches its
lowest value 1.73 for high ˛ and highest influence
of the model gray value model.
The median exhibits a minimum of 1.09 within the parameter range. Results indicate
a better fit of the contour estimate toward small local rough sections of the bone
contour compared to standard ASMs. These occur particularly often on bones of
patients suffering from chronic joint disease.
Joint space width measurement: For joint space narrowing i.e. the development
over time the precision of the measurement method is of prime interest. For 10
repeated measurements on 160 MCP joints with a mean JSW of 1.75 mm, the
mean absolute error of the automatic measurement results compared to a standard
of reference annotated by experts was 0.19 to 0.4 mm. The standard deviation for 10
repeated measurements was between 0.04 to 0.13 mm corresponding to a coefficient
of variation of 2% for non-overlapping bones and 7% if overlap did occur at the
joint. The smallest detectable difference (SDD) for the joint space width is 0.08
mm. The joint space width measurement offers precision similar to existing semi-
automatic approaches [5, 13, 14] but in a fully automatic fashion.
Rheumatoid Arthritis Quantification using Appearance Models 387
9 Conclusion
The method explained in this chapter automatically measures joint space width and
erosion extent on hands affected by rheumatoid arthritis. We expect the automatic
assessment of rheumatoid arthritis and other diseases to decrease inter-reader
variability and artifacts introduced by individual readers as described in [29, 33].
Increasing reliability and sensitivity in detecting treatment effects would help to
speed up the development of new and effective disease-controlling, anti-rheumatic
therapies and to reduce the number of patients necessary for clinical trials. It is
particularly relevant, since improved therapies make the changes caused by RA
more subtle. This makes a specific and local tracking of changes as opposed to
global and therefore less sensitive scores necessary. Future research in the field of
automated quantification methods will have to focus on the improvement of their
ability to adapt to different image acquisition protocols and to extend the area of
application to more complex anatomical sites.
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1999.
Medical Image Processing for Analysis
of Colon Motility
1 Introduction
Fig. 1 Coronal Cine MRI slices visualizing the peristaltic wave in the descending colon
this work is to model and quantify the activity of the large bowel hopefully providing
the means to define the clinical significance of a variety of motility disorders in
a wide range of patients. Necessary steps in the image processing workflow are
defined, and technical approaches towards a computer aided diagnosis tool are
proposed.
In the following, we present our preliminary results on a set of experimental
data. Volunteer data was acquired and processed using the imaging techniques and
algorithms presented in the next Sections.
The volunteers undergo functional Cine MRI. The standardized functional Cine
MRI examination is performed at 6 AM, after a minimum starving phase of 8
hours, on 1.5-T system (Siemens Avanto). The volunteers are examined in supine
position. Neither premedication nor contrast agent is applied. The dynamic part
of the examination consists of 2 blocks of repeated measurements covering the
entire abdomen, using a T2-weighted HASTE-sequence. Each block contains a
stack of approximately 200 slices over time orientated in coronal plane adapted
to the anatomic course of the descending colon (see Fig. 1). The image resolution
is 256 320. Between the 2 dynamic blocks of measurements a prokinetic agent is
administered in order to stimulate the colon motility. For the further analysis of the
394 N. Navab et al.
Fig. 2 Our image processing chain within a computer aided diagnosis tool for colon motility
dysfunctions
peristaltic motion, the subsequence (usually about 20 slices) showing this motion is
manually selected from the image blocks. The pre-scan without stimulation was up
to now only used in our previous studies [6, 7].
In order to achieve the fastest possible frame rate for our MRI acquisition, no
respiratory gating can be used during the scans. The time between two successive
frames could be reduced to approximately 1.4 seconds which is fast enough to
visualize the peristaltic wave. Still, the sequences suffer from breathing motion
artifacts which makes the identification of corresponding points in the colon quite
hard. This was not a problem in our previous studies where manually extracted
diameters were measured over time and stimulated and non-stimulated sequences
were compared, the identification of corresponding points could be achieved
manually by the medical expert. In order to automatize such procedures, there is
need for an accurate motion compensation in a post-processing step. This leads us
to the first step in the image processing chain (see Fig 2).
3 Image Processing
In order to develop a computer aided diagnosis tool for colon motility dysfunctions,
we first identify necessary steps within the image processing chain. We already
mentioned the problem of breathing motion artifacts in the Cine MRI data sets.
Once, these artifacts can be successfully removed, all further steps will benefit
from the motion compensation. Our later analysis of the motility is based on the
segmentation of the colon in all slices over time. We propose a semi-automatic
approach based on interactive graph-cuts. This will be explained in more detail in
Sect. 3.2. The actual analysis and our approach for extracting clinically valuable
measurements is then described in Sect. 4. The full image processing chain is
sketched in Fig. 2.
As already mentioned, no respiratory gating techniques are used during the image
acquisition in order to achieve a high frame rate. The resulting breathing artifacts
in the image sequences are visible in a vertical jumping of the abdominal organs
effected by breathing motion such as liver, kidney, and of course the colon itself.
For our further processing steps, a compensation of this motion is of great interest.
In order to make the identification of corresponding points in the colon much
Medical Image Processing for Analysis of Colon Motility 395
Fig. 3 (a) Selected region and extracted Harris feature points. (b) Tracked features in one of the
following frames. (c) Difference image between reference frame and consecutive frame before
compensation, (d) and the difference image after compensation. Clearly visible, the motion at the
lower boundary of the liver has been reduced
The segmentation of the colon is crucial for our further analysis. Shape and
appearance have to be well preserved by the segmentation. The individual patient’s
anatomy is particularly reflected in varying orientation and form of the large bowel.
A segmentation method should be highly flexible to handle these variations. To this
end, we use the interactive graph-cuts approach proposed by Boykov and Jolly [4].
The segmentation is defined as an energy formulation
E.A/ D R.A/ C B.A/ (1)
396 N. Navab et al.
Here, the regional term R represents a priori knowledge given through the user
interactions. Interactively, the user sets so-called seed brushes for the object Sobj
that is considered to be segmented (i.e. the colon) and additionally, seeds for the
background Sbkg (see Fig. 4a). The function R is then defined as
X
R.A/ D Rx .Ax / (3)
x2
where
8
< 1 if Ax D “obj 00 ^ x 2 Sbkg
Rx .Ax / D 1 if Ax D “bkg 00 ^ x 2 Sobj (4)
:
0 otherwise
Intuitively, the regional term forces the pixels belonging to seed brushes to keep
their assignment to the object respectively background segmentation subset. The
second part B of the segmentation energy is the so-called boundary term. Here,
it represents the interaction energy for pairs of neighboring pixels x; y 2 N to
belong to the same segmentation subset and thus provides a certain smoothness on
the segmentation result, or
X
B.A/ D Bx;y ı.Ax ; Ay / (5)
x;y2N
with
1 if Ax 6D Ay
ı.Ax ; Ay / D (6)
0 otherwise
.Ix Iy /2 1
Bx;y / exp. 2
/ (7)
2 d i st.x; y/
Fig. 4 (a) Seed brushes in one frame of the image sequence. (b) Resulting segmentation of the
descending colon. (c) Skeletonization of the segmentation. (d) Extracted longest path which is
used as centerline. (e) Diameter measurement at 20 sample points
image data. The exact global minimum of the energy formulation in (1) can be
computed by using a max-flow algorithm (e.g [5]).
Since we are dealing with MRI time series of 2D slices, each frame is showing a
similar image of the patient’s abdomen with slightly moved, or in case of motility,
extended bowel diameter (see Fig. 1). Furthermore, after performing the motion
compensation, we can assume that the only large bowel motion left in the images is
due to motility. We can make use of this minimal changes within the segmentation
method in order to minimize the user interaction. Actually, we can perform a full
segmentation of the whole time series very efficiently. The user sets the seed brushes
only in one frame. Object seeds have to be set roughly at the centerline of the colon
and background seeds are placed around the colon part of interest (see Fig. 4a).
Thanks to the motion compensation we can benefit from this strategy in two ways:
on the one hand, these brushes can be set automatically in all other frames of
the time series in a “copy & paste" fashion, on the other hand, the surrounding
background seeds can be used as a restriction or bounding box for the computation
of the graph-cuts algorithm. The segmentation of the whole series is then done in
one single energy formulation. Thus, the boundary term B also acts as a smoothness
constraint in the temporal domain. The computation time of one segmentation for a
subsequence of about 20 frames showing the peristaltic wave is less than 10 seconds.
One important property of such a segmentation approach is the extreme flexi-
bility. This method can be used for all parts of the large bowel and can deal with
extreme shape variations which are likely to occur. This is crucial for our further
analysis of the colon motility which is based on the segmentation result.
The aim of the colon motility analysis is to obtain as much information as possible
about the peristaltic motion visible in the Cine MRI sequences. Our approach is
based on the idea of measuring the bowel diameter over time which was previously
398 N. Navab et al.
Extension in mm
14
Frame Index
10 0.7 13.5
Ratio
9 0.65 13
12.5
8 0.6
12
7 0.55
max diameter 11.5
regression line
6 0.5 11
0 5 10 15 20 25 0 5 10 15 20 25 0 5 10 15 20
Sample Point Index Sample Point Index Frame Index
Fig. 5 (a) The maximum diameter tracked over time at each of the 25 sample points. Such a
measure can be used to estimate the speed of the peristaltic wave. (b) Ratio of minimum and
maximum diameter at each sample point is used to assess the activity of the colon. (c) The mean
extension for the lateral and medial side of the colon during a propagating peristaltic wave over 20
frames
presented in [7]. In a first clinical trial, this fully manual approach was able to
measure significant changes in the motility after administration of stimulating
drugs [6]. However, this method was extremely time consuming and tedious in
means of reproducibility. A limited number of 5 diameters were measured manually
in one frame. Then, the corresponding points were identified manually in the
successive frames and again the diameters had to be measured. In order to improve
and automatize this approach and increase the number of measurements to a user
selected bound, we are making use of the two proposed image processing steps so
far, the motion compensation and the segmentation.
At first, we extract the skeleton of the segmented colon in one frame using
a thinning algorithm proposed by Palagyi et al. [13]. From this skeletonization
we construct a graph using a wave propagation approach presented by Zahlten
et al. [15]. The result of these two steps is shown exemplary for one image sequence
in Fig. 4c. We extract the longest path from the resulting graph in order to obtain a
good approximation of the real centerline of the colon (see Fig. 4d). A B-Spline is
fitted to the centerline which then can be subdivided into a user defined number of
segments. At each segment we determine the diameter of the colon by measuring
the extension of the segmentation perpendicular to the centerline (see Fig. 4e).
Since the segmentation is already computed for all slices and thanks to the motion
compensation, we can easily measure the colon diameter at all these specific
positions over time. The user can change the number of measurement points without
any recomputation on the segmentation or centerline and gets the new measurements
within milliseconds.
In order to analyze the present colon motility, we extract several values with
clinical relevance from our measurements. One significant parameter of interest is
the propagation speed of the peristaltic wave. This can be measured by tracking
the maximum diameter along the measurement points (see Fig. 5a). A value also
important in assessing pathologies and dysfunctions of the colon motility is the
ratio of the average maximum and minimum diameter (see Fig. 5b). A ratio close
to 1:0 could indicate a local defect on the contraction ability. Besides these values
Medical Image Processing for Analysis of Colon Motility 399
hopefully leading to a clinical index in near future, other phenomena reported in the
medical literature could be measured for the first time. We could show that there is a
significant difference in the contraction of the large bowel on the lateral and medial
side (see Fig. 5c). This is what clinical experts actually expected. However, up to
now there did not exist any image based method to proof these assumptions.
5 Conclusion
Our experiments focused on the descending part of the colon. This part is most
relevant for clinical interventions as it is suitable for minimally invasive sugery.
We tested our method on volunteer data and compared it to the manual approach
of diameter calculation [7]. Our approach significantly reduces user-interaction and
is fast in delivering quantitative results on colon motility assessment We increased
the number of clinical parameters by for instance the speed of propagation or the
min-max ratio.
400 N. Navab et al.
References
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2000.
Medical Image Processing for Analysis of Colon Motility 401
R. Beichel ()
Department of Electrical and Computer Engineering and Department of Internal Medicine, The
University of Iowa, 4016 Seamans Center, Iowa City, IA 52442, USA
e-mail: [email protected]
C. Bauer
Department of Electrical and Computer Engineering, The University of Iowa, 4016 Seamans
Center, Iowa City, IA 52442, USA
e-mail: [email protected]
A. Bornik • H. Bischof
Institute for Computer Graphics and Vision, Graz University of Technology, Inffeldgasse 16,
8010 Graz, Austria
e-mail: [email protected]; [email protected]
E. Sorantin
Research Unit for Digital Information and Image Processing, Department of Radiology, Medical
University Graz, Auenbruggerplatz 4, 8010 Graz, Austria
e-mail: [email protected]
1 Introduction
Liver cancer is one of the four most common deadly malignant neoplasms in
the world. Approximately 618,000 deaths due to liver cancer were reported in
20021. Tomographic imaging modalities like X-ray computed tomography (CT)
play an important role in diagnosis and treatment of liver diseases like hepatocellular
carcinoma (HCC). Liver resection has evolved as the treatment of choice for various
benign and malignant hepatic tumors. Deriving a digital geometric model of hepatic
(patho)anatomy from preoperative image data facilitates the planning procedure
of liver tumor resections [13]. Thus, methods for liver segmentation in volume
data are needed which are applicable in clinical routine. In this context, several
problems have to be addressed: (a) high shape variation due to natural anatomical
variation, disease (e.g., cirrhosis), or previous surgical interventions (e.g., liver
segment resection), (b) inhomogeneous gray-value appearance caused by tumors
or metastasis, and (c) low contrast to neighboring structures/organs like colon or
stomach. For clinical application, liver segmentation must be able to handle all
possible cases in a time-efficient manner. Especially, livers with large or multiple
tumors are of interest, since treatment selection is crucial in these cases.
A large number of approaches to liver segmentation have been developed using
methods like live wire, level sets, deformable models, or active shape models [8,
11, 12, 15]. Since the performance of the algorithms heavily depends on patient
selection, image quality, imaging protocol, and severeness of the disease, different
approaches can hardly be compared. Therefore, an international competition was
organized by Heimann et al. [7], addressing the problem of liver segmentation in
CT data. This competition was held in the form of a workshop at the 2007 Medical
Image Computing and Computer Assisted Intervention conference. The proceedings
give an overview of current liver segmentation methods and their performance [7].
To this competition, nine fully automated methods, five semi-automated methods,
and two interactive methods were submitted, including our approach [1].
In summary, despite the progress made in the development of liver segmentation
methods, segmentation errors or failure are still common. Tumors or previously
performed resection of liver segments can lead to large variations in the gray value
appearance or in the shape of the liver. No pure bottom-up approach or model-based
approach is able to succeccfully cope with all kinds of possible variations that occur
in clinical practice [7]. In order to make liver segmentation applicable for clinical
routine a method for efficient refinement of segmentation errors is essential.
One of the rare examples of segmentation refinement are reported in [9] and [2],
where Rational Gaussian (RaG) Surfaces are used to represent segmented objects.
Segmentation errors can be corrected by manipulation of control points using a 2D
desktop setup. Another system allowing to alter the boundary of segmented objects
by morphological operations and surface dragging was reported in [10]. A tool for
1
http://www.who.int/whr/2004/en
Segmentation of Diseased Livers: A 3D Refinement Approach 405
2 Methodology
The proposed approach to liver segmentation consists of two main stages: initial
segmentation and interactive segmentation refinement. As input for the first stage,
a CT volume and one or more start regions, marking liver tissue, are used.
The segmentation is then generated using a graph cut approach2. In addition, a
partitioning of the segmentation and the background into volume chunks is derived
from edge/surface features calculated from the CT volume. These two types of
output are passed on to the second stage which allows for the correction/refinement
of segmentation errors remaining after the first stage. Refinement takes place in
two steps. First, volume chunks can be added or removed. This step is usually very
fast, and the majority of segmentation errors occurring in practice can be fixed or
at least significantly reduced. Second, after conversion of the binary segmentation
to a simplex mesh, arbitrary errors can be addressed by deforming the mesh
using various tools. Each of the refinement steps is facilitated using interactive
VR-enabled tools for true 3D segmentation inspection and refinement, allowing for
stereoscopic viewing and true 3D interaction. Since the last stage of the refinement
procedure is mesh-based, a voxelization method is used to generate a labeled
volume [14].
2
Note that graph cut segmentation is not used interactively, as proposed by Boykov et al. in [5],
since the behavior of graph cuts is not always intuitive.
406 R. Beichel et al.
An initial segmentation is generated using a graph cut [5] approach. From image
data, a graph G D (V, E) is built, where nodes are denoted by V and undirected
edges by E. Nodes V of the graph are formed by data elements (voxels), and two
additional terminal nodes, a source node s and sink node t. Edge weights allow
to model different relations between nodes (see [5] for details). Let P denote the
set of voxels from the input volume data set V—to reduce computing time, only
voxels with density values above 600 Hounsfield Units (HU) are considered as
potentially belonging to the liver. The partition A D .A1 ; :::; Ap ; :::; AjP j / with A p 2
f“obj”, “bkg”g can be used to represent the segmentation of P into object (“obj”) and
background (“bkg”) voxels. Let N be the set of unordered neighboring pairs fp, qg
in set P according to the used neighborhood relation. In our case, a 6-neighborhood
relation is used to save memory. The cost of a given graphP cut segmentation A is
defined as E.A/ D B.A/ C R.A/ where P R.A/ D p2P Rp .Ap / takes region
properties into account and B.A/ D p;q2N B p;q ıAp ¤ Aq , with ıAp ¤ Aq
equals 1 if Ap D Aq and 0 if Ap D Aq , being boundary properties. The parameter
œ with œ 0 allows to tradeoff the influence of both cost terms. Using the s-t cut
algorithm, a partition A can be found which globally minimizes E(A).
Region term The region term R(A) specifies the costs of assigning a voxel to a label
based on its gray-value similarity to object and background regions. For this pur-
pose, user defined seed regions are utilized. The region cost Rp () for a given voxel
p is defined for labels “obj” and “bkg” as negative log-likelihoods Rp ."obj "/ D
ln.P r.Ip j"obj
"//
and Rp ."bkg"/ D ln.P r.Ip j"bkg"// with P r.Ip j"obj "/ D
2 2
.Ip mobj / = 2obj
e and P r.I j"bkg"/ D 1 P r.I j"obj"/, respectively. From a
p p
object seed region placed inside the liver, the mean mobj and standard deviation
obj are calculated. Clearly, in the above outlined approach, a simplification is
made since liver gray-value appearance is usually not homogeneous. However, in
combination with the other processing steps this simplification works quite well.
Further, the specified object seeds are incorporated as hard constraints, and the
boundary of the scene is used as background seeds.
Boundary term The basic idea is to utilize a surfaceness measure as boundary
term which is calculated in four steps:
1. Gradient tensor calculation: First, to reduce the effect of unrelated structures on
the gradient, the gray value range of the image is adapted:
8
< vlow if If < tlow
Ĩ f D If D v if If > thigh . Second, a gradient vector rf D
: high
If otherwise
.fx ; fy ; fz /T is calculated for each voxel f on the with gray-value
transformed data volume V by means of Gaussian derivatives with the kernel
Segmentation of Diseased Livers: A 3D Refinement Approach 407
3 x2 Cy 2 Cz2
g D 1= 2 2 2 e 2 2 and standard deviation . The gradient tensor
S D rf rf T is calculated for each voxel after gray-value transformation.
2. Spatial non-linear filtering: To enhance weak edges and to reduce false
responses, a spatial non-linear averaging of the gradient tensors is applied.
The non-linear filter kernel consists of a Gaussian kernel which is modulated
by the local gradient vector rf. Given a vector x that points from the center
of the kernel to any neighboring voxel, the weight for this voxel is calculated
8 tan . /
2
ˆ r
< 1 e 2 0 2 e 22 if ¤
N 2
as: h 0 ;p .x; rf / D 0 if ¤ 2 and r D 0; with r D x x and
T
:̂ 1
N
otherwise
D 2 j arccos.rf T x=.jrf jjxj//j. Parameter determines the strength of
orientedness, and ¢ 0 determines the strength of punishment depending on the
distance. N is a normalization factor that makes the kernel integrate to unity. The
resulting structure tensor is denoted as W.
3. Surfaceness measure calculation: Let e1W.x/ ; e2W.x/ ; e3W.x/ be the eigenvectors
and 1W.x/ 2W.x/ 3W.x/ the corresponding eigenvalues of W(x) at
position x. If x is located on a plane-like structure, we can observe that 1
0; 2 0; and 3 0. Thus, we define the surfaceness measure as t(W(x)) D
q
œ1W.x/ œ2W.x/ and the direction of the normal vector to the surface is given by
e1W.x/ .
4. Boundary weight calculation: In liver CT images, objects are often separated
only by weak boundaries, with higher gray level gradients present in close
proximity. To take these circumstances into account, we propose the following
weighting
8 function Ÿ(t) D
ˆ
< 1c if t < t1
c2 if t > t2 which models an uncertainty zone between
:̂ .t t2 / c2 c1 C c1 otherwise
t2 t1
t1 and t2 (note: t1 < t2 and c 1 > c2 ). Ideally, the graph cut segmentation should
follow the ridges of the gradient magnitude. Therefore, we punish non-maximal
responses in the gradient magnitude volume by adjusting the weighting function
as follows: nonmax .t/ D minf.t/ C ck ; 1g, where ck is a constant.
Summing up, the boundary cost term is determined by
After initial segmentation, objects with a similar gray-value range in close proximity
may be merged or tumors with different gray-value appearance might be missing.
Therefore, a refinement may be needed in some cases. The first refinement stage
408 R. Beichel et al.
Fig. 1 Mesh-based refinement using a sphere deformation tool. In this case the segmentation error
is a leak. (a) Marking the region containing the segmentation error. (b) Refinement using the sphere
tool. (c) After some time using the sphere tool the error is fixed. (d) The corrected region in wire
frame mode highlighting the mesh contour
is based on volume chunks, which subdivide the graph cut segmentation result
(object) as well as the background into disjunct subregions; the segmentation can be
represented by a set of chunks. The presented approach partitions the image based
on constrictions in the initial segmentation and based on boundary information. It
allows to fix larger errors (e.g. due to high contrast tumors) in a time efficient manner
by altering the initial segmentation.
By thresholding t(W), a binary boundary volume (threshold tb ) representing
boundary/surfaces parts is generated and merged with the boundary from the graph
cut segmentation by using a logical “or” operation. Then the distance transformation
is calculated. Inverting this distance map results in an image that can be interpreted
as a height map. To avoid over-segmentation, all small local minima resulting from
quantization noise in the distance map are eliminated. After running a watershed
segmentation, boundary voxels are merged with the neighboring chunks containing
the most similar adjacent voxels. Since the method can handle gaps in the edge
scene, the threshold tb can be set very conservatively to suppress background
noise. Refinement can be done very efficiently, since the user has to select/deselect
predefined chunks, which does not require a detailed border delineation. This step
requires adequate tools for interactive data inspection and selection methods. For
this purpose, a hybrid user interface was developed, which is described in Sect. 2.4.
After the first refinement step, selected chunks are converted to a simplex mesh
representation. Different tools allow then a deformation of the mesh representation.
One example is shown in Fig. 1. More details regarding this mesh-based refinement
step can be found in [4].
Segmentation of Diseased Livers: A 3D Refinement Approach 409
For evaluation of the segmentation approach, ten liver CT data sets with undisclosed
manual reference segmentation were provided by the workshop organizers [7].
Segmentation results were sent to the organizers, which provided in return evalua-
tion results (see [7] for details). For evaluation, the following parameters have been
used: Gaussian derivative kernel: D 3.0; non-linear filtering: 0 D 6.0, D 0.4;
graph cut: œ D 0.05; weighting function: t1 D 2.0, t2 D 10.0, c1 D 1.0, c2 D 0.001,
ck D 0.75; Threshold for chunk generation: tb D 10.0; gray-value transformation:
tlow D 50, ¤low D 150, thigh D 200, and ¤high D 60. To simulate the clinical work-
flow, the initial seed regions were provided manually and the graph cut segmentation
as well as the chunk generation were calculated automatically. Based on the initial
segmentation, a medical expert was asked to perform: (a) chunk-based (CBR) and
(b) mesh-based refinement (MBR). Intermediate results and task completion times
410 R. Beichel et al.
100 12
11
8
60 7
50 6
5
40
4
30
3
20
2
10 1
0 0
GC CBR MBR GC CBR MBR
15
35
14
32.5
13
30
12
27.5 Interaction Time (min)
11
Overlap Error (%)
25
10
22.5
9
20 8
17.5 7
15 6
12.5 5
10 4
7.5 3
5 2
2.5 1
0 0
GC CBR MBR Seed CBR MBR total
Fig. 3 Segmentation quality of the initial graph cut segmentation result, the CBR result, the MBR
result and required user interaction time. See text for details
were recorded. Prior to evaluation, the expert was introduced to the system by an
instructor.
Results of our method for each processing step are summarized in form of box-
and-whisker plots in Fig. 3, and tables for each test case can be found in [1].
Figure 3(a) depicts the overall segmentation score derived from the volumetric
overlap error, the relative absolute volume difference, the average symmetric surface
distance, the RMS symmetric surface distance, and the maximum symmetric surface
distance [7]. A higher overall score implies a better segmentation performance.
The effectiveness of both refinement steps is clearly demonstrated. This is also
reflected in the plots for the mean distance error (Fig. 3(b)) and the overlap error
(Fig. 3(c)). Time required for initial seed placement, CBR, and MBR as well as the
total interaction time is plotted in Fig. 3(d). Results on one CT scan are depicted in
Fig. 4.
As reported in [7], the best overall average segmentation score for automated
segmentation methods was 73, for semi-automated segmentation methods 75, and
for interactive segmentation methods, excluding our method, 76. In comparison, our
method reaches a overall mean segmentation score of 74 after the CBR, requiring
Segmentation of Diseased Livers: A 3D Refinement Approach 411
Fig. 4 Visual comparison of segmentation results for initial graph cut result (a), CBR (b),
and MBR (b). The segmentaion result is shown in blue and the manual reference in red. The
improvement in segmentation quality with each refinement step can be seen clearly
less than one minute of interaction on average. The CBR result can be significantly
improved by the MBR step, which leads to a mean overall score of 82, the best result
of all the fifteen methods evaluated in [7]. For MBR, an additional 5.1 minutes were
required on average. Both results for CBR and MBR are well within score values
gained by comparing the manual reference to an additional independent human
observer, which yield a score of 75 for the liver test cases.
Several additional experiments with different physicians have shown that the system
can be used after a short learning phase (typically less than one hour), because
of the intuitive 3D user interface. The proposed refinement method can easily
be integrated into clinical work-flow. The CT volume together with the manual
generated start region is sent by a radiology assistant to a computing node which
performs the automated segmentation steps. As soon as a result is available, a
radiologist is notified that data are ready for further processing. After inspection,
possible refinement, and approval of correctness, the segmentation can be used for
clinical investigations or planning of treatment. For our experiments, we have used
a full-blown VR setup which is quite expensive. However, a fully functional scaled-
down working setup can be built for a reasonable price, comparable to the costs of
a radiological workstation.
The evaluation of our method on ten test CT data sets shows that a high
segmentation quality (mean average distance of less than 1 mm) can be achieved
by using this approach. In addition, the interaction time needed for refinement is
quite low (approx. 6.5 minutes). Thus, the presented refinement concept is well
suited for clinical application in the context of liver surgery planning. Future work
will focus on making the MBR step faster by incorporating local data terms into
the user-steered deformation process. In general, our approach is not limited to a
specific organ or modality, and therefore, it is very promising for other medical
segmentation applications.
412 R. Beichel et al.
Acknowledgments This work was supported in part by the Austrian Science Fund (FWF) under
Grants P17066-N04 and Y193 and the Doctoral Program Confluence of Vision and Graphics
W1209-N15
References
Abstract This chapter proposes a review of the most prominent issues in analysing
brain functional Magnetic Resonance data. It introduces the domain for readers with
no or little knowledge in the field. The introduction places the context and orients
the reader in the many questions put to the data, and summarizes the currently
most commonly applied approach. The second section deals with intra subject data
analysis, emphasizing hemodynamic response estimation issues. The third section
describes current approaches and advances in analysing group data in a standard
coordinate system. The last section proposes new spatial models for group analyses.
Overall, the chapter gives a brief overview of the field and details some specific
advances that are important for application studies in cognitive neurosciences.
The goal of this section is to present a synthetic view of the principles, goals and
techniques of fMRI data analysis. It does not try to be exhaustive but proposes a
specific view on this domain of research. It may therefore interest readers with some
knowledge of the field as well as naïve readers looking for entry points. As the
first functional Magnetic Resonance Images were acquired in the early nineties, the
domain is still young and the current techniques are evolving quickly. Nevertheless,
the research questions and directions described in this chapter are likely to still
be of interest for some time even with the anticipated evolution of acquisition and
processing techniques.
1.1 Background
As previously described, fMRI data are often used for detecting brain regions whose
hemodynamic varies across experimental conditions. Applications in humans’
studies can be roughly located on two axes: group versus single subject studies and
normal versus patient studies. On the latter axis, the understanding of human brain
functions is opposed to dysfunctions in psychiatric or neurological diseases. On the
former axis, the specific information obtained from a particular subject is contrasted
to the description of the information obtained at the population level. Using groups
of normal subjects, cognitive neuroscientists that use fMRI to probe brain functions
are seriously challenged by philosophers or psychologist such as J. Fodor [1] who
claim that localizing brain regions that respond to certain stimuli does not help to
understand how the brain functions. Fodor uses the mechanistic analogy of a car
engine, and asks how the knowledge of the localisation of pieces such as the piston
or carburettor helps to understand the function of theses pieces in the engine. It does
not, unless one is interested in mending some parts, as the neurosurgeon might be
for pathologies involving brain surgery. While the argument is potent it does not
account for the numerous occasions where the spatial organisation is a reflection of
the functioning, such as the retinotopic organisation of the early visual cortex, and
that brain region characterisation and localisation might be a necessary first step in
the process of defining models of brain functioning.
In this section, we propose a particular view of the current research in the analysis
of fMRI data. While the domain is complex and rapidly growing, the classification
that we describe suggests a certain view on the domain and should help the reader
to orient himself or herself in the current techniques proposed.
The most common approach that has dominated the past decade can be decomposed
in the following steps. It success is linked to freely available tools such as SPM (see
www.fil.ucl.ac.uk/SPM) or FSL (fsl.fmrib.ox.ac.uk/fsl).
Step 1. Data pre-processing: temporal and spatial realignments. Subjects are
never completely still in the scanner and movement needs to be corrected with a
strong impact on the signal obtained. Movements correlated to the experimental
paradigm are particularly difficult to correct if not impossible. Most current
techniques assume a rigid body movement between two brain scans. Temporally,
the slices of one brain volume are not acquired at the same time, and all voxel time
series are usually interpolated to impose a unique timing for all voxels of one brain
volume.
Step 2. (can also be done after step 3) If a group analysis is to be performed,
the data of different subjects need to be placed in a standard coordinate system.
While there are many different techniques to perform this, the most usual procedure
is to first realign the functional volumes to the anatomical volume acquired in the
same scanning session, and use this more detailed image to derive a deformation
field that warps the subject brain anatomy to a standard template (generally the
so called ICBM152 volume image which represents the average of 152 healthy T1
brain images by reducing it to 2 mm isotropic resolution). This template corresponds
(but only approximately) to a brain neurosurgical atlas, the Talairach and Tournoux
atlas [4]. Because of anatomical or functional variability across subjects, the
registration is not perfect and regional activity from different subjects is not located
exactly at the same location in the standard coordinate system. Gaussian filtering
is therefore often applied to fMRI data to enhance the possible overlap of regional
activity across subjects.
Step 3. Modelling the BOLD signal and constructing statistical maps. To a first
approximation the BOLD hemodynamic response function (HRF) can be considered
as a linear phenomenon with respect to stimulation. A linear model is constructed
that includes all experimental factors which are believed to impact the BOLD signal.
For instance, three experimental conditions will be modelled by three regressors.
Each regressor is constructed as the convolution of a standard HRF with a time series
Intra and inter subject analyses of brain functional Magnetic Resonance Images (fMRI) 419
Localising the functional activity, while crucial to the field, is a difficult issue
that meets several challenges. At the single subject level, reporting the localisation
appropriately relies on a good correspondence between the anatomical and func-
tional images, as well as a good identification of the individual brain structures. The
more difficult problem arises when reporting group results. Indeed, the algorithms
that warp a subject anatomy to a template do not and cannot perform a perfect match.
The information used for the warping is the main anatomical features (deep sulci,
ventricules) but the variation of the anatomy between subjects is such that there
is no obvious point to point correspondence between subjects. The identification
of individual structures is not easy either (see [6]). The relation between sulco-
gyral anatomy and functional activity is still to be further studied. Secondly, activity
of different subjects may not be localised exactly at the same location within an
anatomical structure. For instance, the Fusiform Face Area (responding more to
face than to objects) may be localised more anteriorly in the fusiform gyrus in
one subject compared to another. This prompts to other solutions than the standard
stereotactic space to detect and report the localisation of functional activity (see
Sect. 4). A number of laboratories now consider that the appropriate localisation
technique is to define subject per subject functional regions using a first experiment,
then study the activity of those well defined regions in a second step [7]. This also
makes statistical inference trivial.
While the techniques described previously aim at localizing the activity in the
brain, and therefore defining spatially functional modules, an increasingly large
part of the literature is now devoted to establishing functional connections between
brain regions. The original observation by Biswal et al. show that even during no
motor activity (resting state or other such as visual stimulation), BOLD signal of a
series of regions that respond to motor tasks are correlated. Since then, two main
approaches are concurrently explored. The first one tries to extract networks of
correlated activity (or sharing some information) and techniques such as principal
component analysis, independent component analysis (ICA), probabilistic ICA,
partial least square (PLS), various clustering techniques, self organizing maps, etc.
To summarize, those methods aim at defining the various functional networks that
underlie brain activity and their relation to external tasks or stimulations. The
alternative approach consists in defining a specific network, a graphical model,
choosing a priori the nodes and the structure of the graph, and to estimate the
functional links given the experimental paradigm. This led to the development
of structural equation models, dynamical causal models, etc. With the current
approaches, graphical models are generally not able to identify network structures
without strong a priori knowledge, while exploratory approaches often suffer from
a lack of interpretability. Furthermore, the steady states used in many functional
Intra and inter subject analyses of brain functional Magnetic Resonance Images (fMRI) 421
connectivity studies are not always well-defined states, hence it would be of interest
to extend the notion of functional connectivity to states that are controlled to a larger
extent by the experimenter and that follow a predefined dynamic. Finally, signal
similarity does not only come about by functional interaction, but can be influenced
by confounding physiological effects of no interest like heart beat or artefacts like
subject motion (Dodel et al. 2004).
In this last subsection, we review briefly three important axes that should get an
increasing attention in the future.
• Adapting techniques to inter individual variability. The development of spatial
models able to account for (limited) inter individual variability of the activity
localisation is currently being established. This research relates to parcellation
techniques, that define parcels with similar functional activity and close spatial
activity, or hierarchical models of the spatial localisation in which the second
level model parameter corresponds to the group location. Variability is also to be
modelled for the magnitude of the activity once a location is defined, for which
non parametric modelling and testing show promising results. The identification
of individual structures such as sulci or fibre tracks will play an important role
in this by providing better coordinate systems based on individual anatomical or
functional landmarks.
• Decoding versus detecting? Recent works originating from Haxby et al. REF
have reversed the usual data processing by considering how fMRI data can
predict the experimental conditions. This was thought by some to be a step
forward an actual decoding of the brain activity. Often, these works try to extract
the regions or voxels that have the best predictive power. Methods to select those
voxels or regions are still under development and the specificity of those voxels or
regions with respect to the task or condition (their importance for the prediction)
is still an open question. Those techniques are sometime called Multivariate
Pattern Analysis (MPVA) and have hoped to shift the focus from where the
processing occurs in the brain to how that processing represents information.
These methods are likely to be much more sensitive compared to massively
univariate approaches but should lose localisation information.
• Databasing and datamining. The need to store, organise and share the large
amount of information that is acquired and processed in functional neuroimag-
ing has been acknowledge early with various initiatives. We cite here a few
significant attempt. Brainmap from P. Fox and coll. proposes to store biblio-
graphic information, experimental descriptors and 3D Talairach coordinates. The
fMRIDC database contains fMRI scanning data and summary images. The BIRN
initiative has created a repository of anatomical and functional brain images
accessible to a large network of hospitals. Clearly, the results obtained from a
database of hundreds or thousands of brain scan can reach a level of sensitivity
422 J.B. Poline et al.
that is not comparable to the results obtained with ten or twenty subjects.
However, those are yet early attempts limited in their use and in their proposals
that lack query and search systems as well as stable ontology of domains such as
brain localisation and neuropsychology or cognitive neuroscience. Nevertheless,
the need for sharing and exploiting large amounts of imaging, behavioural,
physiological and genetic data is likely to put pressure on neuroimaging as the
human genome project has a decade before.
In this formulation, the modelling of the BOLD response i.e. the definition of the
design matrix X is crucial. In its simplest form, this matrix relies on a spatially
invariant temporal model of the BOLD signal across the brain meaning that the
expected response to each stimulus is modelled by a single regressor. Assuming the
neurovascular system as linear and time-invariant (LTI), this regressor is built up as
the convolution of the stimulation signal xm associated to the mth stimulus type with
the canonical HRF hc , i.e. a composition of two gamma functions which reflects the
BOLD signal best in the visual and motor cortices [8]. The GLM therefore reads:
where yj is the fMRI time series measured in voxel Vj at times .tn /nD1WN and aj 2
RM defines the vector of BOLD effects in Vj for all stimulus type m D 1 W M .
Noise bj is usually modelled as a first-order autoregressive (i.e. AR(1)) process
in order to account for the spatially-varying temporal correlation of fMRI data [5]:
bj;tn D j bj;tn1 C"j;tn ; 8j; t, with "j N .0N ; "2j IN /, where 0N is a null vector
of length N , and IN stands for the identity matrix of size N . Then, the estimated
BOLD magnitudes b aj in Vj are computed in the maximum likelihood sense by:
b
aj D arg min kyj Xaj k2 2 ;
"j b
b ƒj
a2RM
where b 2 b
"j ƒj defines the inverse of the estimated autocorrelation matrix of bj ;
see for instance [9] for details about the identification of the noise structure. Later,
extensions that incorporate prior information on the BOLD effects .aj /j D1WJ have
been developed in the Bayesian framework [10]. In such cases, vectors .b aj /j D1WJ
Intra and inter subject analyses of brain functional Magnetic Resonance Images (fMRI) 423
are computed using more computationally demanding strategies [10]. However, all
these GLM-based contributions consider a unique and global model of the HRF
shape while intra-individual differences in its characteristics have been exhibited
between cortical areas [11].
t statistic can no longer be used to infer on differences aj anj between the mth
m
and nth stimulus types. Rather, an unsigned Fisher statistic has to be computed,
making direct interpretation of activation maps more difficult. Indeed, the null
hypothesis is actually rejected whenever any of the contrast components deviates
from zero and not specifically when the difference of the response magnitudes is far
from zero.
The localisation of brain activation strongly depends on the modelling of the brain
response and thus of its estimation. Of course, the converse also holds: HRF
estimation is only relevant in voxels that elicit signal fluctuations correlated with the
paradigm. Hence, detection and estimation are intrinsically linked to each other. The
key point is therefore to tackle the two problems in a common setting, i.e. to set up
a formulation in which detection and estimation enter naturally and simultaneously.
This setting cannot be the classical hypothesis testing framework. Indeed, the
sequential procedure which consists in first estimating the HRF on a given dataset
and then building a specific GLM upon this estimate for detecting activations in the
same dataset, entails statistical problems in terms of sensitivity and specificity: the
control of the false positive rate actually becomes hazardous due to the use of an
erroneous number of degrees of freedom. Instead, we explore a Bayesian approach
that provides an appropriate framework, called the Joint Detection Estimation (JDE)
framework in what follows, to address both detection and estimation issues in the
same formalism.
424 J.B. Poline et al.
X
M
yj D ajm Xm h C P` j C bj ; 8 j; Vj 2 P: (2)
mD1
Intra and inter subject analyses of brain functional Magnetic Resonance Images (fMRI) 425
Fig. 2 Regional model of the BOLD signal in the JDE framework. The neural response levels ajm
match with the BOLD effects ajm
Xm denotes the N .D C 1/ binary matrix that codes the onsets of the mth
stimulus. Vector h 2 RDC1 represents the unknown HRF shape in P. The term
P`j models a low-frequency trend to account for physiological artifacts and noise
bj Ï N .0N ; "2j ƒ1
j / stands for the above mentioned AR(1) process.
The HRF shape h and the associated BOLD effects .aj /j D1WJ are jointly estimated
in P. Since no parametric model is considered for h, a smoothness constraint on the
second order derivative is introduced to regularise its estimation; see [15]. On the
other hand, our approach also aims at detecting which voxels in P elicit activations
in response to stimulation. To this end, prior mixture models are introduced on
.am /mD1WM to segregate activating voxels from the non-activating ones in a stimulus-
specific manner (i.e. for each m). In [16], it has been shown that Spatial Mixture
Models (SMMs) make it possible to recover clusters of activation instead of isolated
spots and hence to account for spatial correlation in the activation detection process
without smoothing the data. As our approach stands in the Bayesian framework,
other priors are formulated upon every other sought object in model (2). The reader
is referred to [15, 16] for their expressions. Finally, inference is based upon the
full posterior distribution p.h; .aj /; .` j /; ‚ j Y/, which is sampled using a Gibbs
sampling scheme [16]. Posterior meanP (PM) estimates are therefore
˚ computed from
L1
these samples according to: b x PM D kDL0 x .k/
=L; 8 x 2 h; .aj /; ‚ where
L D L1 L0 C 1 and L0 stands for the length of the burn-in period. Note that
this estimation process has to be repeated over each parcel of each subject’s brain.
Since the fMRI data are considered spatially independent across parcels, parallel
implementation makes the computation faster: whole brain analysis is achievable in
about 60 mn for N D 125 and K D 500.
426 J.B. Poline et al.
Real fMRI data were recorded in fifteen volunteers during an experiment, which
consisted of a single session of N D 125 scans lasting TR D 2:4 s each.
The main goal of this experiment was to quickly map several brain functions
such as motor, visual and auditory responses, as well as higher cognitive func-
tions like computation. Here, we only focus on the auditory and visual experi-
mental conditions and so on the auditory-visual contrast of interest (referenced
as A:V:).
2.4.2 Results
We compare the BOLD effect estimates for the two within-subject analyses under
study. Fig. 3 clearly emphasizes for the A:V: contrast that the JDE method
achieves a better sensitivity (bilateral activations) in comparison with GLM-based
inference when processing unsmoothed data. Indeed, the BOLD effects b d jA:V:
have higher values in Fig. 3(b) and appear more enhanced. This is partly due to
the modeling of spatial correlation using SMM in the JDE framework. As shown
in Fig. 3(c)-[red line], notice that the HRF estimate b hP computed in the mostly
activating parcel deviates from the canonical shape depicted in Fig. 3(c)[green line].
Intra and inter subject analyses of brain functional Magnetic Resonance Images (fMRI) 427
To clarify the context, assume that S subjects are selected randomly in a population
of interest and submitted to the same fMRI experiment. As shown in previous
sections, the two types of within-subject analyses produce, in one particular voxel
Vj of the standardized space (usually, the MNI/Talairach space) and for each
subject s, BOLD effect estimatesb aj;s . Comparison between experimental conditions
is usually addressed through contrast definition. For mathematical convenience,
we restrict ourselves to scalar contrasts. Hence we focus on signed differences
b D b̌m b̌n
j;s j;s of the BOLD effect relative to the m and n stimulus types.
mn th th
d j;s
For notational convenience, we will drop index j and the contrast under study m n
in what follows.
While the estimated difference bd s generally differs from the true but unobserved
effect ds , assume for now perfect within-subject estimation so that b d s D ds
for s D 1 W S . We thus are given a sample .d1 ; ; : : : ; dS / drawn from an unknown
probability density function (pdf) f .d / that describes the distribution of the effects
in the population. Here, we are concerned with inferences about a location parameter
(mean, median, mode, ...). Assume for instance we wish to test the null hypothesis
that the population mean is negative:
Z
H0 W G D d f .d /dd 0
where G stands for the group. To that end, we may use the classical one-sample
t test. We start with computing the t statistic:
P P
O G ds O G /2
s .ds
tD p ; with W O G D s
; O G2 D (3)
O G = S S S 1
If normality is not tenable, however, the Student distribution is valid only in the
limit of large samples, and may thus lead to inexact control over the false positive
rate in small samples. This problem can be worked around using non-parametric
calibration schemes such as sign permutations [19], which allow exact inferences
under a milder assumption of symmetry regarding f .d /. Although we recommend
permutation tests, they only provide an alternative strategy of thresholding a given
statistic and, as such, address a specificity issue.
The fact that the sampling pdf f .d / may not be normal also raises a sensitivity
issue as the t statistic may no longer yield optimal power when normality does not
hold. Without prior knowledge of the shape of f .d /, a reasonable default choice for
the test statistic is one that maintains good detection performance over a wide range
of pdfs. Such a statistic is robust, not quite in the classical sense of being resistant
to outliers, but in the looser sense of being resistant to distributions that tend to
produce outliers, such as heavy-tailed, or multimodal distributions. In the following,
we use Wilcoxon’s signed rank (WSR) statistic while other robust choices could
be envisaged (Fisher’s sign test, empirical likelihood ratio). As a matter of fact,
such statistics have been used previously in fMRI group analyses [20], most often
combined with permutation tests.
To enforce the coherence of our group level comparison with actual pipelines for
fMRI data processing (SPM, FSL), the fMRI images that enter in model (1) were
spatially filtered using isotropic Gaussian smoothing at 5 mm. In the JDE formalism,
we still consider unsmoothed but normalized data to build the group parcellation as
described in Fig. 4. Note that both approaches will be available in the next release
of BrainVisa (http://brainvisa.info) in March, 2008.
Fig. 5 provides us with the WSR statistical maps, corrected for multiple
comparisons in the permutation testing framework. The displayed slices matched
with the place of most significant activations. Activation clusters appear larger
in Fig. 5(b-d-f), i.e. using the GLM based approach, as a direct consequence of
smoothing. The statistical map derived at the group level from the JDE analyses
seems to have a lesser extent while being more significant at the cluster level
than the GLM counterpart in the right hemisphere (left side). Moreover, the JDE
formalism allows us to detect a gain in sensitivity since activations in Broca’s area
can be seen in the front of Fig. 5(a), right side. Table 1 confirms quantitatively these
results and emphasizes that GLM-based inference systematically reports clusters
of larger size (see col. 3). However, in terms of significance, the situation appears
more contrasted since cluster level p-value is lower in the right hemisphere for
Intra and inter subject analyses of brain functional Magnetic Resonance Images (fMRI) 429
Fig. 5 RFX analysis maps based on the WSR statistics in the slice corresponding to the mostly
activated cluster. Radiological convention: left is right. (a)-(c)-(e) and (b)-(d)-(f): results obtained
using the JDE and SPM analyses at the subject level, respectively
430 J.B. Poline et al.
JDE (top line in Table 1) in one cluster over two and thus provides most significant
activation. This might be a consequence of the between-subject variability that we
observed in the HRF estimate as reported in Fig. 6.
In group analyses of fMRI data, the question is to decide which regions show a
positive effect in average across subjects for a given functional contrast. This can
be assessed in mass univariate framework through a normalization of the images to
a common template, which in turns coregisters the data across subjects. However,
as discussed in Sect. 4.1, this procedure aligns neither anatomical landmarks nor
functional regions very accurately. Some solutions are thus proposed, which fall
into two categories: i) a prior subdivision of the brain into putatively homogeneous
regions (parcels) that may be better matched across subjects than voxels (Sect. 4.2)
and ii) structural approaches that try to extract individual patterns and compare them
at the group level (Sect. 4.3).
Intra and inter subject analyses of brain functional Magnetic Resonance Images (fMRI) 431
A parcellation of the brain is a division of the brain into entities which are thought to
correspond to well-defined anatomical or functional regions. In the context of group
inference for neuroimaging, basing the analysis on parcels amounts to sacrificing
spatial resolution to obtain a more reliable as well as interpretable matching of
functional regions. Although atlas-based divisions are quite frequently used, it
should be pointed out that these procedures do not adapt to the individual anatomy,
and thus do not address the problem raised here.
Parcellations can be based on anatomical or functional features. Anatomical
parcellations are usually based on sulco-gyral anatomy [26], and yield some
segmentations of the main cortical lobes into a few tens of connected regions.
Basal ganglia and the cerebellum are handled with specific (usually atlas-based)
procedures. However, these procedures yield extremely coarse divisions of the
brain, and thus cannot be used straightforwardly for brain mapping. Sulci-based
parcellations can be performed at a much finer scale in individual datasets [27] but
then the correspondence of the parcels between subject can be difficult to guarantee.
As we have noticed, functional information itself could ultimately be a very
useful feature to segment the brain into small homogeneous regions. Brain par-
cellation can thus be driven by both functional and anatomical information. Such
procedures are usually based on clustering algorithms that segment small clusters
of voxels so that i) each parcel should be defined in each subject of the group under
study, ii) the parcels should be functionally homogeneous and spatially connected
within subjects iii) they should have similar functional properties and position across
subjects. Ideally, parcellations could be performed on some functional localizer
experiment, and then used to perform group inference in some experiment of
interest. Alternatively, the same data can be used for parcellation and inference,
but then the inference procedure should be based on a costly non-parametric test
which involves the computation of parcellation and statistic [17].
Parcellations are an especially interesting tool if one is interested in describing
the modular structure of the brain. This perspective raises important questions on
how many brain modules could be delineated at the population level based on some
functional information. There is clearly a compromise between the accuracy of the
description, which would favor small parcels, and the inter-subject reproducibility
of the structures, which is better assessed with coarse descriptions.
Fig. 7 structural analysis of the regions involved in a computation task: (a) Group template built
from datasets from 10 subjects. (b-f) corresponding regions in 5 representative subjects. It is
important to notice that there is no one-to-one correspondence, but a global pattern similarity
between subjects. Moreover, the group template should be taken as an abstract model of the
individual maps, while each individual data represent true activations; see [29] for more details
terms of blobs, peaks or gradients. Finding which patterns of that kind are present in
a dataset and how frequent/typical they are in a population of subjects is what we call
here a structural approach to understanding brain functional anatomy. By contrast
with traditional approaches this kind of inference follows bottom-up strategy, where
objects extracted individually are compared at a high-level of description.
Typically, structural features or patterns that are relevant for descriptions are local
maxima of activity, regions segmented by watershed methods or blob models. The
emphasis may be either on the structure of the active regions (bifurcations pattern),
or merely the peaks (local maxima).
Whatever the kind of pattern extracted from the data, the most difficult questions
are i) to decide how likely these patterns represent true activity or noise-related
artifacts; ii) to infer a pattern common to the population of subjects. Several
approaches have been discussed in the literature
• The description in terms of scale-space blobs embedded in a Markov-Random
field was introduced in [28] in order to yield a kind of threshold-free analysis,
where inter-subject reproducibility plays a key role for inference. A stepwise
re-formulation of this approach was proposed in [29]. See Fig. 7.
• The idea that peaks could be a reliable feature to describe the information carried
by an activity map and implicitly align the subjects yielded the concept of brain
functional landmark [30].
434 J.B. Poline et al.
The benefit of this kind of structural method is that regions extracted from
individual datasets can then be compared across subjects or groups from the point
of view of their position, size or shape, which is not possible in traditional voxel-,
cluster- or even parcel-based inference framework.
Conclusion
References
R. Neji
Siemens Healthcare, UK
e-mail: [email protected]
N. Azzabou ()
Institute of Myology 47 Boulevard Hôpital, 75013 Paris, France
e-mail: [email protected]
G. Fleury
Ecole Centrale Pékin
No. 37 Xueyuan Street, Haidian District Beijing, 100191, P.R. China
e-mail: [email protected]
N. Paragios
Center for Visual Computing, Department of Applied Mathematics, Ecole Centrale Paris, Paris,
France
e-mail: [email protected]
or from distance substitution in the Gaussian Radial Basis Function (RBF) kernel.
Experimental results on diffusion tensor images of the human skeletal muscle (calf)
show the potential of our algorithms both in denoising and SVM-driven Markov
random field segmentation.
1 Introduction
2 Previous work
Let us assume that n DTI acquisitions (Sk )kD1 : : : n with respect to different magnetic
gradient directions (gk )kD1 : : : n are available. Ideally, the expected signal at a voxel x
for the direction k as explained in [24] should respect the following condition
Sk .x/ D S0 .x/ exp bgtk D .x/ gk
with the tensor D being the unknown variable and b a value that depends on the
acquisition settings. The estimation of the tensors in the volume domain can
be done through direct inference (6 acquisitions are at least available), which is
equivalent to minimizing:
Z X
n
2
Edat a .D/ D log .Sk .x/ =S0 .x// C bgtk D .x/ gk d x
kD1
This energy is based on the linearized diffusion tensor model which is reasonable for
moderate values of SNR [23]. Such a direct estimation is quite sensitive to noise, on
the other hand, it refers to a convex term, which is rather convenient when seeking
its lowest potential. The most common approach to account for noise is through the
use of an additional regularization term which constrains the estimation of D to be
locally smooth. One of the most prominent uses of DTI is fiber extraction. Therefore
it is natural to assume that locally these fibers do have similar orientations. In such a
context, the tensor can be expressed as a linear combination of the tensors lying in its
neighborhood since they are likely to represent the same population of fibers. Such a
regularization constraint was introduced in the case of image restoration in [1]. This
assumption still holds at the boundaries between different groups of fibers as long as
the linear combination is thoroughly chosen to ensure that the contribution of tensors
belonging to a different fiber population is negligible. It is also more accurate than
the underlying assumption of total-variation based approaches where the tensor field
is considered piecewise constant. This leads us to define the following regularization
component:
Z Z 2
1
Esmoot h .D/ D D.x/ w.x; y/D.y/d y
Z.x/ dx
y2Nx F
One can easily show that such an expression does not reflect similarity between
tensors according to the norm k kF . In fact, this leads to
v
uN
uX
d .D.x/; D .y// D t < D .x/ D .y/; Gk >2F
kD1
One now can seek the lowest potential of the cost function towards recovering
the optimal solution on the tensor space. The present framework consists of a
convex energy with a unique minimum which can be reached using a projected
gradient descent on the space of semi-definitive positive matrices. The projection
from S3 onto S3C denoted by …S 3 is well defined and has an explicit expression.
C
Indeed, projecting M amounts to replacing the negative eigenvalues in its spectral
decomposition by 0 [8, 12]. Note that we minimize over the set of semi-definite
positive matrices because it is topologically closed, as opposed to the set of definite
positive matrices. In the current setting, the problem is well posed and the projected
gradient descent algorithm is convergent for a suitable choice of the time step dt.
Using a weighting factor between the data attachment term and the regularization
energy, the gradient descent can be expressed as the following equation
t C1 @E
D .x/ D …S 3 D .x/ dt
t t
.D /
C @D .x/
@Esmoot h t @Edat a t
D …S 3 D .x/ dt
t
.D / dt .D /
C @D .x/ @D .x/
where
Z
@Esmoot h w .x; y/
.D/ D 2D .x/ 2 D .y/ d y
@D .x/ y2Nx Z .x/ !
Z Z
w .x; y/ w .x; y/
–2 D .y/ – D .z/ d z d y
y2Nx Z .x/ z2Ny Z .y/
@Edat a XN
.D/ D 2b log .sk .x/ =s0 .x// C bgtk D .x/ gk Gk
@D .x/
kD1
R us define the norm k kTF over the whole tensor field D as k D kTF D
Let
˝ k D(x) kF dx. Considering two tensor fields D1 and D2 , we show in the following
that the gradient of our energy functional is L-Lipschitz. The constant L will allow
us to choose automatically a time step that insures the convergence of the algorithm.
N
@Edat a X
@E dat a
@D .x/ 1.D / .D /
2 D 2b 2
< Gk ;D 1 D 2 F k
> G
@D .x/ F
kD1 F
X
N
2b 2
k Gk k2F k D1 D2 kF
kD1
PN
Therefore k rEdata (D1 ) rEdata (D2 ) kTF 2b 2 kD1 k Gk k 2F k D1 D2 kTF .
Besides, we can easily show the following inequality
Diffusion Tensor Estimation, Regularization and Classification 443
k rEsmoot h .D1 / rEsmoot h .D2 / kTF 2 1 C 2 jNx j C jNx j 2 k D1 D2 kTF
where jNx j is the number of the considered neighbors. Thus the gradient of the
XN
objective function is L-Lipschitz with L D 2b 2 k Gk k2F C 2œ.jNx j C 1/2 .
kD1
1
Choosing 0 < dt < XN makes the projected gradient
b2 k Gk k2F Cœ.jNx jC1/2
kD1
descent convergent [3].
We can give an interpretation of our regularization energy in terms of diffusion-
weighted images smoothing. It can be easily verified that for each direction k
Z
R w.x; y/
< D.x/ y2Nx D.y/d y; Gk >2F d x D
2 Z.x/ 0 13 2
Z Y
w.x;y/
1 4log Sk .x/ log @ Sk .y/ Z.x/
A5 d x
. /
b2 S0 .x/ S0 .y/
y2Nx
We can see that minimizing Esmooth has a direct implication on the normalized
diffusion weighted images SSk0 . Reconstructing the tensors using a linear combination
of the tensors in its neighborhood leads to the reconstruction of the normalized
signals using a weighted geometric mean of the neighboring signals where the
weights are not calculated only with a single volume Sk but also with the volumes
obtained from the other magnetic gradient directions.
We briefly review the principles of two class SVMs [26]. Given N points xi with
known class information yi (either C1 or 1), SVM training consists in finding
the optimal separating hyperplane described by the equation wt x C b D 0 with the
maximum distance to the training examples. It amounts to solving a dual convex
quadratic optimization problem and each data point x is classified using the SVM
output function f (x) D (†Ni ˛ i yi xxi ) C b. The algorithm is extended to achieve non
linear separation using a kernel function K(x,y)(symmetric, positive definite) that is
used instead of the standard inner product.
444 R. Neji and N. Azzabou
In order to define a kernel on the set of definite positive matrices, we can propagate
class and structure information using its geometry as a Riemannian manifold [22].
Intuitively, we can see the construction of this kernel as diffusing the labels of the
training set to the whole set of definite positive matrices. Therefore, similarly to heat
diffusion on a Euclidean space, where the solution is given by the convolution of the
initial condition by a Gaussian kernel, heat diffusion on a Riemannian manifold
is driven by a kernel function Kt and given by the following asymptotic series
expansion [17]:
1
d 2 .D1 ; D2 / X
Kt .D1 ; D2 / / exp an .D1 ; D2 /t n
4t nD0
Instead of using the geodesic distance in the information diffusion kernel, one
can instead use the Bregman divergence framework [25] to define a rich class of
kernels parametrized by a convex scalar function W sC 3
! R that extend in a
natural way the Euclidean distance and therefore the standard Gaussian radial basis
function kernel. Knowing , one can define the corresponding Bregman divergence
D between two matrices D1 and D2 as follows:
D .D1 ; D2 / D .D1 / .D2 / t r r.D2 /t .D1 D2 /
_
The symmetrization of the divergence gives the following similarity measure D:
_
D .D1 ; D2 / D t r .r .D1 / r .D2 //t .D1 D2 /
Diffusion Tensor Estimation, Regularization and Classification 445
It is clear that choosing .D/ D 12 kDk2F yields the standard Euclidean distance.
Therefore, we extend the Gaussian radial basis function (RBF) kernel using the
exponential embedding:
_
K.D1 ; D2 / D exp ” D .D1 ; D2 /
Two interesting cases of are the Burg entropy [Eq. (1)] and the Von Neumann
Entropy [Eq. (2)]:
K1 .D1 ; D2 / D exp.
t r..D1 D2 /.D1 1
1 D2 //
K2 .D1 ; D2 / D exp.
t r..D1 D2 /.log.D1 / log.D2 ///
These kernels provide global similarity measures that quantify the differences
between tensors both in eigenvalues and eigenvectors. Note that the divergence that
derives from Burg entropy can also be obtained from a Kullback-Leibler divergence
between Gaussian distributions with zero mean [28].
The third kernel we will study is a probability product kernel [13] to derive a class
of kernels over the set of positive definite matrices. We consider again the set of
Gaussian probability distributions of zero mean, two elements p1 and p2 of this set
with D1 and D2 their covariance matrices and the corresponding probability product
kernel:
Z
K.p1 ; p2 / D p1 .x/ p2 .x/ d x D< p1 ; p2 >L2
where is a positive constant. Note that the special case D 1/ 2 coincides with
the well known Bhattacharyya kernel. Replacing the probabilities p1 and p2 by their
expressions gives the following kernel:
1
K.D1 ; D2 / D det.D1 /=2 det.D2 /=2 det D1
1 C D2
an advantage over the two above-cited classes of kernels which are not necessarily
positive definite. Note however that in practice, a thorough choice of the parameter
will ensure the positive definiteness in a statistical sense, i.e. the property will
hold with high probability [5].
The goal behind the use of an MRF model is two-fold: we aim at including spatial
information, i.e. tensors along the same fiber should belong to the same class and
we also try to minimize the effect of noise during segmentation. Besides, the MRF
framework allows to use all the scores given by the SVMs, instead of making the
labeling decision by simply taking the maximum score. Therefore, we define the
following energy E to minimize:
X X
ED us .l.i // C up .l.i //; l.j / (3)
i 2 i 2 ;j 2N .i /
where is the image domain, l(i) is the label of the voxel i; N .i / is the
considered neighborhood, us is the potential given by the SVM scores and up is
a pairwise potential that imposes spatial regularization. We choose us .l.i // D
exp.˛fl .D.i /// which is a decreasing potential in the score given by a one-
against-all SVM classifier fl . The choice of the pairwise potential up is application-
dependent and should include prior knowledge about the structure of the anatomical
region that is to be segmented. For the case of the muscles of the calf, we know
that the fibers have a privileged orientation since they follow the direction of the leg
with a pennation angle, accordingly we propose two different costs for neighboring
voxels: if the voxels i and j belong to the same axial slice, the pairwise potential up
is set to
where v D kii j
j k
and max .i / is the largest eigenvalue of D.i /; max .i / D
maxkZkD1 zt D.i /z. This potential is low for tensors belonging to the same fiber.
To minimize the energy defined in [Eq. (3)], we use the optimization algorithm
proposed in [16].
Diffusion Tensor Estimation, Regularization and Classification 447
Fig. 1 Tensors on a volume slice: (a) Noisy tensors (b) Ground-truth (c) Result obtained with [8]
(d) Result obtained with our method
Let us consider two volumes, one that consists of two classes with orthogonal axes
on a 20 20 20 lattice and a helix in which the internal voxels are anisotropic and
the external ones are spheric [Fig. 1-b]. For the first volume, the tensor fields for
each region are D1 D 0.001 [1 0.5 0.5 0 0 0] and D2 D 0.001 [0.2 0.4 0.2 0 0 0]
where D is presented in the form of D D [Dxx Dyy Dzz Dxy Dxz Dyz ]. We considered
for both datasets a field strength b D 700 s.mm2 , a constant value for S0 D 60 for
all volume voxels and twelve different directions for diffusion gradient, which are
used to generate the DTI corresponding to such tensor estimations.
The images were corrupted with a white zero-mean Gaussian noise forming a
data set where ground-truth on the tensor are available. An estimation of the tensor
448 R. Neji and N. Azzabou
Table 1 Average Sum of Square Differences (SSD) 104 . Comparisons between our method and
the one in [8]
Helix dataset Homogeneous regions
n 0.5 1.2 3 1.5 4 9
Noisy Tensor 1.08 6.24 39.54 9.82 71.25 393.38
Method in [8] 0.33 1.60 10.57 3.32 22.47 120.70
Our Method 0.41 1.38 3.78 0.44 4.23 18.30
field relative to the noisy images provides the noisy tensors data. Then, to perform
comparisons we considered the regularization algorithm on noisy tensors presented
in [8]. The following parameters were used for our method: D 50; Nx D
3 3 3; dt D 107 with 50 iterations. To evaluate the performance of these
methods, we considered the average sum of squared differences (SSD) between
the regularized tensors and ground truth ones. In [Table 1], we can see that our
estimation and regularization approach achieves better results and produces a tensor
close to the ground truth. Our method outperforms the one of [8] when the level
of noise is relatively important. In fact, it considers a more robust resemblance
degree between voxels. Such a criterion insures a better selection of neighboring
tensors involved in the estimation of a given tensor. On the other hand, the
anisotropic diffusion based regularization relies on gradient information which is
not robust in case of high noise. In order to assess qualitatively our algorithm,
we reported in [Fig. 1] the resulting tensors using our regularization method and
the constrained anisotropic one. We can observe that our method achieves a better
direction preservation, even in the presence of a strong noise.
In order to perform validation using real data, the following experiment was
considered. DTI acquisitions of human skeletal muscle (calf) using 12 directions
were carried out on a 1.5 T MRI scanner with the following parameters : repetition
time (TR) D 3600 ms, echo time(TE) D 70 ms, slice thickness D 7 mm and b value
of 700 s.mm2 . In order to improve the signal-to-noise ratio, the acquisition was
repeated thirteen times (one can use the average of the measurements) while a
high resolution T1-weighted volume was also obtained and manually segmented
[Fig. 2]. The muscles that were considered in our study were the soleus (SOL),
lateral gastrocnemius (LG), medial gastrocnemius (MG), posterior tibialis (PT),
anterior tibialis (AT), extensor digitorum longus (EDL), and the peroneus longus
(PL).
In order to proceed with an evaluation of the proposed method, the following
scenario was considered: Using the manual segmentation, and the observed mea-
surements of a given acquisition (12 directions), we have constructed seven linear
classifiers (a multi-class linear SVM [14]) separating each class of muscle versus
Diffusion Tensor Estimation, Regularization and Classification 449
Fig. 2 A slice of the T1-weighted volume, different muscle groups segmented manually
Table 2 Correct classification rates for the different methods and for each
muscle group. The first and third row show the average correct classification
rates for the set of 13 volumes
Overall MG LG SOL
DE 78.1 % 86.16 % 51.1 % 84.43 %
ADE 84.46 % 90.47 % 65.72 % 88.43 %
DER 86.45 % 91.82 % 69.76 % 89.97 %
all others. Then, the success rate (percentage of voxels being attributed to the right
class) from the classifier with respect to the ground truth was determined. We remark
that linear separation is hardly achieved for PT, PL, EDL and AT while it yields
quite satisfactory results for the MG, LG and to a lesser extent SOL which form the
major part of the muscle. We have performed this test thirteen times for: (i) direct
estimation (DE), (ii) direct estimation and regularization (DER), as well as using
direct estimation of the average measurements of the thirteen acquisitions (ADE).
One would expect that since muscles consist of myo-fibers of the same nature, the
classification should be improved if the estimation of the tensors is properly done,
i.e. with appropriate regularization. However, it is important to note that the aim of
this paper is not automatic classification of voxels in different muscle regions using
DTI (in such a case more advanced classifiers can be used).
In [Table 2], we present quantitative validation of the present framework for the
linearly separable muscles. One can see that our method leads to an improvement
in the correct classification rates with respect to a plain direct estimation. We also
obtain better results when compared to the averaging C estimation method. We also
show the result of our regularization on a slice of the volume in [Fig. 3].
450 R. Neji and N. Azzabou
Fig. 3 Estimated tensors without regularization, tensors obtained with our method
In order to assess the behavior of the defined kernels, we consider the SOL and MG
muscle groups. SVM classification was performed both in a linear and a non linear
fashion using the above-defined kernels.
We motivate the use of kernel-based SVMs by focusing on the architecture of the
soleus muscle. While the medial gastrocnemius is a unipennate muscle (the fibers
have one line of action), the soleus is a bipennate one (the fibers have two lines of
action) and exhibits a richer structure. As can be seen in [Fig. 4] where the principal
directions of diffusion in the MG and SOL muscles are displayed as points on the
unit sphere, it is more natural and mathematically more sound to trace the decision
boundary while respecting the manifold structure, rather than using a hyperplane
to separate the different classes or flattening the manifold using the Gaussian RBF
kernel. We compared the behavior of the defined kernels in separating the MG from
the SOL using a set of 9904 diffusion tensors with approximately the same number
of tensors for each class (4976 tensors belonging to MG, 4928 tensors from the SOL
muscle). We subdivided this set into a training set and a testing one to evaluate the
generalization errors (50 % of the set for the training and 50 % for the testing). As
shown in [Table 3], the kernels that are specific to the space of symmetric positive
definite matrices perform better than the linear classification both in the training and
testing phases. The best result was obtained for the information diffusion kernel with
approximately 3 % of classification error. Note that the number of support vectors
has not increased much with respect to a linear classification.
Diffusion Tensor Estimation, Regularization and Classification 451
Fig. 5 Obtained 3D
segmentation in three groups
with some misclassifications
visible, axial slice of the
baseline image with overlaid
segmentation for the ground
truth, SVM classification and
SVM C MRF algorithm
respectively
6 Discussion
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From Local Q-Ball Estimation to Fibre
Crossing Tractography
Abstract Fibre crossing is an important problem for most existing diffusion tensor
imaging (DTI) based tractography algorithms. To overcome limitations of DTI, high
angular resolution diffusion imaging (HARDI) techniques such as q-ball imaging
(QBI) have been introduced. The purpose of this chapter is to first give state of
the art review of the existing local HARDI reconstruction techniques as well as the
existing HARDI-based tractography algorithms. Then, we describe our analytical
QBI solution to reconstruct the diffusion orientation distribution function (ODF) of
water molecules and we propose a spherical deconvolution method to transform the
diffusion ODF into a sharper fibre ODF. Finally, we propose a new deterministic and
a new probabilistic algorithm based on this fibre ODF. We show that the diffusion
ODF and fibre ODF can recover fibre crossing in simulated data, in a biological
phantom and in real datasets. The fibre ODF improves angular resolution of QBI by
more than 15ı and greatly improves tractography results in regions of complex fibre
crossing, fanning and branching.
M. Descoteaux ()
Department of computer Science, 2500 Blv. Université, Sherbrooke, Quebec JIK 2RI, Canada
e-mail: [email protected]
R. Deriche
Athena Project Team, INRIA Sophia Antipolis-Méditerranée, 2004 Route des Lucioles, BP 93
06902 Sophia Antipolis Cedex
We know that in these locations, the diffusion is non-Gaussian and the diffusion
tensor (DT) [8] is limited due to its intrinsic Gaussian diffusion assumption. Hence,
DT-based tractography algorithms can follow false tracts and produce unreliable
tracking results. To overcome limitations of the DT, new high angular resolution
diffusion imaging (HARDI) techniques [2, 65] have been proposed to estimate the
diffusion orientation distribution function (ODF) [66] of water molecules or other
high order spherical function estimate of the diffusion profile [4, 5, 20, 34, 37, 38, 40,
52, 58, 63, 64], These HARDI techniques (see Fig. 1) were developed to deal with
non-Gaussian diffusion process and to reconstruct spherical functions with maxima
aligned with the underlying fibre populations.
In this chapter, we focus on deterministic and probabilistic tractography using
state of the art reconstruction of the diffusion and fibre ODF from QBI. QBI
is of interest because it is model-free and it can be computed analytically and
robustly with low computational cost [23]. First, we review the existing HARDI
reconstruction techniques and state of the art HARDI-based tractography algorithms
to put our new methods into context. Then, we develop our analytical solution
to reconstruct the diffusion ODF and the fibre ODF from QBI data. Finally,
we describe a new deterministic tractography algorithm and a new probabilistic
tractography algorithm able to recover complex fibre tracts with known crossing,
fanning and branching configurations. Most current DTI based methods neglect
these fibres, which might lead to wrong interpretations of the brain functions.
2 Prior Art
1
There is very recent development in multiple-shell acquisition schemes (see [41]).
From Local Q-Ball Estimation to Fibre Crossing Tractography 457
The goal of HARDI is to capture multiple fibre directions within the same imaging
voxel. Some HARDI reconstruction techniques are model dependent, some model-
free, some have linear solutions whereas others require non-linear optimization
schemes. A schematic view of the major multiple fibre HARDI reconstruction
algorithms is shown in Fig. 1. A good review of these methods up to 2005 can be
found in [2]. We now summarize the major techniques.
It is a simple extension of the DTI model to assume that a mixture of Gaussians
can describe the diffusion PDF. [65] proposed the initial solution and many other
works [1, 13, 18, 48, 55, 65, 67] proposed variants of the multi-Gaussian with
constraints such as forcing symmetry of eigenvalues, forcing certain magnitude
and ratios of eigenvalues or imposing positive definiteness of the DT (see [2]).
A similar approach to multi-Gaussian modeling is the ball & stick mixture model. It
assumes that water molecules in an imaging voxel belong to one of two populations,
a restricted population within or near fibre structures (stick), modeled with an
anisotropic Gaussian distribution, and a free population that is not affected by
fibre structure barriers (ball), modeling by an isotropic Gaussian distribution. The
approach extends to a mixture of restricted compartments and is thus able to recover
multiple fibre compartments [10, 33]. Another similar approach is the CHARMED
technique [7]. This technique assumes a highly restricted compartment that is
non-Gaussian and a hindered compartment that is approximately Gaussian. The
approach can also be formulated as a mixture of restricted compartments and is thus
able to recover multiple fibre compartments. The multi-Gaussian, ball & stick and
CHARMED all suffer from the same shortcomings regarding model selection and
numerical implementation. One must select the number of compartments a priori,
one must use non-linear optimization to solve for the parameters and the methods
are sensitive to noise and to the number of measurements.
Spherical deconvolution (SD) methods generalize the mixture modeling meth-
ods of the previous section by assuming a distribution of fibre orientations to
overcome the limitation of the number of compartment selection n. The original
SD method [64] was improved in [4, 20, 37, 40, 57] using non-linear optimization
techniques that better deal with the SD instabilities, noise and negative diffusion
appearing in the deconvolution process. A recent review SD methods can be
found in [37]. In [38], the case of multiple fibre bundles is handled in a similar
way to the SD methods. The novelty is that each fibre bundle is represented by
a Wishart distribution. This leads to a reformulation of DTI in the presence of
a single orientation but is also able to account for multiple fibre crossings. In
contrast, in [49], the diffusion ODF is modeled with a mixture of von Mises-Fisher
distributions, which allows for the definition of a closed-form Riemannian distance
between diffusion ODFs.
Another model-independent method reconstructs the radially persistent angular
structure (PAS) [2, 34] of the diffusion PDF. The reconstruction forces probabilities
to be non-zero only on a spherical shell of a certain radius. The PAS reconstruction
458 M. Descoteaux and R. Deriche
is non-linear and computationally very heavy but recent efforts [61] have been done
to propose a linearized solution to PAS-MRI based on the fact that it is a special
case of SD methods (relation indicated by an arrow between SD and PAS-MRI in
Fig. 1).
Finally, the diffusion orientation transform (DOT) proposed in [52] is yet another
model-independent reconstruction algorithm. The DOT is a function that maps the
apparent diffusion coefficient (ADC) profile to the diffusion PDF. Using similar
techniques, [51] fit high-order tensors (HOT) to the HARDI measurements to model
the ADC. ADC modeling is not discussed in this chapter because it is not an
appropriate function for fibre tractography (see [22]) but it can also be modeled with
spherical harmonics (SH) [3, 26] or generalized DTI (gDTI) [47]. Finally, similar to
QBI, the DOT has a possible multiple shell HARDI extension with the bi and tri
exponential fit [52].
From Local Q-Ball Estimation to Fibre Crossing Tractography 459
where .; / obey physics convention ( 2 Œ0; ; 2 Œ0; 2). [66] showed that it
was possible to reconstruct a smoothed version of the diffusion ODF directly from
single shell HARDI acquisition with the Funk-Radon transform (FRT). Intuitively,
the FRT value at a given spherical point is the great circle integral of the signal
on the sphere defined by the plane through the origin perpendicular to the point
of evaluation. The original QBI has a numerical solution [66] and more recent
methods [5, 23, 32] have introduced an analytical spherical harmonic reconstruction
solution that is faster and more robust. To develop the analytical solution to QBI, we
first need to estimate the HARDI signal with spherical harmonics (SH) and then, to
solve the FRT analytically with SH.
Letting Y`m denote the SH of order ` and degree m (m D `; :::; `), we define a
modified SH basis that is real and symmetric. For even order `, we define a single
index j in terms of ` and m such that j.`; m/ D .`2 C ` C 2/=2 C m. The modified
basis is given by
8p
ˆ jmj
< 2 Re Y` ; if m < 0
Yj D Y m ; if m D 0 (2)
:̂ p` m
2 Im.Y` /; if m > 0:
where Re.Y`m / and Im.Y`m / represent the real and imaginary parts of Y`m respec-
tively. The basis is designed to be symmetric, real and orthonormal. It is then
possible to obtain an analytical diffusion ODF estimate,‰, with
X
L
‰.; / D 2P`.j / .0/cj Yj .; /; (3)
j D1
„ ƒ‚ …
cj0
2
`.j / is the order associated with the j th element of the SH basis, i.e. for j D 1; 2; 3; 4; 5;
6; 7; ::: `.j / D 0; 2; 2; 2; 2; 2; 4; :::
From Local Q-Ball Estimation to Fibre Crossing Tractography 461
Fig. 2 Left: The convolution between the diffusion ODF kernel, R, and true fibre ODF produces
a smooth diffusion ODF estimate, ‰. Right: The Funk-Radon transform of the HARDI signal, S,
produces a smooth diffusion ODF, ‰, which is transformed into a sharper fibre ODF estimate, F ,
by the deconvolution
The relation between the measured diffusion ODF and the underlying fibre dis-
tribution, the fibre ODF, is still an important open question in the field [56, 65].
The diffusion ODF is a blurred version of the “true” fibre ODF. Because of this
blurring effect, the extracted maxima of the diffusion ODF are often used for
fibre tractography. An alternative is to use spherical deconvolution methods that
provide an estimate of the fibre ODF [5, 20, 25, 37, 40, 58, 63, 64]. These techniques
have better angular resolution than QBI and produce sharper fibre ODF profiles
than the q-ball diffusion ODF. Smaller fibre compartments with smaller volume
fractions are visible with fibre ODF and not with the diffusion ODF. SD and fibre
ODF estimation are currently subject to active research. Here, we use a simple linear
transformation of our analytical QBI solution. A schematic view of our spherical
deconvolution method is shown in Fig. 2.
The fibre ODF is reconstructed in three steps. 1) The regularized diffusion
ODF coefficients cj0 are reconstructed using Eq. (3) of the last section, cj0 D
2P`.j / .0/cj =S0 , where S0 is the unweighted b D 0 diffusion image.
2) The single fibre diffusion ODF, R, used as deconvolution kernel is estimated from
the real data. As in [5, 64], we assume an axially symmetric diffusion tensor model
with eigenvalues .e2 ; e2 ; e1 / and e1 >> e2 for the underlying single fibre diffusion
model. The values of e1 and e2 are estimated from 300 voxels with highest FA value
in our real dataset, as these voxels can each be assumed to contain a single fibre
population. The single fibre diffusion ODF kernel has an analytical expression [25]
and is given by
.1 ˛t 2 /1=2
R.t/ D p ; (4)
8b e1 e2
where ˛ D .1 e2 =e1 /, b is the b-value of the real dataset and t 2 Œ1; 1 is the
variable that represents the dot product between the direction of the fibre and the
point of evaluation .; / on the sphere.
462 M. Descoteaux and R. Deriche
3) The SH coefficient of the fiber ODF, fj , are then obtained by a simple linear
transformation,
Z 1
fj D cj0 =r`.j /; with r`.j / D 2 R.t/P`.j / .t/dt; (5)
1
which can be solved analytically by taking the power expansion of P`.j / .t/ and
integrating r`.j / term by term. As for the analytical diffusion ODF solution, the
spherical deconvolution is obtained with the Funk-Hecke theorem [23]. Therefore,
the fibre ODF in terms of the HARDI signal is
p
8b e1 e2 P`.j / .0/
fj D cj ; (6)
S0 A` .˛/
R1
where A` .˛/ D 1 .1 ˛t 2 /1=2 P` .t/dt. The final fibre ODF is reconstructed for
P
any .; / and point p as F .; /p D R j D1 fj Yj .; /. In [25], the fibre ODF is
shown to be a valid choice of fibre ODF that is in close agreement with the classical
SD method [64].
4 Q-Ball Tractography
We extend the classical streamline techniques [9, 19, 50] based on diffusion tensor
principal direction to take into account multiple fibre ODF maxima at each step.
We denote p.s/ as the curve parameterized by its arc-length. This curve can be
computed as a 3D path adapting its tangent orientation locally according
Rt to vector
field v. Hence, for a given starting point p0 , we solve p.t/ D p0 C 0 v.p.s//ds: The
integration is typically performed numerically with Euler or Runge-Kutta schemes
of order 2 or 4. In the Euler case, we have the discrete evolution equation
fODF-STR refer to the STR tracking using a single diffusion ODF and fibre ODF
maxima that is the closest to the incoming tangent direction of the curve and SPLIT-
STR refers to STR tracking using the fibre ODF maxima with splitting if there are
multiple maxima [21, 25].
We propose an extension of the random walk method proposed in [42] to use the
distribution profile of the fibre ODF. We start a large number of particles from the
same seed point, let the particles move randomly according to our local fibre ODF
estimate, F , and count the number of times a voxel is reached by the path of a
particle. This yields higher transitional probabilities along the main fibre directions.
The random walk is stopped when the particle leaves the white matter mask.
For each elementary transition of the particle, the probability for a movement
from the seed point x to the target point y in direction uxy is computed as the
product of the local fibre ODFs in direction uxy , i.e.
Our synthetic HARDI data is generated with the multi-tensor model [3, 22, 23, 66],
which can control the separation angle, anisotropy, volume fraction of each fibre
compartment as well as the signal to noise ratio (SNR) and number of gradient
directions N . Then, we use a biological phantom dataset obtained from a 1.5 T
scanner with 90 gradient directions and a b D 3000 s/mm2 [15]. We also use a
human brain dataset obtained on a 3 T scanner, which has 1:7 mm3 cubic grid and
contains 116, 93 x 93 slices with 60 gradient directions and a b D 1000 s/mm2 [6].
464 M. Descoteaux and R. Deriche
Fig. 3 Diffusion ODF (dODF) and fibre ODF recover multiple fibre crossing in the rat biological
phantom [15]
Fig. 4 The fibre ODF (fODF) improves angular resolution of the diffusion ODF (dODF) by more
than 15ı . The signal is generated with fibres equal volume fraction and FA D 0.7, N D 60 data
points, b D 3000 s/mm2 and SNR 30. The opaque surface is the mean fibre ODF over 100 noise
trials, whereas the transparent surface corresponds to the mean C 2 standard deviations. Blue and
red lines correspond to ground truth fibre directions and detected maxima respectively
The analytical QBI reconstruction has several advantages over the classical numer-
ical QBI reconstruction [66]. Overall, the analytical QBI reconstruction of the
diffusion ODF has the following four major advantages. (1) It is up to 15 times
faster than the numerical QBI implementation. (2) It is more robust to noise than the
numerical QBI solution. (3) It allows for more precise diffusion ODF reconstruction
for lower number of gradient directions N in the acquisition. (4) Most of the
information is contained in harmonic orders of order 6 and less. Higher order
harmonics contain small perturbations due to noise. To illustrate some of these
properties, Figs. 3 and 5 show that diffusion ODFs can recover multiple fibre
crossings in real HARDI datasets. In Fig. 3, the diffusion ODFs have multiple peaks
that agree with the known underlying fibre populations. For extensive details and
discussion, we refer the reader to [23] and [32].
From Local Q-Ball Estimation to Fibre Crossing Tractography 465
Fig. 5 The fibre ODF improves fibre detection of QBI. There are more crossings detected using
the fibre ODF (a,b) than diffusion ODF (a’,b’)
In [25], we show that the fibre ODF obtained from QBI is a valid choice which
agrees with the classical SD method [64]. Overall, the fibre ODF has a striking
angular resolution gain over the q-ball diffusion ODF of more than 15ı . This is
seen in Fig. 4, where the fibre ODF is able to better discriminate the two fibre
compartments at a separation angle of 45ı whereas the diffusion ODF is limited
to the separation angle of 60ı . In general, as also seen in Figs. 3 and 5, fibre ODF
can recover fibre crossings more easily while noise effect is kept under control.
Figure 5 shows the multi-directional information coming from the diffusion ODF
and the fibre ODF on a region of interest in a coronal slice (Talairach -4) of the
human brain dataset. In this ROI, the corpus callosum (CC) forms the roof of the
lateral ventricles and fans out in a massive collateral radiation, the corticospinal tract
(CST) lies lateral to the ventricle and is directed vertically and the SLF crosses the
base of the precentral gyrus in anterior-posterior direction. The lateral projections
of the CC cross the CST and the SLF. Fibres of the SLF partly intersect with the
fibres of the CST and the CC.
466 M. Descoteaux and R. Deriche
dODF/fODF
Fig. 7 SPLIT-STR recovers known fanning/crossing configurations to the two motor gyri from
both seed points
Fig. 8 Deterministic and probabilistic tracking of the anterior commissure (AC) fibres
Fig. 9 Deterministic and probabilistic tracking of the projections of the corpus callosum
to a lower extent on the right. The tractogram computed with the fODF-PROBA
method reveals a strong interhemispheric connection of the lateral parts of the
frontal lobe. Additional fibres are found branching to the anterior thalamic radiation.
The tractogram shows asymmetry with stronger connections to the left inferior and
middle frontal gyrus than to the homologue area. We also show a selection of the
probabilistic fibres colored differently depending on their end point projections to
the lateral or medial areas. From the deterministic methods only SPLIT-STR can
reconstruct this complex structure.
are useful but their configurations are not complex enough. We believe that further
development of realistic and complex phantoms will greatly help the validation
problem.
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From Local Q-Ball Estimation to Fibre Crossing Tractography 473
Abstract With the huge amount of cell images produced in bio-imaging, automatic
methods for segmentation are needed in order to evaluate the content of the images
with respect to types of cells and their sizes. Traditional PDE-based methods using
level-sets can perform automatic segmentation, but do not perform well on images
with clustered cells containing sub-structures. We present two modifications for
popular methods and show the improved results.
1 Introduction
Automatic cell segmentation and cell scan analysis belong to the challenging tasks
in image processing. Due to different types of microscopy, e.g. fluorescence, trans-
mission or phase contrast microscopy, no general solution is applicable. Whereas
A. Kuijper ()
Fraunhofer IGD, Institute for Computer Graphics Research, Department of Computer
Science, TU Darmstadt, Darmstadt, Germany
e-mail: [email protected]
B. Heise
Department of Knowledge-Based Mathematical Systems,
Johannes Kepler University, Linz, Austria
Y. Zhou
Department of Virtual Design, Siemens AG, Munich, Germany
L. He
Luminescent Technologies Inc., Palo Alto, USA
H. Wolinski • S. Kohlwein
SFB Biomembrane Research Center, Institute of Molecular Biosciences,
Department Biochemistry, University of Graz, Graz, Austria
Fig. 1 Top row: Yeast cells in different concentrations recorded by transmission microscopy.
Bottom row: Yeast cells in different concentrations recorded by DIC microscopy and the
reconstructed OPL map. Note the wide variations in image quality
The task of automatic segmentation is to find coherent regions that relate to objects
the observer is interested in. Typically, these regions are bounded and the boundary
of objects are often found as the location where the intensity changes significantly.
However, methods that use such edge information only, perform unsatisfactory
as locally this edge information may be missing. In order to find edges at these
locations, iterative schemes can be used that are based on Partial Differential
Equations (PDEs). Roughly speaking, these PDEs are designed using driving forces
that evolve curves towards edges. Usually, the PDE contains an edge detector which
depends on the gradient of the image. Alternatively, a homogeneous area detector
can be used which favours areas without much intensity changes. To minimise the
influence of noise and missing information, constraints that penalise (for instance)
the length of edges are added.
Examples of such approaches relate for instance to the active contour model
[6], and modifications of it. The initial curve is to be placed around the object
to be detected. The curve moves in the normal dimension to itself and ideally
stops at the boundary of the object. The main drawbacks of the original snakes are
their sensitivity to initial conditions and the difficulties associated with topological
transformations.
Other approaches arise from the Mumford-Shah model [11]. It minimises a
proposed energy of an image. This energy depends on piecewise smooth approxi-
mations for the given image. Although the model has its mathematical peculiarities,
it formed the basis of many segmentation algorithms. For an overview of the ample
literature on geometric pde models in image analysis, one can consult the collections
of papers in e.g. [9, 13, 15].
A drawback of many PDEs approaches is the computation time. Often, the dis-
cretisation scheme requires small time steps in order to maintain a stable evolution.
Secondly, PDE methods require an initial guess, which may heavily influence the
final result. Thirdly, as one doesn’t know the number of objects at forehand, the
number of available edge contours has to be flexible.
A framework that overcomes these problems to a large extent use level sets,
initiated by Osher and Sethian [14, 18]. It exploits mathematical properties of
equations of the form
t C F jrj D 0; (1)
Fig. 2 Level Set implementations may fail. From left to right: The initial contour; results after
100, 1000, and 2000 iterations
Fig. 3 Segmentation result of the Multiphase Chan-Vese model. From left to right: original image;
initial condition; final contour after 2000 iterations, D 0:0015 2552 ; final phase
In image segmentation, one can think of being (a level line of) the image that
evolves as a function of its gradient, or, more explicitly: as the evolution of edges
towards their mathematically optimal position. The level set framework allows for a
flexible setup, as it is able to split and merge curves during the process. To some
extent, this also overcomes the initialisation problem. Finally, fast methods are
available for implementation [8, 10].
Chan and Vese [1] proposed a model for image segmentation based on the Mumford-
Shah functional and level sets. This model does not explicitly depend on the gradient
of the image. It therefore performs well in images with ambiguous boundaries.
The model is defined as the following minimisation problem [1, 2]: Given the
original image u0 in and two unknown constants c1 and c2 in the inside and
outside region, respectively, which are separated by the curve ı./jrj, minimise
the following energy with respect to c1 ; c2 and :
R
F .c1 ; c2 ; / D 1 .u0 c1 /2 H./ C 2 .u0 c2 /2 .1 H.//
(2)
Cı./jrjd ;
where H denotes the Heaviside function and ı the Dirac measure. The first and
second term penalise the L2 distance in the inside and outside regions, and the third
term measures the length of the curve.
The traditional Chan-Vese model can segment the image into two regions -
background and foreground. In order to segment images into more regions, a
Multiphase Level Set Method has been developed [4, 23]. It is motivated by the
Four Colour Theorem which states that only four colours are enough to dye all the
regions in a partition. Therefore, only two level set functions will suffice to represent
any partition. The multiphase level set method is the direct extension of Eq. (2) and
is defined as follows:
R
F .c; / D R.u0 c11 /2 H.1 /H.2 /d
C .u0 c10 /2 H.1 /.1 H.2 //d
R
C .u0 c01 /2 .1 H.1 //H.2 /d (3)
R
C R.u0 c00 /2 .1 H.
R 1 //.1 H. 2 //d
C jrH.1 /j C jrH.2 /j;
where the first four integrals compute the L2 distance of a constant cij to u0 in each
of the four difference regions (c11 2 f.x; y/ W 1 > 0; 2 > 0g, etc.). The Euler-
Lagrange equations obtained by minimising Eq. (3) with respect to c and are:
@1 r1
@t D ı .1 /f div. jr 1j
/
Œ..u0 c11 / .u0 c01 /2 /H.2 /
2 (4)
C..u0 c10 /2 .u0 c00 /2 /.1 H.2 //g;
480 A. Kuijper et al.
@2 r2
@t D ı .2 /f div. jr 2j
/
Œ..u0 c11 / .u0 c10 /2 /H.1 /
2 (5)
C..u0 c01 /2 .u0 c00 /2 /.1 H.1 //g:
2.2 Pre-processing
In order to remove the substructures, one can try to detect these small parts and
remove them [25]. This is not only computationally intensive, but also assumes
that the locations of the cells (including boundaries!) are more or less known.
We therefore proceed with a PDE-based pre-processing method that smoothes
regions with small variability and maintains edges. The most popular among such
approaches is the one by Perona and Malik [17]:
Here c.jrI j/ is a decreasing function of the gradient. In this work, we choose the
2
rather standard function c./ D .1 C K 2 /1 .
In Fig. 4 we show the result of the Perona - Malik pre-processing, followed by the
multiphase Chan-Vese model. Indeed, the sub-structures are removed and the cells
and background are properly segmented.
The Perona - Malik pre-processing method performs well for images with
sufficiently contrast between cells and background, cf. Figs. 3 and 4. In most images
of our data base, cf. Fig. 1, this is the case. However, in some cases the final result
is not satisfactory due to the merging of cells. This happens when the cells in the
Segmentation of Clustered Cells in Microscopy Images by Geometric PDEs. . . 481
Fig. 4 Segmentation result after pre-processing. From left to right: Result of Perona-Malik
processing (K=10, 30 iterations) of Fig. 3a; initial contours; final contour after 2000 iterations,
D 0:0015 2552 ; final phase
image are too close to each other or even overlap each other. We therefore consider
a different approach in the next section which enforces the non-merging of cells.
The first step for this segmentation method is the detection of the centres of the cells.
In the second step these locations are used as seed points for a PDE-based region
growing method that stops at the cell boundaries.
The shape of a cell has some characteristic properties, like symmetry, continuity,
and closure. Therefore, we apply an iterative method using oriented kernels to detect
the candidate position for the centre of the cell [3, 16, 26]. The basic idea of this
algorithm is a voting method. It defines a series of cone-shaped kernels that vote
iteratively along radial directions the likeness of the point as being the middle of a
rather homogeneous structure. Applying this kernel along the gradient direction, at
each iteration and each grid location, the orientation of the kernel is updated. The
shape of the kernel is also refined and focused as the iterative process continues.
Finally, the point of interest is selected by certain threshold.
Numerical results
The algorithm is tested on a data base with different types of images, cf. Fig. 1. We
present the results of four typical images, showing different types of cell clustering
for which results can be verified by human observers. The complete data base also
contains images with completely overlapping and out-of-focus cells. In these cases,
human observers cannot distinguish individual cells. In Fig. 5, the first column
shows the original images. The second row shows the last image of the iterative
482 A. Kuijper et al.
voting method. These images are thresholded in order to get the binary images in
the last column, yielding the location of the seeds, located approximately in the
middle of each cell, as expected.
In the next step, the detected centre is used to define the initial condition for
detecting the boundary. A sequence of three level set functions are set up for each
cell. See [9, 20, 28] for more details.
Motivated by the traditional level set model, the following level set equation is
defined [20]:
where g D e ˛jr.GI0 .x//j ; ˛ > 0, G I0 .x/ is the convolution of the original image
I0 .x/ with a Gaussian function G. The function g .1 / contains an inflationary
term (C1), which determines the direction of evolution to be outward. The curvature
term () regularises the surface by accelerating the movement of those parts of
surface behind the average of the front and slowing down the advanced parts of flow.
The parameter determines the strength of regularisation, if is large, it will smooth
out front irregularities. For extreme cases, the final front will become a circle. If
is small, the front will maintain sharp corners. In practise, an intermediate value of
is chosen that allows the front to have concavities (concavities are possible for the
cell border), while small gaps and noise are smoothed. The effect of g is to speed
up the flow in those areas where the image gradient is low and slowing down where
the image gradient is high. Because of this term, the front slows down almost to
stop when it reaches the internal cell boundary. The parameter ˛ determines the
sensitivity of the flow to the gradient. The extra term ˇrg r is a parabolic term
that enhances the edge effect.
In this step, there is another restriction condition for the equation: The growing
front may not invade (and merge with) other cells’ region when seed grows. By
using this level set equation, the internal boundary of the cells is detected.
The initial expansion level set function usually causes underestimation of cell area
due to the thick boundary. So a second and third step are added to compensate the
result. The second step is the free expansion, in which the front is allowed to expand
freely and the speed of evolution doesn’t rely on the gradient of original image. The
level set equation is simply defined as below:
Segmentation of Clustered Cells in Microscopy Images by Geometric PDEs. . . 483
Fig. 5 Seed Detection Result for several types of images. For visualisation purposes we selected
a smaller part of the original images. From left to right: Initial image; final voting result; resulting
seed point
t C jrj D 0: (8)
Similar as the first step, the growing fronts may not penetrate each other when
the front expands. This expansion only needs a small number of steps to ensure that
all the fronts move beyond the external boundary of cells. The number of iteration
depends on the thickness of the cell boundary.
After the free expansion step, the fronts are located outside the cells’ boundary. The
last step is to move the front inwards to get the exact location of the external cell
484 A. Kuijper et al.
boundary using
This is similar to initial expansion except for the shrinking term (1), which
determines the direction of evolution to be inward.
Reinitialisation
For the three level set phases described above, reinitialisation is necessary. The
purpose of reinitialisation is to keep the evolving level set function close to a signed
distance function during the evolution. It is a numerical remedy for maintaining
stable curve evolution [22]. The reinitialisation step is to solve the following
evolution equation:
D sign..t//.1 jr j/;
(10)
.0; / D .t; /:
Numerical results
Figure 6 shows the results on the images used in Fig. 5. The columns show the initial
condition for level set function, the results after the three level set phases, and the
final segmentation. Note that in the DIC image (the last row), the mother cells are
segmented successfully.
We discussed two PDE-based methods to segment cells with level sets: the Chan-
Vese model and geometric PDEs. In case of clustered cells with sub-structures, these
models perform unsatisfactory. We presented possible pre-processing methods, viz.
Perona-Malik smoothing and voting, which provide a modified image and starting
conditions, respectively.
The methods are tested on different types of cell images, with both regular and
irregular patterns, and overlapping cells. The modified Chan-Vese model is fast and
performs well in most cases. The performance of the geometric PDEs combined
with voting performs better, but requires more computation time, see [28] for full
details. As long as the cells are distinguishable by the human eye, the method can
segment individual cells properly. Both methods require parameter settings that need
Segmentation of Clustered Cells in Microscopy Images by Geometric PDEs. . . 485
Fig. 6 Results for the seeded images of Fig. 5. From left to right: Initial Contour; Result after
Initial Expansion; Result after Free Expansion; Result after Surface Wrapping; Final Result
to be determined once, as long as the intrinsic properties of the cell images are stable,
i.e. when the images are not too much out of focus. In the latter case, even human
observers are unable to segment the cells.
Acknowledgements The work was partially supported by the mYeasty pilot-project by the
Austrian GEN_AU research program (www.gen-au.at). It was carried out when A. Kuijper,
Y. Zhou, and L. He were with the Johann Radon Institute for Computational and Applied
Mathematics (RICAM), Linz, Austria.
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Atlas-based whole-body registration in mice
1 Introduction
In recent years, two widely applied imaging modalities in clinical practice, Com-
puted Tomography (CT) and Magnetic Resonance Imaging (MRI), have been
adapted for small animal applications. Due to their non-invasive nature and the
imaging field of view, the new modalities (CT and MRI) can be used for
monitoring dynamic processes under realistic conditions in-vivo and in the entire
animal. This adds a new dimension to animal experiments, since it enables studying
the effect of e.g. genetic manipulations or drug administration within the same
subject, at subsequent points in time. Therefore, the traditional cross-sectional
studies using different animals can be extended to follow-up studies.
2 Problem Statement
In the literature, there are two approaches for the problem of matching anatomical
structures with heterogeneous and potentially articulated parts:
1. Data-driven registration of the entire body or body parts, based on the data
directly or on extracted features like points or surfaces.
2. Registration based on an underlying model of the relation between subparts of
the body (articulated registration), applied to body parts. Again, the registration
can be based on the data or extracted features like points or surfaces.
An example of a data-driven approach is presented in Chaudhari et al. [6].
The authors perform a surface-based registration between an entire mouse body
and the Digimouse atlas (Dogdas et al. [8]). They segment the animal interior by
surface-constrained warping of the atlas volume to the subject using harmonic maps.
Atlas-based whole-body registration in mice 491
The method does not take anatomical heterogeneity into account. Li et al. [11]
present a whole-body intra-modality approach (CT) for mice that besides the skin
uses the skeleton for registration. They put additional constraints on a point match-
ing framework to account for rigidity of bones. Kovacevic et al. [10] demonstrate
whole-body registration in mice based on a basic model, the “part-of” concept.
This is a hierarchical intra-modality approach that first separates the main organ
compound and refines that division as the registration progresses, down to single
bones and organs. While the method integrates inter-structure relationships inside
the body, these are only exploited for initializing the registration of low-hierarchical
elements by the result from high-hierarchical elements.
Martin-Fernandez et al. [13] make use of an anatomically realistic articulation
model to register 2D hand radiographs. The bones are thereby represented by a
wire-frame where individual ‘rods’ are registered imposing kinematic constraints.
Papademetris et al. [14] register the legs of a mouse by modeling the joints. After
registration of the leg bones, they pay special attention on the propagation of the
deformations to soft tissue parts by focusing on the folding problem at interfaces
of articulated parts. Du Bois d’Aische et al. [9] register a human head, based on
a model of the jugular part of the spine. Articulated cervices are registered to the
target image and the deformation is propagated to the rest of the head using a linear
elastic model.
In summary, some available methods can be used either for whole-body appli-
cations, as long as differences in posture and shape are small, or for registration
of subparts of a body. However, most methods need a significant amount of
user interaction e.g. to define joint locations or manually segment bones prior to
registration.
3 Methodology
In this section, a method is proposed to segment an entire mouse body from Micro-
CT data using an anatomical mouse atlas that contains the skeleton and major
organs (Segars et al. [16]). To this end, the skeleton is registered as a first step,
because it 1) forms the rigid, articulated frame of a body, 2) is the main determinant
of whole-body posture and 3) can be robustly and automatically extracted from
the data. Combining the “part-of” concept with a hierarchical anatomical model
and articulated registration enables fully automated registration of the atlas to the
skeleton of a given mouse.
Due to the lack of soft-tissue contrast in Micro-CT data, intensity-based organ
registration is not possible. However, the mouse atlas contains all major organs
which can be mapped from the atlas domain to the subject domain using Thin-Plate-
Spline (TPS) interpolation [5]. While the necessary set of corresponding anatomical
landmarks is mainly determined by the result of the skeleton registration, more
lateral landmarks are needed in the ventral part of the animal abdomen to sufficiently
constrain the TPS mapping. Besides bone, also the lung and the skin show sufficient
contrast for robust segmentation from CT data. Therefore, corresponding lung
492 M. Baiker et al.
Fig. 1 The mouse skeleton as included in the atlas (top) and after segmentation of single bones
and adding joints (bottom)(adapted from [2], ©2007 IEEE)
The used atlas skeleton (Segars et al. [16]) does not distinguish between individual
bones. Therefore, these were manually segmented (Fig. 1). Second, the position and
the DoFs were specified for each joint.
Three types of joints have to be modeled: ball joints, hinge joints and the shoulder
complex (both shoulders combined). Table 1 shows the DoFs for the ball and hinge
Atlas-based whole-body registration in mice 493
joints. In addition to these anatomically relevant DoFs, three translations for both
joint types and two rotations for the hinge joints are allowed to a small extent, to
be able to compensate for potential errors that have been made during previous
registration of another bone that is rigidly connected. Due to the large number of
DoFs in the shoulder, an additional motion constraint has to be introduced for the
shoulder by allowing only a coupled, symmetric displacement of both front upper
limbs, with a varying distance between the shoulders and a rotation towards and
away from each other. Subsequently, the left and the right front upper limb can be
decoupled.
The hierarchical anatomical tree used for this work is shown in Fig. 2. The strategy
to incorporate the entire bone structure is to first align the atlas and the subject
skeleton coarsely and then to apply an articulated registration scheme traversing
the hierarchical tree. In this way, lower tree levels are initialized and constrained
by higher level transformations. The highest hierarchical level is the entire mouse
skeleton itself (L0). The skull is placed on the next lower level (L1), because its
registration result initializes the matching of all other parts. The rest of the skeleton
is divided into three subparts, consisting either of single bones or bone compounds
(L2 L6).
These are the rear part consisting of spine, pelvis, upper and lower hind limbs
and the paws, the front part consisting of upper and lower front limbs and the paws
and the ribcage, represented by the sternum. The relations between all elements in
the three subparts are fully determined by rigid connections (joints). Including the
shoulder blade into the tree or making further distinctions such as refining the paws
is not relevant for the goal of capturing the animal posture and therefore can be
omitted. Assuming that the spine and the sternum sufficiently constrain the shape of
the ribcage, the ribs can be left out as well.
For initialization of the articulated registration, the mouse atlas needs to be coarsely
aligned to the skeleton segmented from CT i.e. global DoFs have to be removed.
Taking the nodes of a skeleton surface representation as a 3D point set enables to
resolve several global DoFs by aligning the principal axes. Subsequent extraction
and analysis of a 3D curve that represents the skeleton allows to resolve all other
possible global DoFs (refer to Baiker et al. [2] for details).
494 M. Baiker et al.
Fig. 2 Hierarchical
anatomical tree for the
skeleton. The connections
depict relations between
single bones or bone
compounds such that a part
on a lower level is initialized
by the registration result on a
high level (figure adapted
from [2], ©2007 IEEE)
Two problems arise in matching two point sets: correspondence and transformation.
A method that solves for both simultaneously is the Iterative Closest Point (ICP)
algorithm (Besl et al. [4]). While originally been developed for incorporating rigid
transformations only, pilot experiments have shown that non-isotropic scaling can
be integrated too as long as it is moderate. In this way, it is possible to account for
inter-subject variability. The articulated registration of the skeleton is performed by
stepwise traversing the hierarchical anatomical tree (Fig. 2) in a top-down manner.
If the correspondence, i.e. the Euclidean distance between the point sets representing
the atlas bone and the target bone surfaces respectively does not improve any more
within an iteration step, the final transformation function is used to initialize the
registration of a bone at a lower hierarchical level. Depending on the joint type,
the DoFs for this node level are kinematically constrained. Traversing the tree, the
overall correspondence improves gradually. The lung is registered in the same way
as the bones including non-isotropic scaling, to account for shape variations due to
breathing.
There is one exception to the registration scheme. Due to its high flexibility, the
spine is not determined by registration but by binning the bone point set along its
longitudinal axis and applying three dimensional region growing using the head-
spine connection as seed point after the head is registered. The number of bone
voxels per bin enables to determine the spine-pelvis connection and therefore to
initialize the pelvis registration.
Atlas-based whole-body registration in mice 495
Cij D †K
kD1 jhi .k/ hj .k/j
Based on landmarks on bone, lung and skin, organs can be warped from the atlas
domain to the subject domain. In its original form i.e. if used as an interpolant, the
TPS does force landmarks in the source domain to fit landmarks in the target domain
exactly. However in general small spatial errors may occur and this can cause
local distortions of the mapping. A remedy is to allow small landmark localization
errors and relax the constraint of interpolation towards approximation (thin-plate
smoothing spline [18]).
4 Implementation details/Evaluation
For evaluation, 26 data volumes of 22 animals in prone and supine position and
with arbitrary limb position were acquired with a Skyscan 1178 Micro-CT scanner
(Kontich, Belgium). In a follow-up study, one mouse was scanned five times within
five weeks.
The data was subsampled and smoothed, yielding a voxel size of 320 320
320 m3 . Subsequently, the skeleton was segmented through isodata thresholding
(Ridler et al. [15]). The skin and the lung were extracted using object-background
thresholding and 3D region growing respectively, with a seed point relative to
selected points on the spine and sternum. Triangular meshes of the skeleton, the lung
and the skin were determined from the volume labels, smoothed and subsampled.
The atlas elements were represented as triangular meshes as well.
The registration of the bones and the lung was done in two iterations, using
ICP together with Levenberg-Marquardt minimization to optimize correspondence
with respect to the parameters (DoFs). The first iteration was used for coarse
rigid alignment allowing 6 DoFs. The second iteration incorporated scaling as
well (9 DoFs). The minimization scheme was terminated if the difference between
subsequently estimated parameters was below a certain threshold. This was 0.01
degrees for the rotation, 3.2 m for the translation and 0.001 for the scaling
parameters. For determining correspondences on the skin, a triangulated surface
Atlas-based whole-body registration in mice 497
12
− − Before
10 −−− After
Euclidean distance [mm]
0
5 10 15
Bone as indicated in the list
Fig. 3 Mean error of specific bones for 26 datasets ([2] ©2007 IEEE)
representation and a sparse set of 32 landmarks, derived from the joints, the
spine and the skull were used. Geodesic distances were determined using the Fast
Marching Algorithm [17] and the error criterion was based on the eight closest
landmarks (i.e. K=8). The initial set was replenished by 120 landmarks from the
skin all over the torso and 30 landmarks on the lung, yielding a total set of 182
corresponding nodes to constrain the TPS approximation.
During registration, the error decreased from an average of 2.93 ˙ 0.63 mm
to 0.58 ˙ 0.04 mm for the skeleton and from an average of 1.76 ˙ 0.49 mm to
0.42 ˙ 0.068 mm for the lung, including all 26 cases. A detailed overview of the
registration error for specific bones is given in Fig. 3. The mean Euclidean distance
between atlas and subject skin decreased from 1.73 ˙ 0.4 mm to 0.34 ˙ 0.036 mm.
Two examples of the skeleton registration and subsequent organ approximation are
shown in Fig. 4. Results of the follow-up study are given in Fig. 5 and Table 2.
5 Discussion/Future Work
Fig. 4 Registration results between the atlas (red) and two different subjects (gray) after coarsely
aligning the skeleton (top), after the articulated registration (middle) and after organ approximation
(bottom) (adapted from [2], ©2007 IEEE)
Fig. 5 Skeleton registration and organ approximation for a follow-up study over five weeks (t1-t5)
with the subject in supine (t1-t3) and prone (t4-t5) position respectively
Table 2 Organ volumes (in mm3 ) of the original atlas and after mapping for a follow-up study of
a mouse acquired at 5 subsequent time points (t1-t5)
Brain Heart Lungs Liver Kidneys
Atlas 415,05 200,93 330,67 1779,87 257,24
Subject t1 449,09 196,25 380,40 1624,68 246,99
Subject t2 363,50 206,72 392,08 1902,58 267,40
Subject t3 389,99 201,12 363,25 1797,59 262,07
Subject t4 384,69 239,10 426,37 1822,90 194,83
Subject t5 448,88 242,03 425,04 1970,06 245,92
Mean (t1-t5) 407,23 217,04 397,43 1823,56 243,44
Std (t1-t5) 39,39 21,81 27,78 130,32 28,73
% 9,67 10,05 6,99 7,15 11,80
mean skin distance between the atlas and a subject within the data resolution range.
The results of the organ approximation for the follow-up study (Fig. 5 and Table 2)
reveal, that the method allows consistent localization and shape approximation of
the brain, the heart, the lungs, the liver and the kidneys with a low variability in
organ volume estimation (standard deviation <12%). The stomach and the spleen
are shown for referencing, but no volume data is given due to the very large
environmentally dependent variability of shape, location and volume. The same
holds for the small and large intestine and the bladder, which have therefore not
been included.
In conclusion, the presented method is applicable for referencing of internal
processes in molecular imaging research or whole-body segmentation (e.g. to
provide a heterogeneous tissue model for bioluminescence tomography). Further-
more, the approximation could serve to initialize a subsequent highly accurate
registration of specific bones or organs, as long as the image data shows sufficient
contrast. For CT data this might be realized using a contrast agent. In return, the
approximation could be improved using organ registration results. We expect that
this method generalizes well towards other rodents, provided that an anatomical
atlas is available.
Acknowledgements The authors gratefully acknowledge Dr Paul Segars for providing the mouse
atlas, Ivo Que for generating the CT datasets and Elke van de Casteele from Skyscan for providing
the Micro-CT scanner used in this research.
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Potential carotid atherosclerosis biomarkers
based on ultrasound image analysis
1 Introduction
The carotid arteries are responsible for supplying blood to the brain. Each common
carotid artery divides into an external and an internal branch at the carotid
bifurcation. The external carotids supply blood to the neck, pharynx, larynx, lower
jaw and face, whereas the internal carotids enter the skull delivering blood to the
brain. The presence of an atheromatous lesion, or plaque, in the carotid arteries, also
S. Golemati ()
School of Medicine, University of Athens, Greece
J. Stoitsis • K. Nikita
Electrical and Computer Engineering, Technical University of Athens, Greece
known as carotid atherosclerosis, may disturb the normal circulatory supply to the
brain. Carotid atherosclerosis may produce total occlusion of a specific arterial site
or cause a thromboembolic event. In advanced stages of the disease, cerebrovascular
symptoms, such as transient ischaemic attack, amaurosis fugax (temporal blinding)
or stroke, may occur.
Ultrasound imaging of the carotid artery is the most widely used modality in the
diagnosis of carotid atherosclerosis due to its noninvasiveness, non-ionizing nature
and low cost. In particular, B (Brightness)-mode imaging, i.e. the reproduction of
the amplitude of the reflected waves by their brightness, is commonly used to assess
arterial wall morphology. B-mode images exhibit a granular appearance, called
speckle pattern, which is caused by the constructive and destructive interference
of the wavelets scattered by the tissue components. In B-mode ultrasound, blood
reflects very little and the vessel lumen appears as a hypoechoic band. Figure 1
shows examples of B-mode ultrasound images of (a) a healthy (non-atherosclerotic)
and (b) a diseased (atherosclerotic) carotid artery.
and motion analysis, may be used to extract useful diagnostic indices of the
geometry, echogenicity and strain, respectively, of the carotid artery wall.
The methodologies described in this chapter are suitable for two-dimensional (2D)
B-mode ultrasound imaging. This is the most widely used modality for the assess-
ment of the carotid artery. The methodologies aim at (a) automatic segmentation
of the arterial wall from longitudinal and transverse sections, (b) texture analysis
of atheromatous plaque and (c) analysis and quantification of motion of the arterial
wall. It is recommended that the methodologies be applied to normalized ultrasound
images, according to widely accepted specifications [6], to minimize variability
introduced by different equipment, operators and gain settings and facilitate imaged
504 S. Golemati et al.
Early disease stages may be assessed by interrogating the arterial wall on which
focal lesions (plaques) may not yet have become obvious. The suggested HT
technique allows the automatic extraction of straight lines and circles to approximate
the wall-lumen boundary in longitudinal and transverse sections, respectively. HT
can be used to detect parametric curves of the form v.c; pi / D 0 in digital images,
where c is the vector of coordinates, p the vector of parameters and i D 1:::n,
the number of parameters required to define the curve. HT transforms the image
to an n-dimensional parametric space, called the accumulator array. Operating on a
binary image of edge pixels, all possible curves v.c; pi / D 0 through a pixel with
vector coordinates c are transformed to a combination of parameters pi , which then
increment the corresponding cell of the accumulator array. The main steps of the
methodology, which are described in detail in [8], include:
Reduction of image area This may be achieved by automatically isolating a
rectangular area containing the vessel lumen. To this end, four points may be
defined to delimit the area to be investigated. This is an important step because
it minimizes the possibility to detect unwanted structures, which may be present
biasing the representation of the arterial lumen and, thus, reduces the computa-
tional cost and the time required to perform the segmentation task.
Image pre-processing This step includes removal of high frequency noise using a
symmetric Gaussian lowpass filter and morphological closing to suppress small
‘channels’ and ‘openings’ of the image.
Edge detection The image is first transformed into binary through the application
of a global threshold and then a Sobel gradient operator may be applied.
Hough Transform Longitudinal sections are searched for lines defined as z D
xcos C ysi n, where z is the distance from the left upper corner of the image
and is the angle with the x-axis. Transverse sections are searched for circles
defined as .x a/2 C .y b/2 D r 2 , where .a; b/ are the coordinates of the
center and r is the radius of the circle.
Selection of dominant lines/circle Two lines in longitudinal sections and one
circle in transverse sections with the maximal values in the corresponding
accumulator arrays are eventually selected, representing the boundaries of the
wall-lumen interface.
Figure 2 shows examples of the application of the HT technique in longitudinal and
transverse sections of ultrasound images of the carotid artery. Arterial diameters
can be calculated through the application of the previously described methodology,
Potential carotid atherosclerosis biomarkers based on ultrasound image analysis 505
Fig. 2 Examples of the application of the HT technique in longitudinal and transverse sections of
ultrasound images of the carotid artery. (a), (d) original images, (b), (e) images after morphological
closing, thresholding and edge detection. (c), (f) HT technique result shown on original image
namely from the distance of the two lines in longitudinal sections and the circle
diameter in transverse sections. The arterial distension waveform can then easily
be estimated by recording the diameter values in all images of the sequences.
Furthermore, in longitudinal sections, the HT methodology can be applied to the
far wall alone, to extract two dominant lines corresponding to the boundaries of the
wall, from which the intima-media thickness can be evaluated.
A methodology combining HT and active contours is also suggested, in an
attempt to achieve a more accurate approximation of the arterial wall geometry in
transverse sections. Departure from the strict geometrical shape indicated by HT is
more evident in these sections. The methodology is based on the generation of a
gradient vector flow field [18], an approach attempting to overcome conventional
active contours constraints. The main steps include:
HT technique Application of the HT methodology described above allows the
estimation of a circle, which is subsequently used for initializing the active
contour.
Image pre-processing This step includes a number of tasks (calculation of gra-
dient field, thresholding, morphological closing and smoothing, and gradient
operator application) to estimate the image edge map.
Calculation of gradient vector flow field
Contour estimation Deformation of initial curve (circle) based on gradient vector
flow field.
Figure 3 shows an example of the application of the combined HT-active-contours
methodology in a transverse section of the carotid artery. As we can see, the
methodology results in a random shaped boundary which follows more closely the
506 S. Golemati et al.
actual wall-lumen interface than the circle. However, widely used physiological
indices, such as the arterial distension waveform, may be more easily estimated
from the latter.
The severity of the carotid atherosclerotic plaque, an advanced disease stage, can
be assessed through its echogenicity estimated by a number of texture analysis
techniques. The use of transform-based texture analysis is suggested here, which
has not been previously applied in ultrasound images of the carotid artery. The
Fourier Transform (FT), the Wavelet Transform (WT) and Gabor filters allow
the estimation of texture features capable of characterizing symptomatic and
asymptomatic plaques.
The discrete 2D FT [9] can be used to quantify image texture in the frequency
domain. The radial distribution of values in Fourier Power Spectrum (FPS) is
sensitive to texture coarseness in an image, whereas their angular distribution is
sensitive to the directionality of the texture. Power concentration in low spatial
frequencies indicates coarse texture, while power concentration in high frequencies
indicates fine texture. Texture with strong directional characteristics produces a
power spectrum concentrated along lines perpendicular to the texture direction.
A total of nine texture features can be extracted from the FPS, five corresponding to
the radial and four to the angular distribution of the FPS.
The 2D WT can be used to analyze the frequency content of an image within
different scales [1] and, thus, to extract information about the low and high fre-
quencies of an image at different resolutions. The resulting wavelet coefficients are
called the sub-images at different resolutions and consist of an approximation image
and three detail images, namely the horizontal, vertical and diagonal detail images.
Quantitative texture measures can be extracted from the wavelet coefficients. Each
Potential carotid atherosclerosis biomarkers based on ultrasound image analysis 507
u rI.x; t/ C It .x; t/ D 0
where u D u t D .ux ; uy /, and rI.x; t/ and It denote spatial and temporal partial
derivatives, respectively, of the image I .
A common way to constrain velocity is to use gradient constraints from neigh-
boring pixels, assuming that they share the same 2D velocity. In reality, there may
be no single velocity value that simultaneously satisfies all pixels of the region, so
the velocity that minimizes the constraint errors is found instead. The least-squares
estimator that minimizes the squared errors is:
X
E.u/ D g.x/ Œu rI.x; t/ C It .x; t/2
x
can be found from the critical points, where derivatives with respect to u are equal
to zero:
#E.u/ X
D g.x/ Œux Ix2 C uy Ix Iy C Ix It
#ux x
#E.u/ X
D g.x/ Œuy Iy2 C ux Ix Iy C Iy It
#uy x
The above equations can be written in matrix form and the resulting linear system
can be solved using the Gaussian elimination method.
To compute spatial .Ix ; Iy / and temporal .It / gradients, the images can first be
smoothed using a Gaussian 7 7 kernel with standard deviation 0.8. Use of the
Gaussian lowpass filter also allows removal of high frequency noise inherent in
ultrasound images.
To estimate arterial wall motion, the previous method can be applied to appropri-
ately selected image areas. These include pixels of the normal and/or diseased wall
and exclude pixels of the lumen and the surrounding tissue. Specifically, pixels at
a distance of 1.5 mm along the interface, i.e. in the longitudinal direction, and at a
distance of 0.5 mm through the tissue, i.e. in the radial direction, can be selected.
Pixel density is lower in the longitudinal direction because less relative motion is
expected compared to the radial direction. Reduction of the image area to a set of
individual pixels for further investigation reduces significantly the computational
cost without compromising the related physiological information.
Figure 4 shows examples of velocity fields of the far arterial wall of a normal
artery, as well as for a symptomatic and an asymptomatic case. In the same figure,
examples of longitudinal and radial displacement waveforms for two points on the
wall are also shown. The points distance is approximately 12.5 mm; in the case
of the diseased (atherosclerotic) wall one point is on the plaque and the other
on the adjacent normal part of the wall. As we can see, axial displacement, i.e.
displacement along the arterial wall, exhibits a periodic pattern of frequency equal
to almost double the frequency of the radial displacement. This finding agrees with
recently reported results [5].
The methodologies presented here are useful for the quantitative assessment
of carotid atherosclerosis. In combination with the experience of a specialized
physician, they may improve the diagnostic power of ultrasound imaging. Their
integration into clinical practice depends not only on their performance but also on
how well the physician performs a task when the computer output is used as an aid.
More specifically, the suggested HT technique provides a simple, fast and
accurate way to identify the arterial wall in longitudinal and transverse sections
of the carotid artery and can be used in clinical practice to estimate indices of
Potential carotid atherosclerosis biomarkers based on ultrasound image analysis 509
Fig. 4 Examples of velocity fields and displacement waveforms obtained by the application of
the WLSOF methodology in a healthy (non-atherosclerotic) arterial wall (a, d), an asymptomatic
plaque (b, e) and a symptomatic plaque (c, f). Illustrated vectors were enhanced by a factor of 10.
Velocities correspond to beginning of systole
arterial wall physiology, such as the IMT and the ADW. In ten normal subjects, the
specificity and accuracy of HT-based segmentation were on average higher than 0.96
for both sections, whereas the sensitivity was higher than 0.96 in longitudinal and
higher than 0.82 in transverse sections. The corresponding validation parameters for
IMT estimation were generally higher than 0.90. The HT technique was also applied
to 4 subjects with atherosclerosis, in which sensitivity, specificity and accuracy were
comparable to those of normal subjects; the low values of sensitivity in transverse
sections may reflect departure from the circular model due to the presence of plaque.
For these cases, the combined HT-active-contours technique was found to increase
the sensitivity values.
Texture features using the three transform-based methods described previously
were extracted from a limited number of symptomatic (ten plaques) and asymp-
tomatic (nine plaques) cases. Differences between the two case types were estimated
using bootstrapping. Both the WT- and the Gabor-filter-based methodologies
resulted in significantly different features, which characterized texture at low
resolutions and in the horizontal direction. Features at low resolutions are indicative
of fine texture; finer texture was found in symptomatic compared to asymptomatic
plaques. Horizontal texture patterns are an interesting finding, especially when one
combines this information with arterial wall biomechanics. Mechanical stresses due
to blood blow may be responsible for such texture patterns; compared to blood
pressure, the other main cause of stress on the arterial wall, the effect of blood flow is
more pronounced around a plaque. The discriminative ability of the transform-based
510 S. Golemati et al.
texture features was found superior to that of the gray-scale median, a widely used
texture parameter of carotid plaque, for the small population that was interrogated,
emphasizing the need for using advanced techniques to efficiently characterize
atheromatous plaque.
Reliable estimation of arterial wall motion is a challenging task and is believed
to provide a powerful tool in the study of the physiology and biomechanics
of atheromatous plaque. The strain experienced by the arterial wall is a crucial
biomarker of carotid atherosclerosis and can be assessed through motion analysis.
In combination with information of the exerted stresses, it can prove useful for the
study of the mechanical behavior of cardiovascular tissue.
8 Conclusion
The methodologies presented in this chapter are expected to provide powerful tools
in the diagnosis of carotid atherosclerosis because they can assist interpretation of
ultrasound images. Individual techniques facilitate the diagnostic tasks of vessel
wall identification, plaque characterization and strain estimation of normal and
diseased arterial wall.
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