NeuroImage 118 (2015) 13–25

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NeuroImage

journal homepage: www.elsevier.com/locate/ynimg

3D MR ventricle segmentation in pre-term infants with

post-hemorrhagic ventricle dilatation (PHVD) using multi-phase
geodesic level-sets
Wu Qiu a,⁎,1, Jing Yuan a,1, Martin Rajchl a,b, Jessica Kishimoto a,c, Yimin Chen e, Sandrine de Ribaupierre d,
Bernard Chiu e, Aaron Fenster a,b,c
a
Robarts Research Institute, University of Western Ontario, London, ON, Canada
b
Biomedical Engineering Graduate Program, University of Western Ontario, London, ON, Canada
c
Medical Biophysics, University of Western Ontario, London, ON, Canada
d
Neurosurgery, Department of Clinical Neurological Sciences, University of Western Ontario, London, ON, Canada
e
Department of Electronic Engineering, City University of Hong Kong, PR China

a r t i c l e i n f o a b s t r a c t

Article history: Intraventricular hemorrhage (IVH) or bleed within the cerebral ventricles is a common condition among very
Received 30 January 2015 low birth weight pre-term neonates. The prognosis for these patients is worsened should they develop progres-
Accepted 21 May 2015 sive ventricular dilatation, i.e., post-hemorrhagic ventricle dilatation (PHVD), which occurs in 10–30% of IVH pa-
Available online 10 June 2015
tients. Accurate measurement of ventricular volume would be valuable information and could be used to predict
PHVD and determine whether that specific patient with ventricular dilatation requires treatment. While the
Keywords:
Ventricle segmentation
monitoring of PHVD in infants is typically done by repeated transfontanell 2D ultrasound (US) and not MRI,
3D pre-term neonatal MR with IVH once the patient's fontanels have closed around 12–18 months of life, the follow-up patient scans are done by
Multi-phase geodesic level-sets MRI. Manual segmentation of ventricles from MR images is still seen as a gold standard. However, it is extremely
Multi-atlas initialization time- and labor-consuming, and it also has observer variability. This paper proposes an accurate multiphase geo-
Convex optimization desic level-set segmentation algorithm for the extraction of the cerebral ventricle system of pre-term PHVD ne-
onates from 3D T1 weighted MR images. The proposed segmentation algorithm makes use of multi-region
segmentation technique associated with spatial priors built from a multi-atlas registration scheme. The leave-
one-out cross validation with 19 patients with mild enlargement of ventricles and 7 hydrocephalus patients
shows that the proposed method is accurate, suggesting that the proposed approach could be potentially used
for volumetric and morphological analysis of the ventricle system of IVH neonatal brains in clinical practice.
© 2015 Elsevier Inc. All rights reserved.

1. Introduction those patients will consequently develop hydrocephalus, necessitating

The mild enlargement of the cerebral ventricles, called
ventriculomegaly (VM), is often seen in neonates born prematurely
with the highest risk population being those born at b32 weeks gesta-
tion or with very low birth weight (b 1500 g). One of the primary
non-congenital causes of ventriculomegaly is intraventricular hemor-
rhage (IVH), which is brain bleeding that occurs in 15–30% of very
low birth weight pre-term neonates and is predictive of an adverse neu-
rological outcome (Synnes et al., 2001; Adams-Chapman et al., 2008;
Klebermass-Schrehof et al., 2013). Infants with IVH are at risk of devel-
oping progressive dilatation of the ventricles, a pathology called hydro-
cephalus. About 30–50% of infants with a severe IVH develop post-
hemorrhagic ventricular dilatation (PHVD) and around 20–40% of
⁎ Corresponding author.
E-mail addresses: wqiu@robarts.ca (W. Qiu), cn.jingyuan@gmail.com (J. Yuan).
1
Contributed equally.
to be treated with a permanent ventriculo-peritoneal shunt
(Adams-Chapman et al., 2008; Klebermass-Schrehof et al., 2013). Pre-
term infants are at risk of white matter injury, due to either a unilateral
parenchymal hemorrhage or a more diffuse bilateral white matter dam-
age, and the development of PHVD increases the risk of an adverse
neurodevelopmental outcome. Around 45–60% of infants with PHVD
have marked cognitive impairment (developmental quotient equivalent
of less than 70) (Adams-Chapman et al., 2008; Klebermass-Schrehof
et al., 2013). Any patient with VM will be followed for 1–2 years, as
they are at risk of developing hydrocephalus. However, it is difficult to
determine how quickly ventricle dilatation is progressing through cur-
rently used qualitative viewing of the MR images. During the follow-
up, ultrasound (US) or MR images of their brains are acquired to quanti-
tatively monitor the ventricular size. However, while clinicians have a
good sense of what VM looks like compared to normal ventricles, there
is little information available on what quantitative volumetric normal
ranges are for ventricle volume of the cerebral ventricles in pre-term

http://dx.doi.org/10.1016/j.neuroimage.2015.05.099
1053-8119/© 2015 Elsevier Inc. All rights reserved.
14 W. Qiu et al. / NeuroImage 118 (2015) 13–25
neonates as they mature, and only a few investigative studies (Haiden
et al., 2005; Knickmeyer et al., 2008) have been conducted. In addition,
VM is considered to be related to diagnosed anomalies of the central ner-
vous system (CNS) (Guibaud, 2009). Although the sources and outcomes
of VM have been extensively investigated (Weisglas-Kuperus et al.,
1992; Gaglioti et al., 2005; Breeze et al., 2007; Beeghly et al., 2010),
much remains unknown due to its variable etiology, complicated patho-
physiology, and poorly understood natural history (Gaglioti et al., 2005;
Beeghly et al., 2010). Volumetric analysis based on volumetric and mor-
phological biomarkers of the developing neonatal brain can greatly im-
prove the diagnosis, prognosis, and treatment of VM, which requires a
robust and accurate automatic segmentation algorithm.
Previous brain segmentation algorithms have been extensively
investigated in adult brain MR images, leading to several successful
methods and software packages, such as SPM (Ashburner and Friston,
2005) and FreeSurfer (Fischl et al., 2002).
However, there is limited publicly available software for neonatal
brain MR image segmentation. Neonatal brain MR images tend to suffer
from high image noise, low tissue contrast, and considerable inter-
subject anatomical variability, which make most of the methods used
for the adult population not applicable to these images (Gui et al.,
2012). Segmentation is even more difficult in infants with IVH as their
ventricles contain heterogeneous cerebrospinal fluid (CSF) due to the
hemorrhage. Wang et al. (2011) developed a coupled level-set method
initialized by convex optimization technique for automatic neonatal MR
images. Shi et al. (2010a) built a subject-specific tissue probabilistic
atlas to segment longitudinal neonatal brain MR images. Wang et al.
(2014a) integrated this probabilistic atlas into a patch-driven level-set
framework for more accurate segmentation of neonatal MR images.
Three different image sets of preterm infants provided in the
NeoBrainS12 study (http://neobrains12.isi.uu.nl) (Isgum et al., 2015)
were set up to allow a comparison of 8 brain tissue segmentation
methods. The results demonstrated that the participating methods
were able to segment all tissue classes well, except myelinated white
matter. Even though several methods tend to perform better than
others, areas of poor segmentation were common to all methods.
Most of previous work (Gui et al., 2012; Wang et al., 2011, 2014a; Shi
et al., 2010a; Isgum et al., 2015) segmented neonatal brain MR images
into different brain tissues, such as white matter (WM), gray matter
(GM), and CSF, but did not focus on the ventricular system. Moreover,
these methods were only validated on high-quality healthy neonate im-
ages generated for research purposes only while patients were sedated.
Gholipour et al. (2012) developed a ventricle segmentation method of
fetal brain MRIs using 13 normal brains and 12 fetuses with mild VM,
which is the most similar study to ours. However, unlike the healthy
brains and the brains with mild VM, the MR images of neonatal patients
with IVH and hydrocephalus used in this study provide greater chal-
lenges for segmentation. The poor physical condition of these patients
does not allow for a normal acquisition time or patient sedation, leading
to a much poorer image quality. Furthermore, heterogeneous CSF with
degrading blood products and dilatation of the ventricles cause large
brain deformation and drastic inter-subject variations in the anatomy
from patient to patient (Fig. 1). The blood clots from IVH are not only
in the ventricles, but also at the junction between the ventricles and
the brain, and infiltrating the brain creating heterogeneous imaging
properties. For some severe cases, the ventricle volume is N 70% of the
whole brain compared to b30% of patients with mild VM, making it
much more challenging to capture such large shape variability for
most multi-atlas registration-based approaches (Warfield et al., 2004;
Aljabar et al., 2009). Although manual segmentation is an option, it is
too arduous and time consuming to be clinically feasible. Thus, an accu-
rate and robust automatic cerebral ventricle segmentation algorithm
from IVH neonatal MRIs is still highly desirable in clinical practice in
order to handle images of poor quality and large shape variability.
In this study, we propose a multi-region segmentation approach for
delineating the brain ventricle system of pre-term IVH neonate patients
from acquired 3D T1 weighted (T1w) MR images. The proposed algo-
rithm is initialized by non-linearly registering multiple pre-segmented
patient images onto the subject image using a duality-based convex op-
timization registration scheme. A variational time-implicit multiphase
geodesic level-sets (MGLS) is then proposed to automatically extract
the ventricle system, which incorporates an intensity probability
density function (PDF) and a probabilistic labeling map as shape priors
generated in the initialization procedure. In particular, the major com-
ponents of the whole segmentation pipeline are implemented using
general-purpose programming on graphics processing units (GPGPU)
to obtain a high computational efficiency.
The proposed MGLS algorithm is the extension of a 2015 EMMCVPR
paper (Rajchl et al., 2015), which only provided a segmentation frame-
work, and was evaluated on one 3D adult MR image. Compared to the
previous version based on classic level sets (Rajchl et al., 2015), the geo-
desic level-sets (Criminisi et al., 2008) is incorporated into the surface
evolution to improve the segmentation accuracy, especially for the
hydrocephalus patient images. The improved algorithm has been evalu-
ated on a larger number of patient images. To the best of our knowledge,
this paper is the first study focusing on automated ventricle segmenta-
tion of pre-term neonatal MR images with VM and hydrocephalus.
2. Method
2.1. Segmentation pipeline
Fig. 2 shows an overview of the proposed segmentation pipeline. An
input subject image is first classified into a specified patient group
(patients with mild enlarged ventricles or hydrocephalus patients)
based on the Bhattacharyya distance (Michailovich et al., 2007)
between the background and foreground defined by registered pre-
segmented labels. Multiple manually pre-segmented patient images
from the specified group are registered to the subject image using affine
and deformable registration techniques. The multiple registered labels
are fused via a weighting strategy to acquire a probabilistic labeling
map, which is used as a spatial prior for a subsequent segmentation
step. A thresholding procedure follows to generate the initial guess for
the ventricles and to approximate the intensity appearance models,
i.e., the probability density functions (PDFs), for the left, right, third
ventricle, and background regions respectively. Finally, a multi-phase
geodesic level-sets based multi-region segmentation approach is pro-
posed to globally minimize an introduced continuous min-cut energy
function, which incorporates the information including the shape
prior, the constraints to avoid intersections among structures, the
image intensity model, as well as a gradient edge map.
2.2. Pre-processing
All images are bias corrected using the N3 algorithm (Sled et al.,
1998), and subsequently head masked via the BET algorithm (Smith,
2002). Note that the head mask is only used to locate the position of
the head, and is used to exclude the regions with image noise outside
of the skull. The segmentation is carried out without skull-stripping
to avoid potential poor skull-stripping since the BET algorithm was
developed for the adult brain images.
2.2.1. A. Grouping image based on Bhattacharyya distance
In this work, all testing images are classified into two groups Gi,i =
n,h. (n, h denote patients with mild VM and hydrocephalus patients, re-
spectively). Two manually specified reference image Mi,i = n,h with
pre-segmented labels Li,i = n,h from two groups, are registered onto
the new subject image using the registration technique described in
the Section 2.2B, giving rise to two registered labels ~Li . We calculate
the Bhattacharyya intensity distance (Michailovich et al., 2007; Rathi
et al., 2006), Bi,i = n,h, between the foreground and background voxels
 W. Qiu et al. / NeuroImage 118 (2015) 13–25 15

Fig. 1. Sagittal views of two IVH neonatal ventricles. Left: patient with mild VM (patient 3) and right: patient with hydrocephalus (patient 11).

labeled by registered labels ~Li, where the structures of the left, right, and delineation of lesions in digital mammograms, which showed better perfor-
the third ventricles, regarded as one whole part, are labeled as the mance than the KL metric. In this study, the Bhattacharyya metric is used
foreground and the remaining region of the brain is labeled as the only for the procedure of classifying the subject image into its correspond-
background. Bi is defined as: ing patient group, and a completely accurate segmentation is not required.

 rffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi


ffi
X
Bi ~Li ¼ − p f ~Li ; z pb ~Li ; z ; i ¼ n; h ð1Þ 2.2.2. B. Construction of spatial shape priors
z∈Z
The grouping procedure categorizes the subject image into its corre-
sponding group: patient group with mild VM or hydrocephalus group.
where Z is the set of image intensity values, b,f denote the background

 After that, another multiple training set of images from its correspond-
and foreground regions. For region R, the PDF p j ~Li ; z is estimated by ing group are registered onto the subject image to construct the spatial
the Parzen method (Parzen, 1962), such that shape prior. In particular, a typical registration strategy is used while
performing multi-atlas registration, which applies a non-linear registra-
Z
tion followed by an affine transformation (Heckemann et al., 2010;

 K ðz−IðxÞÞ ~Li dx
Ωj Cabezas et al., 2011; Shi et al., 2010b; Wang et al., 2013, 2014a). The
p j ~Li ; z ¼ Z ; j ¼ f ; b; ð2Þ details are as follows. Each training image of (Ii(x),i = 1,2,…,n) is
~Li dx
Ωj
registered by uaffine
i (x) to the subject image Is(x) using an affine block-
matching approach with default parameters, which is implemented in
the Nifty Reg package (Ourselin et al., 2002; Modat et al., 2010). Follow-
where K(⋅) is the Gaussian kernel function such that K ðxÞ ¼
  ing the affine registration, a recently developed novel deformable regis-
pffiffiffiffiffiffiffiffi
1 ffi
exp −x2 =2σ 2 . The subject image is classified into the group
2πσ 2 tration algorithm (RANCOR) (Rajchl et al., 2014) is used to efficiently
− linear
defined by the greater Bi. and accurately extract the non-linear registration unon i (x), i =
It should be noted that there are also some other distribution similar- 1,2,…,n, from each pre-segmented image Ii to the subject image Is.
ity metrics demonstrating good performance in other applications. For ex- Especially, it makes use of a coarse-to-fine strategy to capture the
ample, Sandhu et al. (2008) developed a new metric, which large deformations and employs iterative convexification to address de-
outperformed both Bhattacharyya (Michailovich et al., 2007) and formable registration problems under total-variation regularization.
Kullback–Leibler (KL) (Kullback, 1987) divergence metrics. Georgiou Furthermore, the used registration algorithm is implemented using
et al. (2007) provided a review of PDF similarity metrics. In addition, general-purpose programming on graphics processing units (GPGPU)
Rahmati et al. (2012) proposed a level set active contour segmentation and present run times of only several minutes on commercially
approach based on the maximum likelihood (ML) algorithm for the available hardware (for more details refer to Rajchl et al. (2014)).

Fig. 2. Block diagram of the proposed segmentation pipeline.

16 W. Qiu et al. / NeuroImage 118 (2015) 13–25
Let Si(x) ∈ {0,1} i = 0,1,2,…,n, be the label function of each pre-
segmented image. For simplicity, the average of each label Si(x) is
used as the probabilistic label function Ŝi(x), which is used as a probabi-
listic shape prior and provides a global shape-associated energy cost
term in the applied multi-region continuous min-cut segmentation.
Specifically, one probabilistic atlas for each label is created by averaging
all the training label maps for the same label. Eighteen training images
were used to create the atlas for the subject image with mild VM, and
six training images were used for the hydrocephalus subject image.
Note that more advanced shape prior representations (Andrews et al.,
2014), such as shape probability vector, could be applied.
Thresholding Ŝi(x) by a value of 0.8 generates a binary labeling image
for each label, which gives a proper initial guess to the ventricle seg-
mentation agreed by all the training images. The complete consensus
of all the training images (threshold of Ŝi(x) is 1 for each label) is not
used in the case of an empty set of the intersections of all deformed la-
bels. Therefore, the voxels labeled by this binary image are sampled to
approximate the intensity PDF prior Fi(I(x)) for each ventricle sub-
region (i = 1,2,3). In particular, the head mask is shrunk by a distance
based on the signed distance function, and the thresholded binary label-
ing image is also dilated by a distance. The voxels between the shrunk
mask and the dilated labeling image are sampled to compute the PDF
prior BLi ðIðxÞÞ for the background. It should be noted that the used
label fusion strategy is not optimal (Heckemann et al., 2006; Wang
et al., 2013), due to: i) each atlas contributed equally although registration
errors might occur; ii) only label information is used without image infor-
mation when performing label fusion; and iii) the weight is assigned for
each atlas globally, without taking into account the fact that different
local regions of each atlas may contribute differently. Since this paper is
focusing on the multi-region segmentation, not the label fusion tech-
nique, and the generated label probability map only serves as one of
data costs during the segmentation, we used a simple label fusion tech-
nique, which is incorporated into our proposed multi-phase geodesic
level-set evolution. Although the statistical shape model has been used
successfully in other applications (Leventon et al., 2000; Pohl et al.,
2007; Andrews et al., 2014), label fusion based shape prior construction
is used in our study. Compared to the statistical shape model learned by
principle component analysis (PCA), which required the estimation of
shape and rigid pose parameters at each step of the evolution, the shape
atlas built in our study only serves as a data cost term for each voxel be-
fore the segmentation procedure. Once the shape data cost is assigned,
the shape atlas is not involved in the subsequent segmentation module.
2.3. Multi-region segmentation with spatial priors based on variational
time-implicit multiphase geodesic level-sets (MGLS)
2.3.1. A. Revisiting time-implicit level-set method
A fully time-implicit level-set scheme has been proposed in recent
studies (Almgren et al., 1993; Luckhaus and Sturzenhecker, 1995;
Boykov et al., 2006; Chambolle, 2004; Yuan et al., 2012, 2013), which
is substantially distinct from classical level-set approach (Chan and
Vese, 2000, 2001), making use of global optimization technique with
advantages in both implementation and computation.
Almgren et al. (1993) and Luckhaus and Sturzenhecker (1995) first
proved that, given the outer force f and mean-curvature K, the mean-
curvature-driven level-set problem:
∂t C ¼ −κ þ f
can be solved iteratively. For each discrete time frame from t to t + h,
this level-set problem (Eq. (3)) can be solved by minimizing the varia-
tional energy (Luckhaus and Sturzenhecker, 1995):
Z Z Z developments in level-set methods and establishes a variational basis
1 for simultaneously propagating multiple disjoint level-sets by means
C tþh :¼ min ds þ distðx; ∂C t Þdx− f dx;
C ∂C CΔC t h C
where the function dist(x, ∂Ct) denotes the distance from x to the region
boundary ∂Ct, Ct and Ct + h is the respective position of the region at time
t and t + h, and CtΔCt + h denotes the symmetric difference between Ct
and Ct + h. This problem (4) can be expressed as:
Z Z  
1
min ds þ sdistðx; ∂C t Þ−f dx; ð5Þ
C ∂C C h
where sdist(x, ∂Ct) denotes the signed distance of x to ∂Ct. More recent de-
velopments in convex optimization proved that the minimization
problems (4) or (5) can be solved exactly by means of the continuous
min-cut (Chan et al., 2006; Yuan et al., 2010a), which indicates that the
level-set can be moved to the globally optimal position at each discrete
time-frame without further constraints on the time step-size h. This ap-
proach is theoretically different from classical time-explicit ones, which
are based on approximations strictly requiring the time step-size to be
sufficiently small to converge. Another advantage of time-implicit ap-
proaches is the availability of fast global optimizers via convex optimiza-
tion (Yuan et al., 2010a; Pock et al., 2009; Lellmann et al., 2010), or graph-
cuts (Boykov et al., 2001; Boykov and Kolmogorov, 2001).
Boykov et al. (2006) proposed the same variational principle (4) to
the mean-curvature-driven level-set evolution and studied it under a
discrete graph-cut perspective. Yuan et al. (2012) investigated the
time-implicit level-set evolution scheme introduced in Luckhaus and
Sturzenhecker (1995) with help of continuous max-flow theory (Yuan
et al., 2010a), which demonstrated that the global optimum to (4) or
(5) is essentially the backward motion of (3), that is:
x ¼ xt −hðκ−f ÞðxÞnðxt Þ; ð6Þ
where the projection of any pixel x at the computed new boundary
∂Ct + h, on the boundary ∂Ct, is xt, and n(xt) is the unit outward normal
to Ct at xt. Obviously, (6) tends to approximate an ideal mean-curvature
motion in (3) when h → 0.
It should be noted that Chambolle (2004) also studied the mean-
curvature driven motion (3) of contours with the force term f(x) = 0,
which showed that the next contour position Ct + h can be obtained at
each discrete time frame by the zero level-set of the total-variation reg-
ularized signed distance function sdist(x, ∂Ct) w.r.t. Ct, with the back-
ward motion scheme
x ¼ xt −hκ ðxÞnðxt Þ; ð7Þ
which is equal to (6) given f(x) = 0. Bresson and Chan (2007) extended
Chambolle's work (Chambolle, 2004) to the case of geodesic level-set
evolution with region forces.
Despite the advantages of the time-implicit level-set methods in both
theory and implementation, very few studies have dealt with the propaga-
tion of multiple level-sets in a fully time-implicit style. We proposed a novel
global optimization scheme for the evolution of multiple level-sets Ci, i =
1…n (Yuan et al., 2013) while preserving a linear order over level-sets:
C n ⊂…⊂C 1 :
Yuan et al. (2013) demonstrated that such level-sets can be simulta-
neously moved to their globally best positions in a fully time-implicit
manner.
ð3Þ 2.3.2. B. Variational time-implicit multiphase geodesic level-sets with
variational region competition
In this section, we study the evolution of multiple mean-curvature-
driven contours with respect to a disjoint region constraint, for which
we propose a novel variational principle, i.e., the variational region com-
petition. The proposed variational region competition generalizes recent
ð4Þ
of minimizing costs w.r.t. region changes. We show that previous
 W. Qiu et al. / NeuroImage 118 (2015) 13–25 17

approaches for single level-set under via a minimum cost of re- 1…n, to be proportional to the geodesic distance function from x to
gion changes w.r.t. foreground and background (Luckhaus and the current boundary ∂Cti such that
Sturzenhecker, 1995; Boykov et al., 2006; Yuan et al., 2012), are
 t
a special case of the proposed theory. In addition, the proposed princi- c− þ
i ðxÞ ¼ ci ðxÞ ¼ gdist x; ∂C i =h; i ¼ 1…n ð10Þ
ple can be reformulated as a spatially continuous Potts problem
(Potts, 1952), i.e., a continuous multi-region min-cut problem, which where h N 0 is constant, and gdist is geodesic distance defining dis-
can be solved via convex relaxation, i.e., the convex relaxed Potts tances from x to the contour ∂Ct using the shortest path along the
model under a continuous max-flow perspective. image intensities, which could provide more adaptive spatial con-
texts compared to Euclidean distance (Toivanen, 1996; Criminisi
(i) Principle of variational region competition
et al., 2008; Wang et al., 2014b). Geodesic distance defines distances
We consider the evolution of n disjoint regions/level-sets Ci, i = 1…
between structures using the shortest path along the image intensi-
n, under the constraint:
ties rather than through physical space while taking gradient infor-
Ω ¼ ∪ni¼1 C i ; C k ∩ C l ¼ ∅; ∀k ≠ l ð8Þ mation into account. Geodesic distance provides more adaptive
spatial contexts compared to Euclidean distance. In general, the geo-
where Ω means image domain. Let Cti , i = 1…n, be the i-th region at desic distance between two points p1,p2 within an image I is defined
the current time frame t, which moves to position Cti + 1 at the next as follows:
time frame t + 1. Z rffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
ffi
l ðΓ Þ
 2 
For each region Cti , i = 1…n, at time t, we define two types of differ- dðp1 ; p2 Þ ¼ inf 1 þ γ 2 ∇ IðsÞ  Γ0 ðsÞ ds ð11Þ
ence regions with respect to Cti + 1 (see Fig. 3 for an illustration): Γ∈P p1 ;p2 0

1. C+ t
i indicates expansion of Ci w.r.t. Ci
t+1
: x ∈ C+ t
i , it is outside Ci at
time t, but inside Ci t+1
at t + 1; for such an expansion of x, with where Γ is a path in the set of all paths P p1 ;p2 between p1 and p2 and is
cost c+ parameterised by its arc length s ∈ [0, l(Γ)]. The Euclidean distance
i (x).
2. C− t t+1
: x ∈ C− t can be regarded as a special case of the geodesic distance when γ
i indicates shrinkage of Ci w.r.t. Ci i , it is inside Ci at
time t, but outside Ci t+1
at t + 1; for such a shrinkage of x, with is set to 0. In this work, we implemented the computation of geode-
cost c− sic distance using Toivanen (1996) and Criminisi et al. (2008).
i (x).
With these definitions, we propose the variational principle as: Using the variational region competition principle (9), we have:
Variational region competition principle (VRCP). For n disjoint re-
Corollary 1. The mean-curvature-driven evolution of multiple disjoint
gions Ci, i = 1…n, the evolution of each region over the discrete time
level-sets Ci, i = 1…n, during time frame t to t + 1 minimizes the cost
frame from t to t + 1 minimizes total cost of region changes. That is,
w.r.t. region changes. The optimal new regions Cti + 1, i = 1…n, therefore
the new optimal contours Cti + 1, i = 1…n, minimize the energy: minimize:
(Z Z )
X n Z
X n Z Z
n
c− cþ ðxÞdx X   Xn
i ðxÞdx þ þ g ðsÞds ð9Þ
min 1
Ci − þ i min gdist x; ∂C ti dx þ ds ð12Þ
i¼1 Ci Ci i¼1 ∂C i Ci t h
i¼1 C i ΔC i i¼1 ∂C i

subject to (8), where g(s) is the weighting function along the contour subject to the constraint (8).
boundaries. The evolution of each region is intended to minimize the
discrepancy between shrinkage and expansion over the discrete time
2.3.3. C. Multiphase geodesic level-set evolution with VRCP with application
frame while also minimizing contour length. to multi-region segmentation (MGLS)
(ii) Multiphase geodesic level-set evolution with VRCP For multi-region image segmentation, the level-set evolution is driv-
For the mean-curvature-driven evolution of multiple disjoint level- en not only by the geodesic distance functions as above, but also by
sets Ci, i = 1…n, we define the cost functions c− +
i (x) and ci (x), i = image features. In general, the cost functions c− +
i (x) and ci (x), i = 1…

Fig. 3. An example of the evolution of 4 disjoint regions. (a) Shows the 4 disjoint regions at the current time frame t; (b) shows the evolution of the contour ∂Ct1 from discrete time t to the
−
next time frame t + 1, where ∂Ct1 + 1 is the evolved contour at the time frame t + 1, and C+ 1 and C1 show the regions of expansion and shrinkage, respectively.
18 W. Qiu et al. / NeuroImage 118 (2015) 13–25

n, w.r.t. region changes are given by the combination of the image 3. Experiments and results
feature costs and the geodesic distance functions. In this application,
we define the cost functions as follows: 3.1. Image acquisition


cþ − ^
i ðxÞ ¼ ci ðxÞ ¼ −ω1 log F i ðI ðxÞÞ−ω2 log Si ðxÞ  Gσ ðxÞ
All patients were imaged following a protocol approved by the
1   ethics review board at the University of Western Ontario (REB
þ ω3 gdist x; ∂C ti ∀x ∈ C ti #100315). After an initial diagnosis of IVH on a clinical 2D US exam,
h
the parents of the patient were approached to enroll their child in the
where the weighting parameters ω1, ω2, ω3 N 0, ω1 + ω2 + ω3 = 1 study. Imaging sessions would be canceled if patients were not stable
weight the contributions from the intensity, shape priors and geodesic as judged by the attending team and nursing staff. Preterm-born pa-
distance for each voxel, respectively, and Gσ(x) is the Gaussian smooth- tients with different IVH grades were imaged upon reaching term-
ing function. The corresponding optimization formulation is then given equivalent age with a 1.5T Signa HDxt MRI scanner (General Electric
by the variational region competition principle (9) directly, which is Health Care, Milwaukee, WI) without sedation. IVH was graded using
slightly different from (10). the Papile classification (Papile et al., 1978), which is the clinical stan-
We show that the variational problem (9) introduced by the varia- dard. A 3D T1-weighted (T1w) MR image of each brain was acquired
tional region competition principle can be equally reformulated as the while the patient was bundled inside a MedVac blanket (CFI Medical
Potts problem (Potts, 1952). For this purpose, we define two cost func- Solutions Inc, Fenton, MI), just after being fed, in order to reduce patient
tions Dsi (x) and Dti (x) w.r.t. the current contour Cti , i = 1…n, at time t: movement. 28 patients (with the gestation from 37 to 42 weeks) with
different IVH grades were recruited in this study. The T1w MR images
c− t
i ðxÞ; where x ∈ C i were acquired axially with the following parameters: TR = 9.29 ms,
Dsi ðxÞ :¼ ð13Þ
0; otherwise TE = 4.20 ms, and scan time = 9 min. A typical reconstructed image
size was 512 × 512 × (180–250) voxels with a voxel spacing of
cþ
i ðxÞ; where x ∉ C ti 0.39 × 0.39 × (0.5–1) mm3, and the acquisition voxel size was
Dti ðxÞ :¼ : ð14Þ
0; otherwise 1 × 1 × 1 mm3.
The 28 patient images were classified into two subsets: 20 images
Let ui(x) ∈ {0, 1}, i = 1…n, be the indicator function of the region Ci. with mild VM (dataset 1) and 8 images with hydrocephalus (dataset
Therefore, the disjoint constraint in (8) can be represented by 2). The ventricle volume ranged from 4.9 cm3 to 648.1 cm3 (mean =
85.5 ± 160.4 cm3). One image from each subset was manually selected
X
n
as the reference image of its subset, used for image grouping described
ui ðxÞ ¼ 1; ui ðxÞ∈f0; 1g ; ∀x∈Ω: ð15Þ
i¼1 in Section 2.2A. Specifically, two reference images from two groups
were manually selected by an expert prior to atlas registration, based
Via the cost functions (13) and (14), we can prove on the mean ventricle volume of the patients. In particular, one IVH
grade 2 patient image with a volume size of 9.8 cm3 was selected
Proposition. The variational formulation (9) associated with the varia- from the patient group with mild VM, which is nearest to the mean vol-
tional region competition principle can be expressed as the Potts problem ume of 10.1 cm3 of the patient group with mild VM, and one hydroceph-
alus patient image with a ventricle volume of 164.1 cm3 was chosen
X
n
 Xn Z
min ui ; Dti −Dsi þ g ðxÞj∇ui j dx ð16Þ from the hydrocephalus patient group, which is nearest to the mean
ui ðxÞ∈f0;1g
i¼1 i¼1 Ω volume of 170.5 cm3 of the patient group with mild VM. The rest 26
images (19 patient images with mild VM and 7 patient images with
subject to the contour disjointness constraint (15), where ∇ is Laplace hydrocephalus) were used for the leave-one-out cross validation,
operator and ∇ui denotes the gradient of ui. The weighted length term in which means that 18 images with manual annotations were used for
(9) is encoded by the weighted total-variation functions. atlas registration for each patient image with mild VM, and 6 images
The detailed proof of the equivalence between the optimization with manual annotations were used for atlas registration for each
function (9) and the variational formulation (16) in the Appendix A. patient image with mild hydrocephalus.

2.3.4. D. Continuous max-flow approach and dual optimization 3.2. Evaluation metrics
The resulting formulation (16) gives rise to a challenging combina-
torial optimization problem. From recent developments of convex We used volume-based and distance-based metrics to evaluate the
optimization (Pock et al., 2009; Lellmann et al., 2009, 2010; Yuan accuracy of the algorithm. All manual segmentations of our data sets
et al., 2010b), its global optimum can be approximated efficiently were generated by a trained graduate student and examined, modified
through convex relaxation, i.e. and approved by a neurosurgeon consultant. The manual contours were
drawn through the saggital plane on parallel slices 1 mm apart. These
X Z
n
 Xn contours were reconstructed and meshed to generate a 3D surface,
min ui ; Dti −Dsi þ g ðxÞj∇ui jdx ð17Þ and the volume was later filled.
uðxÞ∈Δþ Ω
i¼1 i¼1
We denote the manual segmented surface M as a set of vertices
where Δ+ is the simplex set {mi: i = 1,…,K}, and the algorithm-generated surface A as the vertex
set {ai : i = 1,..., N}. We used the Dice similarity coefficient (DSC)
X
n (Qiu et al., 2014a,b; Litjens et al., 2014): DSC ¼ 2ðRRMMþR
∩RA Þ
 100% as a
for ∀ x ∈ Ω; ui ðxÞ ¼ 1; ui ðxÞ ∈ ½0; 1; i ¼ 1…n: A

i¼1
The minimization problem (17) is a special case of that studied in
Yuan et al. (2010b) where ρ(i, x) = Dti − Dsi . To solve (17), we use an
efficient algorithm proposed in Yuan et al. (2010b), which solves a
max-flow formulation of (17) by the augmented Lagrangian method.
We refer to Appendix B for details.
region-based metric, where RM and RA define the regions enclosed by
the manual and algorithm-segmented surfaces. Let d(mi,A) be the
distance between vertex mi of the surface M and its closest vertex on
K
the surface A. The mean absolute distance MAD ¼ K1 ∑i¼1 dðmi ; AÞ and
the maximum absolute distance MAXD = max{d(mi, A)} were used as
distance-based metrics (Qiu et al., 2014a,b). Let VA be the algorithm
segmented volume and VM be the manually segmented volume for a
 W. Qiu et al. / NeuroImage 118 (2015) 13–25
Fig. 4. Four segmented ventricles using the proposed approach with left, right, and the third ventricles colored in red, green and blue, respectively. DSCs for two patients with mild ventricle
enlargement are 91.5% in (a) and 86.3% in (b), and 92.3% in (c) and 94.2% in (d) for two patients with hydrocephalus.
single 3D MR image. We used volume error δVE = VA − VM and percent-
age volume error δV P ¼ ðV AV−V
M
MÞ
 100% for volume-based metrics. In
addition, we also computed absolute volume error |δVE| = |VA − VM|
and absolute percentage volume error δV P ¼ jδV Ej
V M  100% (Qiu et al.,
2013).
3.3. Segmentation accuracy
Fig. 4 shows four algorithm segmented ventricles. Table 1 shows the
quantitative segmentation results for 26 patient images using the pro-
posed method. Our approach generated a mean DSC of 86.4% ± 8.3%
for all tested images compared to manual segmentations. Specifically,
a mean DSC of 84.6 ± 4.5% was obtained for 19 images with mild ven-
tricle enlargement while 91.4 ± 4.0% for 7 images with hydrocephalus.
The proposed method generated the highest DSC of 94.8% from a hydro-
cephalus patient image with a ventricle volume of 277 cm3 and the low-
est DSC of 78.2% from a patient with mild VM with a ventricle volume of
5.6 cm3. Other results in terms of MAD, MAXD, volume error and
volume percentage volume are also reported in Table 1. It should be
noted that the DSC obtained for the dataset 2 is greater than the DSC ob-
tained for the dataset 1, which does not necessarily mean more accurate
segmentation since the volume size will lead to the bias of the DSC
value. Other metrics, such as MAD and MAXD, are considered while
evaluating a segmentation algorithm.
In order to quantify the local extent of segmentation errors of the
proposed algorithm, the mean and standard deviation maps of segmen-
tation errors for two datasets are shown in Figs. 5 and 6, respectively.
These maps were generated by registering the algorithm-segmented
surfaces onto a template surface using a 3D symmetric correspondence
algorithm (Papademetris et al., 2002) and a non-rigid point-set registra-
tion algorithm (Myronenko and Song, 2010). Figs. 5 and 6 present the
local segmentation errors on a point-by-point basis. In Figs. 5(a) and
6(a), the mean segmentation error for a point with over-segmentation
was set to be positive while it was negative for a point with under-
segmentation, color-coded and super imposed on the 3D template sur-
face. In Figs. 5(b) and 6(b), the standard deviation of segmentation er-
rors are shown at each point on the template surface. It can be seen in
Fig. 5 that most disagreements between the algorithms with manually
segmented surfaces occurred in the regions of the posterior and inferior
Table 1
Accuracy results for 26 3D T1w MR images of pre-term neonate ventricle system using the proposed algorithm in terms of DSC, MAD, MAXD, volume error (|δVE|), and percentage volume
error (|δVP|), represented as mean ± standard deviation, [worst, best].
DSC (%)
Dataset 1 (19 images) 84.6 ± 4.5
[78.2,91.6]
Dataset 2 (7 images) 91.4 ± 4.0
[84.1,94.8]
In total 86.4 ± 5.3
19
horn of the ventricles for the patient group with mild VM. In contrast,
the segmentation errors for the hydrocephalus patient group mostly
occurred in the posterior and occipital horn of the ventricles in Fig. 6.
Although the proposed algorithm is specially developed for neonatal
ventricle segmentation, it can be also potentially applied on other im-
ages. We additionally tested the proposed ventricle segmentation
method on 20 adult MR images from the Open Access Series of Imaging
Studies (OASIS-TRT-20) database with manually segmented label maps
(Marcus et al., 2007; Klein and Tourville, 2012). Each entry in the
database contains a defaced T1-weighted volume (MPRAGE sequence
at 1.5T, TR = 9.7, TE = 4.0, TI = 20.0, flip angle = 10°) with
1 × 1 × 1.25 mm voxel sizes. The labeling protocol for the OASIS data-
base in its original form is a brain parcellation protocol using 134
labels, but only three labels for ventricles were used in this experiment.
10 images randomly selected were used as atlases while other 10
images were used for validation. The validation results show that the
proposed method yielded a mean DSC of 88.7 ± 3.5%, a MAD of 1.5 ±
0.5 mm, and a MAXD of 2.5 ± 1.0, suggesting its general applicability.
3.4. Computational time
Computations were carried out on a Tesla C2070 GPU (NVIDIA,
St. Clara, CA) with an Ubuntu 12.04 machine and 144 GB RAM, where
each computation of convex optimization required approximately
1.5 min. Each pairwise registration from one training image to the
target subject was composed of an affine registration (no GPU accelera-
tion: 3 min) and deformable registration (GPU: 50 s). Thus, the leave-
one-out cross validation required approximately 28 h to complete the
entire pipeline, 24.5 h for the dataset 1 and 3.5 h for the dataset 2. An av-
erage of 1.3 h and 0.5 h was required for each subject image of dataset 1
and dataset 2, respectively.
3.5. Comparison with other methods
Compared to MR ventricle segmentation methods in the literature,
the mean DSC of 86.4 ± 5.3% generated by our proposed method is com-
parable to a mean DSC of 89.9% for CSF reported in Anbeek et al. (2008).
But the DSC value of 89.9% in Anbeek et al. (2008) was generated for
CSF, not ventricles. In addition, the method in Anbeek et al. (2008)
was only validated using 13 images of healthy infant. Our reported
MAD (mm) MAXD (mm) |δVE|(cm3) |δVP|(%)
0.8 ± 0.31 9.8 ± 3.2 1.9 ± 3.2 13.6 ± 11.4
[1.7,0.43] [13.6,5.5] [3.1,0.4] [16.5,1.8]
2.0 ± 1.3 14.7 ± 5.2 9.0 ± 2.3 11.4 ± 6.0
[3.6,0.3] [19.8,8.2] [28.7,1.9] [14.8,2.2]
1.2 ± 0.9 10.5 ± 4.1 5.4 ± 8.6 10.7 ± 4.6
20 W. Qiu et al. / NeuroImage 118 (2015) 13–25
Fig. 5. Group mean and standard deviation map of segmentation errors of left and right ventricles between manual and algorithm segmentation over 19 patient images with mild VM.
(a) Mean map of segmentation errors and (b) standard deviation map of segmentation errors.
ventricle segmentation accuracy is close to most of methods in the
NeoBrainS12 study (Isgum et al., 2015) regardless of healthy infant
images with higher image quality. The mean DSC obtained by the pro-
posed method is lower than a DSC of 87.0% reported in Anbeek et al.
(2005), a median DSC of 95.9% reported in Coupé et al. (2011), and a
mean DSC of 88.0 ± 6.7% reported in Gholipour et al. (2012). However,
both Anbeek et al. (2005) and Coupé et al. (2011) used images from
adult populations, which had better image quality and much less ana-
tomic variation. Gholipour et al. (2012) used 13 normal brains and 12
fetuses with mild VM. Unlike the healthy brains and the brains with
mild VM, the MR images of neonatal patients with IVH and hydroceph-
alus used in this study pose more challenges for segmentation.
In addition, the proposed segmentation approach (MGLS) was com-
pared to several other methods with the same datasets, including
STAPLE (Warfield et al., 2004), majority voting (MV) (Heckemann
et al., 2006), single level-set (SLS), single geodesic level-set (SGLS),
and multi-phase level-sets (MLS) (Yuan et al., 2013; Ukwatta et al.,
2013). The STAPLE and MV methods were re-implemented by the
ITK-SNAP toolbox (Yushkevich et al., 2006). We used the same cost
function (described in Section 2.3C) for the SLS, SGLS, and MLS methods,
and individually adjusted parameters for each method. It should be
noted that the code for re-implementation and parameter settings of
these methods might lead to some differences, which could bias the
accuracy comparison. The comparison results in terms of DSC and
MAD are reported in Tables 2 and 3, respectively. Tables 2 and 3 show
that the proposed MGLS approach generated the highest DSC and low-
est MAD compared to other five methods, outperforming the STAPLE
and MV methods. Fig. 7 shows the segmentation results of patient 2
using different methods including the STAPLE, MV, SLS, SGLS, MLS,
and MGLS methods. Visual inspections show that the level-set based
segmentation methods (SLS, SGLS, MLS, and MGLS) are more accurate
than the MV and STAPLE methods. The multi-region segmentation
methods (MLS and MGLS) are capable of generating more accurate seg-
mentation results in the region between the left and right ventricles
than single level-set based methods (SLS and SGLS) since the regulariza-
tion of single level-set was not efficient enough to separate several close
structures.
4. Discussion and conclusion
This paper proposes an accurate solution to a challenging segmenta-
tion problem of the pre-term IVH neonatal cerebral ventricle from 3D
MR images. The proposed segmentation algorithm makes use of the
convex optimization technique associated with spatial shape prior,
which is built via a multi-atlas non-linear registration scheme. The
proposed segmentation pipeline is used for monitoring the ventricular
size of patients with mild ventricle enlargement and hydrocephalus.
The experimental results using 26 patient images show that the
proposed method yielded favorable results compared to manual
segmentations in terms of DSC, MAD, MAXD, and volume difference.
It should be noted that neonatal patients who had severe IVH
(grades III and IV by the Papile grading system) tend to have visibly en-
larged ventricles even once reaching term equivalent age. Those patient
images were included in our experiments. We also recruited 9 patients
 W. Qiu et al. / NeuroImage 118 (2015) 13–25 21

Fig. 6. Group mean and standard deviation map of segmentation errors of left and right ventricles between manual and algorithm segmentation over 9 hydrocephalus patient images.
(a) Mean map of segmentation errors and (b) standard deviation map of segmentation errors.

who had mild IVH (grade I), which often results in a normal finding
using MR images at term equivalent age. Looking back at the radiologi-
cal records of patients formally diagnosed with mild IVH during the first
few weeks of life, even the ultrasound images taken at a month of life
often will be considered ‘normal’ with no pathology, and the MRI
done at about 2–3 months of life, akin to the ones we have segmented,
will likewise be found normal. Thus, the results reported in our paper
also demonstrated the performance on the images without visible
pathology.
Another finding is that the geodesic level-set-based methods (MGLS
and SGLS) generated better accuracy than the classic level-set-based
methods (MLS and SLS). Fig. 8 shows segmentation results of a hydro-
cephalus patient image using the geodesic distance transform (GDT)
and Euclidean distance transform map (EDT). The GDT map (Fig. 8(c))
provides more adaptive spatial contexts compared to the EDT map
(Fig. 8(b)), since the calculation of geodesic distance takes image inten-
sity and gradient information into account. As a result, the proposed
MGLS method excluded the extra CSF in the subarachnoid (Fig. 8(e))
of hydrocephalus patients, which is challenging for most of segmenta-
tion algorithms since this structure has the same intensity distributions
to ventricles and is physically close to the ventricles of hydrocephalus
patients. In contrast, the extra CSF in the subarachnoid was mistakenly
included by the classic MLS method (Fig. 8(e)).
The developed ventricle segmentation technique can be used to dif-
ferentiate patients with VM from hydrocephalus patients. More impor-
tantly, when following patients with hydrocephalus, the timing for
intervention is difficult to decide for clinicians. Therefore, by providing
clinicians with an accurate measure of increased ventricle volume, our
technique would give them more information to base their decision

Table 2 Table 3
Comparison results in terms of DSC (%) using the same datasets, between the proposed Comparison results in terms of MAD (mm) using the same datasets, between the
MGLS method and other methods, such as STAPLE, MV, SLS, SGLS, and MLS. proposed MGLS method and other methods, such as STAPLE, MV, SLS, SGLS, and MLS.

Dataset 1 Dataset 2 In all Dataset 1 Dataset 2 In all

STAPLE 72.4 ± 11.4 76.4 ± 16.2 73.4 ± 12.4 STAPLE 1.3 ± 1.1 5.7 ± 4.9 2.4 ± 3.1
MV 68.3 ± 13.8 71.7 ± 18.1 69.1 ± 14.6 MV 1.4 ± 1.2 6.0 ± 5.2 2.5 ± 3.3
SLS 78.8 ± 10.1 86.3 ± 9.5 80.6 ± 10.3 SLS 1.1 ± 0.8 3.8 ± 2.2 1.7 ± 1.7
SGLS 79.7 ± 9.2 87.2 ± 9.0 81.4 ± 9.6 SGLS 1.0 ± 0.7 3.6 ± 2.1 1.6 ± 1.6
MLS 81.2 ± 10.4 88.5 ± 9.7 82.9 ± 9.8 MLS 0.9 ± 0.7 3.4 ± 1.9 1.5 ± 1.6
MGLS 84.6 ± 4.5 91.4 ± 4.0 86.4 ± 5.3 MGLS 0.8 ± 0.31 2.0 ± 1.3 1.1 ± 0.9

The highest DSC for each dataset is shown in bold. The lowest MAD for each dataset is shown in bold.
22 W. Qiu et al. / NeuroImage 118 (2015) 13–25

(a) Originalimage (b) SLS (c) SGLS (d) MV (e) STAPLE (f) MLS (g) MGLS (h) Groundtruth

Fig. 7. Segmentation results of one patient with mild enlargement of ventricles using different methods. The first row: transverse views, the second row: saggital views, the third row:
coronal views, and the fourth row: rendered segmented surfaces. The segmented ventricles are colored in red for single level-set based methods ((b) and (c)). The segmented left,
right, and third ventricles are colored in red, and green and blue respectively ((d)–(h)).

on. The approach would be able to detect variation in ventricular vol-
ume over time, and provide a more accurate and precise measurement
than currently used 2D Ultrasound to decide whether an intervention is
needed not only when the infant has become symptomatic, but when
PHVD is progressing. In addition, intervention could be aimed at bring-
ing the ventricular volume closer to the normal ventricular volume and
taps (lumbar or from the reservoir) should not just be performed to
relieve the raised intracranial pressure. Investigations on the normal
range of the ventricular volume rely on the volume measurement
technique. The proposed automatic method would replace manual
segmentation, which is not feasible in a clinical context as it is too
labor intensive and time consuming.

(a) Original image (b) Classic EDT map (c) GDT map

(d) Ground truth (e) Result using MLS (f) Result using MGLS
Fig. 8. Comparison between multi-phase geodesic and classical level-sets on a hydrocephalus patient image. The manual segmentation is colored in red in (d), and the segmentations of
MLS in (e) and MGLS in (f) are colored in green.
 W. Qiu et al. / NeuroImage 118 (2015) 13–25 23

pffiffiffi
The minimal detectable difference MDD ¼ Z α 2  SEM (Mitchell
et al., 1996) between algorithm and manual segmentations was calcu-
lated, where Zα/2 = 1.96 is the critical value corresponding to α =
0.05, and SEM is the standard error of the measurement. The MDD
measurement is the smallest measured volume difference between
two segmentations that can be detectable with 95% confidence. Thus,
if the measured change between two successful measurements is great-
er than this value, then one can be confident (at 95%) that there has
been a volume change. The proposed approach generated a MDD of
1.2 cm3 for the patients with VM and 9.4 cm3 for the hydrocephalus
patients. As reported in Brann et al. (1990), infants with IVH with a ce-
rebral daily volume increase of 4.2 ± 3.3 cm3 will need intervention,
which is greater than the MDD generated by our approach for the pa-
tients with VM. Although the generated MDD value of 9.4 cm3 is greater
than the cerebral daily volume increase, the interval of every two
acquired 3D MR images is more than one week. Thus, the MDD value
of 9.4 cm3 for hydrocephalus patients generated by the proposed ven-
tricular segmentation algorithm is still clinically relevant as a small
change may be detected, indicating this approach might be potentially
used to monitor the ventricular volume change of hydrocephalus
patients.
One limitation of this study is that the proposed segmentation ap-
proach was validated on a limited number of images since MR images
of preterm neonates are usually not performed at our center unless a se-
vere disease is suspected, such as hypoxia-ischemic injury or severe IVH
competition principle. Another advantage is that the proposed method
can be parallelized on GPUs to achieve a fast computation. The experi-
mental results with 19 patients with mild enlargement of ventricles
and 7 hydrocephalus patients showed that the proposed method is ac-
curate, capable of capturing the large inter-subject shape variability.
The high DSC along with low MAD, MAXD, and VD suggests that it
could be potentially used for volumetric and morphological analysis of
the ventricle system of IVH neonatal brain in clinical practice.
Acknowledgments
The authors are grateful for the funding support from the Canadian
Institutes of Health Research (CIHR) and Academic Medical Organiza-
tion of Southwestern Ontario (AMOSO).
Appendix A. Proof: equivalence between the optimization function
(9) and the variational formulation (16)
Proof. To see the equivalence between the two optimization problems
(9) and (16), we first consider the total cost related to the region
changes of the contour Ci, i = 1…n, i.e.
Z Z
c−
i ðxÞ dx þ cþ
i ðxÞdx: ðA:1Þ
C−
i Cþ
i

(grade III, IV). Thus, images such as the ones in our study are not often
available outside of a research center with a program in place to acquire In view of the new cost functions (13) and (14), the above total cost
clinical scans of research subjects. While it may not be obvious, imaging (A.1) can be equally written as
a neonate from the NICU is fairly cumbersome from health safety per-
spective, requiring either a clinician or NICU nurse to be within the


1−ui ; Dsi þ ui ; Dti : ðA:2Þ
MR suite for the entire duration of the scan as well as organizing a feed-
ing schedule that will allow the patient to be sedated for the 2+ hours
Summing (A.2) over the n contours, we obtain
they will be prepared for the imaging study, in transit, and within the
MR scanner. As some patients also require oxygen at this time, a respi-
X
n 

 X
n
 Xn Z
ration therapist is also often required to maintain proper oxygenation 1−ui ; Dsi þ ui ; Dti ¼ ui ; Dti −Dsi þ Dsi ðxÞdx ðA:3Þ
of the patient while they are being scanned. Patients who have mild i¼1 i¼1 i¼1 Ω
and even moderate ventricle dilation are therefore not imaged regular-
ly. In the future, we will test our developed segmentation pipeline in a where the last term is constant.
greater number of patient images, especially for patients with large We can also formulate the weighted perimeter term in (9) by means
ventricles (i.e., hydrocephalus), which greatly concerns obstetricians of the total variation function such that
and neonatologists, and also helps to determine the feasibility of the
Z Z
proposed approach in a clinical context.
g ðsÞds ¼ g ðxÞj∇ui j dx ðA:4Þ
Additionally, based on the extracted ventricles, volumetric and mor- ∂C i Ω
phological analysis is possible to better understand the development of
pre-term neonatal brains and thus improve diagnosis, prognosis, and by combining (A.3) and (A.4), the equivalence between (9) and (16) is
treatment of VM and other complex neurodevelopment disorders. Fu- proved.
ture work will also involve the construction of age- and IVH-grade-
specific atlases, which includes growth- and disease-related changes
in the size and shape of the brain and maturation-related changes in Appendix B. Continuous max-flow model and algorithm
MR intensities of developing brain structures. Numerous studies sug-
gested that the use of specific spatio-temporal atlases can significantly Motivated by Yuan et al. (2010b), a flow maximization configuration
improve the results of automated segmentation algorithms of brain in the spatially continuous setting is first introduced:
MR images (Yoon et al., 2009; Habas et al., 2010; Evans et al., 2012; 1. n copies Ωi, i = 1,…,n, of Ω;
Oishi et al., 2011). The developed multi-atlas multi-phase geodesic 2. For ∀ x ∈ Ω, the same source flow ps(x) from the source s to x ∈ Ωi,
level-set segmentation method can be also applied to segment other i = 1,…,n, simultaneously;
structures in brain MR images. When dealing with the segmentation 3. For ∀ x ∈ Ω, the sink flow pi(x) from x at Ωi, i = 1,…,n, of Ω to the sink
of a larger number of structures, more advanced label fusion strategies t. pi(x), i = 1,…,n, may be different one by one;
(Heckemann et al., 2006; Wang et al., 2013) are required to provide 4. The spatial flow qi(x), i = 1,…,n defined within each Ωi.
more accurate spatial and intensity priors. In addition to the specific
application in neonatal brain MRI, the developed multi-region segmen- Based upon the above settings of flows, we can prove that the con-
tation algorithm is expected to have wide-spread applications in other tinuous max-flow model formulated as follows is mathematically
tasks of medical image analysis. equivalent to Eq. (17):
In conclusion, a novel multi-atlas initialized multiphase geodesic Z 
level-set segmentation algorithm was developed, which was combined max P ðps ; p; qÞ ¼ ps dx ðB:1Þ
with a spatially continuous Potts model and a variational region ps ;p;q Ω
24 W. Qiu et al. / NeuroImage 118 (2015) 13–25

subject to the following flow constraints: Chan, T.F., Vese, L.A., 2000. An efficient variational multiphase motion for the Mumford–
Shah segmentation model. Proc. Conf Signals, Systems and Computers Record of the
Thirty-Fourth Asilomar Conf, pp. 490–494.
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