# Fast and robust parameter estimation for statistical partial volume models in brain MRI

**Abstract**

Due to the finite spatial resolution of imaging devices, a single voxel in a medical image may be composed of mixture of tissue types, an effect known as partial volume effect (PVE). Partial volume estimation, that is, the estimation of the amount of each tissue type within each voxel, has received considerable interest in recent years. Much of this work has been focused on the mixel model, a statistical model of PVE. We propose a novel trimmed minimum covariance determinant (TMCD) method for the estimation of the parameters of the mixel PVE model. In this method, each voxel is first labeled according to the most dominant tissue type. Voxels that are prone to PVE are removed from this labeled set, following which robust location estimators with high breakdown points are used to estimate the mean and the covariance of each tissue class. Comparisons between different methods for parameter estimation based on classified images as well as expectation--maximization-like (EM-like) procedure for simultaneous parameter and partial volume estimation are reported. The robust estimators based on a pruned classification as presented here are shown to perform well even if the initial classification is of poor quality. The results obtained are comparable to those obtained using the EM-like procedure, but require considerably less computation time. Segmentation results of real data based on partial volume estimation are also reported. In addition to considering the parameter estimation problem, we discuss differences between different approximations to the complete mixel model. In summary, the proposed TMCD method allows for the accurate, robust, and efficient estimation of partial volume model parameters, which is crucial to a variety of brain MRI data analysis procedures such as the accurate estimation of tissue volumes and the accurate delineation of the cortical surface.

Fast and robust parameter estimation for statistical partial volume

models in brain MRI

Jussi Tohka,

a,

*

Alex Zijdenbos,

b

and Alan Evans

b

a

Digital Media Institute / Signal Processing, Tampere University of Technology, FIN-33101, Finland

b

McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Canada

Received 5 December 2003; revised 24 April 2004; accepted 11 May 2004

Due to the finite spatial resolution of imaging devices, a single voxel in a

medical image may be composed of mixture of tissue types, an effect

known as partial volume effect (PVE). Partial volume estimation, that

is, the estimation of the amount of each tissue type within each voxel,

has received considerable interest in recent years. Much of this work

has been focused on the mixel model, a statistical model of PVE. We

propose a novel trimmed minimum covariance determinant (TMCD)

method for the estimation of the parameters of the mixel PVE model.

In this method, each voxel is first labeled according to the most

dominant tissue type. Voxels that are prone to PVE are removed from

this labeled set, following which robust location estimators with high

breakdown points are used to estimate the mean and the covariance of

each tis sue class. Compariso ns b etween different methods fo r

parameter estimation based on classified images as well as expecta-

tion – maximization-like (EM-like) procedure for simultaneous param-

eter and partial volume estimation are reported. The robust estimators

based on a pruned classification as presented here are shown to

perform well even if the initial classification is of poor quality. The

results obtained are comparable to those obtained using the EM-like

procedure, but require considerably less computation time. Segmenta-

tion results of real data based on partial volume estimation are also

reported. In addition to considering the parameter estimation problem,

we discuss differences between different approximations to the

complete mixel model. In summary, the proposed TMCD method

allows for the accurate, robust, and efficient estimation of partial

volume model parameters, which is crucial to a variety of brain MRI

data analysis procedures such as the accurate estimation of tissue

volumes and the accurate delineation of the cortical surface.

D 2004 Elsevier Inc. All rights reserved.

Keywords: Partial volume effect; Segmentation; Robust estimation; Mixel

model

Introduction

The quantitative analysis of magnetic resonance (MR) images in

the study of human brain anatomy is becoming more and more

important. For example, a range of brain disorders as well as brain

development and healthy aging can cause structural changes in the

brain. These changes can be quantified by measuring volumes or

other properties of anatomical structures of interest providing

information, for example, on disease severity. Before measure-

ments can be performed, the structures of interest must be extracted

from the image data. This often includes the labeling of voxels

according to their tissue type. This labeling, or classification, can be

performed based on a single MR image or based on a multispectral

image constructed by combining series images of the same subject

acquired with different pulse sequence parameters. Typically, the

tissue types of interest are white matter (WM), gray matter (GM),

and cerebrospinal fluid (CSF), but also more anatomical labels can

be assigned to image voxels (Collins et al., 1999; Fischl et al.,

2002). However, voxel classification with three basic tissue types

has itself rather direct applications such as quantifying disease

burden in multiple sclerosis by estimation of the amount of brain

atrophy (Collins et al., 2001). Moreover, many procedures aiming

at the extraction of particular brain structures, such as cerebral

cortex, can gain from the initial tissue classification (MacDonald et

al., 2000; Xu et al., 1999; Zeng et al., 1999) as can partial volume

correction in positron mission tomography (Rousset et al., 1998).

Because of the finite resolution of the imaging devices, a single

voxel may contain several tissue types. This is known as partial

volume effect (PVE). Due to PVE, the classification of a voxel

reflecting the dominant tissue type (WM, GM, or CSF), does not

reveal all possible information about the tissue content of that

voxel. This can be problematic in small structures or highly

convoluted areas of the brain. For example, algorithms aimed at

extraction of the cortical surface often omit entire sulci due to the

PVE between the thin ribbon of sulcal CSF and the surrounding

gray matter. These problems are especially serious when pediatric

subjects are considered as illustrated in Fig. 1. Estimation of the

amount of each tissue type present in each voxel, that is, partial

volume estimation, provides an interesting possibility to improve

the accu racy of cortical surface extraction (cf. Fig. 1). Other

applications that gain from modeling of PVE have been as well

considered within brain MRI. Santago and Gage (1993) apply

information about partial volume voxels to improve tissue quan-

tification. Gonza

´

lez Ballester et al. (2002) study the asymmetry of

temporal horns taking PVE into account, and in an earlier work

(Gonza

´

lez Ballester et al., 2000 ), they suggest that PVE and

1053-8119/$ - see front matter D 2004 Elsevier Inc. All rights reserved.

doi:10.1016/j.neuroimage.2004.05.007

* Corresponding author. Digital Media Institute/Signal Processing,

Tampere University of Technology, P.O. Box 553, FIN-33101, Finland.

Fax: +358-3-31153087.

E-mail address: jussi.tohka@tut.fi (J. Tohka).

Available online on ScienceDirect (www.sciencedirect.com.)

www.elsevier.com/locate/ynimg

NeuroImage 23 (2004) 84 – 97

discrete sampling at boundary locations can l ead to v olume

measurement errors in the range 20 – 60%.

Partial volume effect and PV estimation have been addressed in

various ways in MR imaging literature. For example, Pham and

Prince (1999) have proposed a fuzzy C-means algorithm. They

have also studied the relationship between the fuzzy C-means

objective function and statistical models of PVE in the simplified

case (only two type is of tissues and single-spectral data), showing

that in this case, these two approaches can be considered equivalent

(Pham and Prince, 1998). However, these considerations do not

extend to more realistic situations where one would have more than

two tissue types and where the data would be multispectral.

Wang et al. (2001) propose to use a Bayesian classifier with a

variable number of tissue classes, including classes of mixed tissue

types. However, as the authors model the image histogram with a

finite mixture of normal distributions and parameters (means and

variances) for mixed tissue classes, which are independent of the

parameters of the related pure tissue classes, there is no explicit

model of the PVE. While the procedure may be reasonable for

detection of voxels containing PVE, estimation of the mixing

proportions can be challenging.

The most commonly used, statistically based model of PVE is

the mixel model proposed by Choi et al. (1991). (A similar model

was proposed earlier by Kent and Mardia, 1988, but without

consideration of medical imaging applications.) This approach

assumes that each intensity value in the image is a realization of

a weighted sum of random variables (RVs), each of which

characterizes a pure tissue type. We call these weighting factors

partial volume coefficients (PVCs). The method involves maxi-

mum-likelihood estimation of the PVCs for each voxel that model

PV fractions of pure tissue types. Some authors have studied the

identification of voxels containing PVE based on the mixel or a

closely related model without trying to estimate the PVCs for each

voxel (Laidlaw et al., 1998; Ruan et al., 2000; Santago and Gage,

1993). Our interest in this study is in estimating PVCs and not in

merely identifying voxels containing PVE.

Before statistical PV estimation can be performed, the proba-

bility density functions (pdfs) of the RVs describing pure tissue

types must be specified. In practice, this typically means that the

parameters of the pdfs—usually normal distributions—need to be

estimated. Unfortunately, errors in the parameter estimation often

have a major impact on the quality of PV estimation. In the case

of statistical ‘‘hard’’ classification, where each voxel is classified

according to the most dominant tissue typ e, the parameter

estimation problem differs from the one studied here as each

intensity is a realization of a single RV. On the other hand, the

mixel model assumes that each voxel’s intensity represents a

weighted sum of several RVs and aims to estimate these unknown

weight parameters.

In general, there are three approaches to the parameter estima-

tion problem: histogram analysis (Santago and Gage, 1993),

simultaneous parameter, and partial volume estimation by expec-

tation maximization (EM)-like algorithms (Noe and Gee, 2001),

and estimation based on a hard segmentat ion of the image

(Shattuck et al., 2001). These three approaches, however, each

have their drawbacks. Histogram analysis requires a mixture

probability density to be fit to an image histogram by parameter

optimization. This involves finding the minimizer of a multimodal

objective function and therefore reliability of histogram analysis

for parameter estimation depends heavily on the optimi zation

algorithm used for the fitting task. If a standard nonlinear optimi-

zation algorithm aimed at local minimization (e.g., Levenberg–

Marquee algorithm used commonly for curve fitting) is used, the

initialization for the algorithm has to be chosen carefully to avoid

convergence to a poor local minimum. These considerations call

for the use of advanced global optimization algorithms, for

example, Santago and Gage (1993) propose to use the tree-

annealing method (Bilbro and Snyder, 1991). The problem with

global optimization methods is that they are usually far more time

consuming than local optimization methods.

Like histogram analysis, expectation –maximization schemes

for parameter estimation are time consuming. Besides, the use of

spatial information in the form of Markov Random Fields (Besag,

1974, 1986) causes practical problems with the E-step of the EM-

algorithm (Van Leemput et al., 2003). To solve this, statistical

dependency between voxel labels can be ignored during the E-step

Fig. 1. PVE in the cortical region, in the top row, a pediatric subject, and in the bottom row, a middle aged subject. Pediatric brain sulci are more compacted

with less (or no) intrasulcal CSF in the segmented image (see left column). However, the partial volume skeleton, estimated automatically by using the method

presented (TMCD) in this study, can penetrate down into that intrasulcal CSF (see middle column) for the pediatric case (top row). Different colors correspond

to different amounts of CSF within the voxels. Consequently, partial volume estimation allows, for example, for more accurate cortical surface extraction than

that could be achieved by methods relying on discrete classification.

J. Tohka et al. / NeuroImage 23 (2004) 84–97 85

as in Noe and Gee (2001). However, this leads to an algorithm that

is merely a heuristic and does not necessarily share the conver-

gence properties of the original EM-algorithm (Dempster et al.,

1977). An elegant solution to this problem based on a Monte Carlo

EM-algorithm (Wei and Tanner, 1990) was recently proposed by

Van Leemput et al. (2003). The algorithm was implemented only

for 2D image slices and the authors reported that partial volume

estimation typically requires about 20 min for a single slice of an

MR image with a very fast 1.7 GHz processor. Hence, the total

time consumption for an (moderately sized) image of 100 slices

would be over 30 h. The authors claimed that the computation time

can be significantly reduced but did not offer any figures to support

this claim.

Parameter estimation based on a hard labeling can be compu-

tationally efficient due to the prior knowledge of labels of voxels

that can be utilized in parameter estimation. However, due to the

PVE and classification errors in the hard labeling, each class in the

hard segmented image contains a large number of outliers. This

fact is taken into the account in Shattuck et al. (2001), but their

approach for the parameter estimation applies only to single-

spectral images and assumes that each tissue type has a Gaussian

noise distribution with the same variance. Also, since this method

involves detecting modes of histograms, it is sensitive to noise and

the estimates may not be unique.

In this study, using minimum volume ellipsoid and minimum

covariance determinant estimators (Rousseeuw, 1984; Rousseeuw

and Leroy, 1987), we propose routines for parameter estimation

based on segmented images that are well-defined and can be used

in single-spectral as well as multispectral cases. The studied

estimators are robust; in other words, they tolerate deviations from

the parametric form of the distribution assumed for the data. This is

important because in our case, part of the data is good (correctly

classified voxels of pure tissue), but the data contain also outliers

(e.g. PV voxels). There are fast algorithms for computing the

estimators and hence increasing the robustness of the parameter

estimation does not lead to significantly increased running time for

the PV estimation. We compare different techniques of parameter

estimation using simulated MR data (Kwan et al., 1999) and

demonstrate how the errors in the parameter estimation affect the

final PV estimation results. The results are also compared against

those obtained from an EM-like method, similar to Noe and Gee

(2001), but with an advanced initialization technique. Furthermore,

we compare our results with a fast PV estimation technique

proposed by Shattuck et al. (2001) and demonstrate that our

technique can yield clear improvements in the accuracy of PV

estimates without considerable loss in time efficiency. As a

secondary contribution, we consider differences between material

and sampling noise models for PVE also on a more theoretical

level (cf. Santago and Gage, 1995).

Methods

Statistical model for the partial volume effect

In this section, we state the PVE parameter estimation

problem and describe the mixel model more formally. In the

following, random variables (RVs) are denoted by boldface

letters, while both scalars and vectors are shown in italics. Let

us denote the observed image by X ={x

i

: i =1,..., N}, with

x

i

aR

K

, and K the number of data channels. Let the set of

possible tissue types present in the image be L = {1,. . ., M}.

Moreover, l

j

is the RV describing the tissue type j and the pdf of

l

j

is Gaussian g(Al

j

, R

j

) with mean l

j

and covariance R

j

. Each x

i

is now a realization of the RV

x

i

¼

X

M

j¼1

w

i

j

l

j

þ a ð1Þ

where a denotes white Gaussian noise and partial volume coef-

ficients (PVCs) w

i

j

a [0,1] for all i, j, and

P

M

j¼1

w

i

j

¼ 1 for all i.A

partial volume context image is denoted by W ={w

i

j

: i =1,...N, j =

1,..., M}. The problem is now to find an estimate W* for the true

partial volume context image, given the observed image X. This

is similar to the fuzzy classification problem, but in this case, the

coefficients w

i

j

specifically model the fraction of tissue type j

present in the voxel i, as opposed to the likelihood that voxel i is

of type j for example. For notational convenience, we set we w

i

=

[w

i

1

,..., w

i

M

]

T

.

The model in Eq. (1) for the formation of image intensities

within MRI is a simplification. Perhaps most importantly, MR

images are known to contain low frequen cy spatial intensity

variations often called RF inhomogeneity or shading artifact. The

correction for this artifact can be assumed to be performed before

PV estimation and there exist several methods for the task (e.g.,

Sled et al., 1998; Wells et al., 1996). Another somewhat contro-

versial issue of the model is the assumed Gaussian distributions for

tissue classes and for the noise component. The assumption is

common within classifiers and PV estimation routines applied to

brain MR images.

Since there are no methods that would allow us to estimate

parameters for l

j

, j =1,..., M, and the parameters for the noise

variable a at the same time, Eq. (1) needs to be simplified. Using

the terminology from Santago and Gage (1995), the material-

dependent noise model is obtained by embedding the sampling

noise component a into RVs l

j

describing the tiss ue types.

Accordingly, the sampling noise model is obtained by ignoring

variations within tissue types, that is, each tissue type is described

by a deterministic but initially unknown intensity value as opposed

to describing tissue types by RVs. Our attention is centered on the

material-dependent noise model, because, for our topic, it can be

considered to be a generalization of the sampling noise model.

Indeed, the methods for the parameter estimation to be proposed

are as well applicable for the sampling noise case, where only a

single covariance matrix describing the sampling noise is required.

This issue can be solved by considering the pooled covariance of

the estimated covariance matrices for the tissue classes (Dougherty,

1990, p. 467).

Algorithm for statistical partial volume estimation

Problem statement

The maximum a posteriori (MAP) criterion is used to find W*

given the observed image, that is,

W * ¼ arg max

W

pðW AX Þ: ð2Þ

We make the assumption that the observed image intensity

value x

i

of voxel i depends only on the RV x

i

related to the same

voxel. In other words, we assume that the intensity at voxel i does

J. Tohka et al. / NeuroImage 23 (2004) 84–9786

not depend on the tissue content of the other voxels. Hence, for the

material-dependent noise model,

pðW AX Þ~pðW ÞpðX AW Þ¼pðW Þ

Y

N

i¼1

pðx

i

Aw

i

Þ; ð3Þ

pðx

i

Aw

i

Þ¼gðx

i

A

X

M

j¼1

w

i

j

l

j

;

X

M

j¼1

w

2

i

j

R

j

Þ; ð4Þ

where

gðxAl; RÞ¼

1

ð2pÞ

K=2

detðRÞ

1=2

exp

1

2

ðx lÞ

T

R

1

ðx lÞ

denotes a multivariate Gaussian pdf with the mean l and the

covariance R. The expression for the likelihood term (4) is derived

using the fact that a weighted sum of Gaussian RVs is a Gaussian

RV with the mean and the covariance as in Eq. (4), (cf., e.g.,

Dougherty, 1990, Theorem 5.9). The prior probability p(W) can be

ignored or modeled by a Markov Random Field (MRF) (Besag,

1974, 1986; Geman and Geman, 1984). However, in MR images,

labels w

i

of nearby voxels are typically correlated. Ignoring these

correlations would lead to loss of relevant information, and hence

MRF modeling of the prior probability is preferable. This has been

also confirmed empirically in some studies (Shattuck et al., 2001;

Van Leemput et al., 2003).

The estimation problem (2) is challenging because both the

PVCs w

i

and the model parameters l

j

, R

j

are initially unknown.

Indeed, even if the model parameters would have been identified,

the estimation problem (2) would be under constrained and could

not be solved directly if the number of data channels K < M 1

(Choi et al., 1991; Kent and Mardia, 1988). In anatomical MRI of

the brain of normal subjects, three labels [white matter (WM), gray

matter (GM) and cerebrospinal fluid (CSF)] are of primary interest;

therefore, at least two data channels are required to solve the

estimation problem. However, often only an image from a single

channel is available, and therefore the requirement for the data to

be at least from two channels is quite restrictive.

An interesting way for solving the PV estimation problem even

with single-spectral data has been presented in Noe and Gee (2001)

and Shattuck et al. (2001) by extending ideas proposed by Santago

and Gage (1993, 1995). For this method, which will be referred as

indirect, we need only to assume that each voxel contains at most

two types of tissue. The indirect method involves the identification

of the tissue types present in each voxel, followed by a simplified

MAP estimation of the proportion of the each tissue type per voxel.

Here, the first step is called partial volume classification and the

second step is called PVC estimation. An overview of the entire

process, including a separate parameter estimation step, is presented

in Fig. 2. Parameter estimation is discussed in the next subsection.

PV classification

In the PV classification step, a label from the set L

ˆ

= L [

{{j, k}: j, k a L} is assigned to each voxel. Labels of type {j,

k} indicate mixed voxels of the tissue types j and k. Let us

Fig. 2. Depiction of the overall process for the PV estimation.

J. Tohka et al. / NeuroImage 23 (2004) 84–97 87

denote a context image, consisting of the labels of each voxel by

C ={c

i

: i =1,..., N, c

i

a L

ˆ

.

}

For the PV classification, the probability densities for mixed

tissue classes consisting of two types of tissue need to be obtained.

This is achieved by marginalizing the densities over all the possible

values of the PVC w (Santago and Gage, 1993, 1995). Since pure

tissue RVs are Gaussian, also their weighted sums are Gaussian

RVs and the marginal density is

pðx

i

Ac

i

¼fj; kgÞ ¼

Z

1

0

g½x

i

; lðwÞ; RðwÞdw; ð5Þ

where

lðwÞ¼wl

j

þð1 wÞl

k

; RðwÞ¼w

2

R

j

þð1 wÞ

2

R

k

; ð6Þ

for the PVC w a [0, 1]. The integral in Eq. (5) has no closed form

solution and hence numerical integration must be used to evaluate

it. Now the context image can be estimated as

C* ¼ arg max

C

PðCA X Þ¼arg max

C

PðCÞ

Y

N

i¼1

pðx

i

Ac

i

Þ; ð7Þ

where the prior term P(C) is modeled by an Markov Random Field

(MRF). Here we use a simple Potts model suggested in Shattuck et

al. (2001):

PðCÞ~exp b

X

N

i¼1

X

kaN

i

a

ik

dði; kÞ

!

; ð8Þ

where b is a user tunable parameter, N

i

is the 26-neighborhood

around voxel i, d(i, k) is the distance between centers of voxels i

and k, and

a

ik

¼

2:c

i

¼ c

k

1:c

i

and c

k

share a component

1 : otherwise

8

>

>

>

>

<

>

>

>

>

:

ð9Þ

The iterated conditional modes (ICM) algorithm (Besag, 1986)

is used to solve Eq. (7) locally. A well-known approach by Geman

and Geman (1984) to solve the optimization problem (7) globally

could also be employed, but since this method is much more time

consuming than ICM, we prefer to use the latter.

PVC estimation

In the second step, PVC estimation, we estimate the proportions

of each tissue type within each voxel. If c

i

*=j, that is labeling of

voxel i indicates that it is a pure voxel, w

i

j

*

= 1 and for all k p jw

i

k

*

=

0. If i is a mixed voxel, c

i

*={j, k}, then we employ the maximum-

likelihood principle:

w

i

j

*

¼ arg max

wa½0;1

gðx

i

AlðwÞ; RðwÞÞ

¼ arg max

wa½0;1

lngðx

i

AlðwÞ; RðwÞÞ

¼ arg min

wa½0;1

½ðx

i

lðwÞÞ

T

RðwÞ

1

ðx

i

lðwÞÞ

þ lndetðRðwÞÞ; ð10Þ

where l(w), R(w) are as in Eq. (6). Furthermore, w

i

k

*

=1 w

i

j

*

and all

the other PVCs are zero. The maximum-likelihood PVC estimate

(10) can be solved by a simple grid search, which we have found to

be surprisingly efficient in our experiments.

Since Shattuck et al. (2001) and Noe and Gee (2001) adopted

the sampling noise model for PVC estimation, we briefly compare

Eq. (10) to the solution derivable from the sampling noise model.

In that case, we would have only a single covariance matrix, which

we denote by R

a

that describes the sampling noise a. Otherwise,

the notation is as above. The sampling noise model leads to the

objective function

½ðx

i

lðwÞÞ

T

R

1

a

ðx

i

lðwÞÞ ð11Þ

to be minimized with respect to w. This minimization problem has

the closed form solution

w

i

j

*

¼ r

ðl

k

x

i

Þ

T

R

1

a

ðl

k

l

j

Þ

ðl

k

l

j

Þ

T

R

1

a

ðl

k

l

j

Þ

!

; ð12Þ

where r(x)=x when x a [0,1], r(x) = 0 when x < 0, and r(x)=

1 when x > 1. The two objective functions (Eqs. (10) and (11))

differ principally by the additional term ln det(R(w)) of Eq. (10).

Multiplying R

a

by a positive constant s does not affect the

solution (12) of the sampling noise problem. On the other hand,

multiplying R(w)bys changes the solution of the problem (10).

More precisely, if s > 1, more weight is put to the term ln

det(R(w)), which does not depend on the data x

i

. Therefore, the

material-depe ndent noise problem (10) can be considered a

regularized version of the sampling noise problem. The regular-

ization term ln det(R(w)) is a logarithm of high degree polyno-

mial in the multispectral case making the precise analysis of its

effect challenging. However, in the single-spectral case, the

minimum of ln det(R(w)) can be solved explicitly as R

k

/(R

j

+

R

k

) if it is in [0, 1]. These considerations are illustrated in Fig.

3, where on the left panel, the minimum of ln det(R(w)) is

shown when R

j

is varied. It can be seen that when the variances

have equal values, then the minimum of the regularization term

is at w

i

j

= 0.5 and hence the regularization term favors the

solution w

i

j

= 0.5. When R

j

is incremented, the value of the

favored solution decreases meaning that the voxel is a priori

assumed to contain less of the tissue type j than the tissue type

k, which has a smaller variance. On the right panel of Fig. 3, all

variances, R

j

, R

k

, R

a

, are assumed to have an equal value. When

this value is incremented, the sampling noise solution does not

change but the material noise solution tends slowly towards the

value 0.5.

Parameter estimation

As already noted, the model parameters l

j

, R

j

, j =1,.. ., M must

be estimated before (or during) the PV estimation. An efficient way

to do this is to first label each voxel in the image X by a hard label

belonging to L, and then to estimate the parameters based on the

intensity distribution of the labeled voxels for each tissue class. In

the following, we denote the set of the intensity values of voxels

labeled as belonging to the class j by D

j

. However, now each D

j

contains values that do not repr esent t he pure tissue type in

question due to the PVE as well as to misclassified voxels. These

values are called outliers. From this, it follows that the set of

samples D

j

contains samples that are not drawn from the distribu-

J. Tohka et al. / NeuroImage 23 (2004) 84–9788

tion describing the tissue type j that leads to problems when

applying conventional techniques, such as the maximum-likeli-

hood principle, for parameter estimation. Particularly, in the

Gaussian case, the sample mean and covariance are poor estimators

of l

j

and R

j

when the data are contaminated by PVE.

However, we can tackle the problem by using point estimation

techniques from robust statistics (Hampel et al., 1985). These

robust estimators are designed to tolerate significant deviations

from the assumed model while still being able to use information

about the model. Especially, we apply the minimum variance

ellipsoid (MVE) and the minimum covariance determinant

(MCD) estimators (Rousseeuw, 1984; Rousseeuw and Leroy,

1987) for the parameter estimation task and also combine a simple

outlier detection procedure with robust estimators. We will show

experimental ly that these techniques combined produce better

parameter estimates than either of the techniques alone. We start

by introducing the method for outlier detection. It is reasonable to

assume that voxels lying on the boundaries between tissue types in

hard-segmented image are likely to contain PVE, and that their

intensity values are therefore outliers. For this reason, voxels with

at least one of their 6 neighbors belonging to a different class than

the voxel itself are discarded from parameter estimation. We could

as well consider 26-neighborhoods instead of 6-neighborhoods, but

6-neighborhoods lead to faster computations. We will refer to the

estimates computed based on this kind of reduced data set as

‘‘trimmed estimates’’.

Since the above procedure does not guarantee outlier-free

sample sets, robust estimation techniques, namely the minimum

variance ellipsoid (MVE) and the minimum covariance determi-

nant (MCD) estimators are used to estimate parameters l

j

, R

j

.

MVE estimates the mean l of the set of data samples DoR

K

by

setting (Rousseeuw and Leroy, 1987):

l is the center of the ellipsoid with the minimal volume

covering at least h points in D.

Here, h is t

ADA

2

b þ 1, that is, we employ approximately 50% of the

data samples to estimate the mean. The covariance is then the matrix

defining the minimal ellipsoid around l multiplied by (v

2

K, 0.5

)

1

,

where (v

2

K, 0.5

) is the median of the chi-squared distribution with K

degrees of freedom. The MCD estimate is obtained by setting

(Rousseeuw and Leroy, 1987):

l is the mean of h points of D for which the determinant of the

covariance matrix is minimal.

Again, h is t

ADA

2

b þ 1 . The covariance matrix is then the

covariance matrix of those minimizing h points inflated or defeated

to contain exactly h points multiplied by (v

2

K, 0.5

)

1

.

In the single-spectral case, both estimators can be computed

exactly in O(jDj log jDj) time (Rousseeuw and Leroy, 1987). For

the multispectral case, there are computationally efficient algo-

rithms for approximating the estimators (Rousseeuw and Leroy,

1987, MVE, Rousseeuw and Van Driessen, 1999, MCD).

Besides that they can be computed efficiently, the MVE and

the MCD estimators for location and scatter have several favor-

able properties due to which we adopted them for parameter

estimation. The global reliability of a robust estimator can be

measured using the concept of a breakdown point. The (finite-

sample) breakdown point of an estimator is the smallest percent-

age of contaminated data that can cause the estimator to take on

arbitrarily large aberrant values. The breakdown points of MVE

and MCD estimators converge to 50% as the number of samples

approaches infinity, whereas the breakdown point of the sample

mean tends toward 0%. Note that 50% may be considered as the

best possible breakdown point. In addition, the MVE and the

MCD estimators are affine equivariant. This means that these

estimators commute with the affine transformations, which implies

that reparametrization of the sample space does not affect the

estimate. This is clearly an important property in multispectral

MRI. The combination of the affine equivariance and a high

breakdown point is not a common property for robust estimators

of multivariate location. For example, affine equivariant M

estimators have rather low breakdown points (cf. Rousseeuw

and Leroy, 1987 ). The MCD estimator is asymptotically normal

and has a better convergence rate than the MVE-estimator (see

Rousseeuw and Van Driessen, 1999), but the algorithm for the

multivariate MVE is easier to implement and therefore both

estimators are implemented.

Simultaneous parameter estimation and PV classification

To compare our results with other techniques, we also imple-

mented an EM-like algorithm for simultaneous parameter estima-

tion and PV classification. The outline of the algorithm is

(1) Initialize parameters l

j

, R

j

for every pure voxel class;

(2) Initialize ICM by maximum-likelihood estimation;

(3) Carry out one round of ICM to maximize Eq. (7);

(4) Reestimate the parameters l

j

, R

j

for j =1,..., M based on

posterior probabilities resulting from step 3;

(5) Finish if the termination condition is satisfied; else go to step 3.

Fig. 3. Differences between the material-dependent and sampling noise models. On left, the minimum of the regularization term ln det R(w) is shown when

R

k

= 1 and the value of R

j

is varied. On right, the PVC estimates obtained by sampling noise Eq. (12) (dotted line) and by material noise Eq. (10) (solid

line) are shown when the variances (R

a

, R

j

, R

jk

) increase, x

i

=7,l

j

=0,l

k

= 10.

J. Tohka et al. / NeuroImage 23 (2004) 84–97 89

This algorithm, here referred to as EM-ICM, was suggested by

Besag (1986). A similar algorithm was used for PV estimation by

Noe and Gee (2001), from which our EM-ICM algorithm differs

only with respect to its initialization. For initialization, we incor-

porated an advanced routine based on statistical probability of

anatomy maps (SPAMs) (Kamber et al., 1995; Kollokian, 1996).

Given that images to be segmented are registered to a common

stereotaxic space, SPAMs provide information on the probability of

voxels to be dominantly of certain tissue type. Based on SPAMs, it

is possible to automatically select a training sample for each tissue

class. The training sample then consists of the intensity values of

those voxels, which are very likely to be of the tissue type in

question. This sample can then be used for training a classifier or

for initializing clustering algorithms. Obviously, supervised clas-

sifiers trained this way are sensitive to misregistrations and unusual

anatomy (Cocosco et al., 2002).

The EM-ICM algorithm is considerably more computationally

expensive compared to the one suggested in the previous section

for two reasons: (1) it usually takes more iterations to converge and

(2) each iteration is more time consuming than a simple iteration of

ICM, which has fixed model parameters. This is because each

iteration involves computing new likelihoods based on updated

parameter estimates and new parameter estimates in addition to the

standard ICM cycle.

For example, whereas the procedure for PV estimation imple-

mented in C for a single-spectral 181

217

181 image takes

about 20 min using the ideas proposed in Parameter estimation

section, the EM-ICM algorithm can be expected to take slightly

over 2 h, both on a 400 MHz MIPS R12000 processor

(SGIROriginR 3800 compute server).

Experiments

Simulated data

Different methods for parameter estimation and the influence of

the quality of parameter estimates to PVC estimates were studied

using the BrainWeb Simulated Brain Database of Montreal Neu-

rological Institute (Cocosco et al., 1997) that is available at http://

www.bic.mni.mcgill.ca/brainweb. The images in the database are

generated by an MRI simulator (Kwan et al., 1999), which models

the MRI data acquisition process starting from the Bloch equation.

The input for simulations is a fuzzy realistic brain phantom

(Collins et al., 1998) as opposed to a discrete phantom, which

makes the evaluation of PV estimation algorithms possible. Exam-

ples of transverse slices of simulated T1-, T2-, and proton density

(PD)-weighted images are shown in Fig. 2.

All experiments were performed using single-spectral T1-

weighted as well as multispectral (T1-, T2-, and PD-weighted)

images. Four image sets for both single-spectral and multispectral

cases were used. Each set contained three images with varying

noise levels. The voxel size of the images of the first and the

second sets was 1

1

1 mm. The intensity across the images of

the first set was uniform, but the images in the second set were

simulated with 40% intensity nonuniformity (see Cocosco et al.,

1997). The third set contained images with no intensity nonuni-

formity but the voxel size was 1

1

3 mm. The images in the

fourth set were as those in the first set except that as opposed to the

other sets, they were not properly registered to the stereotaxic,

Talairach-based brain space used by BrainWeb. The initial classi-

fication algorithm used here (see Implementation section) is

sensitive to misregistrations and hence the fourth image set allows

us to study the dependence of the parameter estimates on the

quality of the initial hard classification. The image sets are

summarized in Table 1.

Implementation

Preprocessing steps included the correction of the intensity

inhomogeneity where necessary (Sled et al., 1998) and the classifi-

cation into hard labels (WM, GM, and CSF) by a neural network

classifier that was trained automatically using SPAMs (Kollokian,

1996). (The classifier used was a standard back propagation artificial

neural network with one hidden layer with 10 nodes.) As described

in Simultaneous parameter estimation and PV classification section,

the use of SPAMs for automatic training of unsupervised classifiers

is sensitive to errors in registering images to the stereotaxic space.

Voxels containing primarily nonbrain tissues were labeled as back-

ground before parameter estimation. Six methods for the parameter

estimation based on a hard labeling were examined. In the maxi-

mum-likelihood (ML) method, parameters for each class were the

sample-mean and the sample-covariance of that class in the hard

labeled image. Trimmed maximum-likelihood (TML) estimates

were the sample-mean and the sample-covariance of that class in

the trimmed hard labeled image. By trimming, it is meant that

outliers were detected and removed for each class as described in

Parameter estimation section. Minimum volume ellipsoid (MVE)

and minimum covariance determinant (MCD), respectively, esti-

mates were obtained by applying MVE and MCD estimators to the

classes in the hard labeled image. Trimmed minimum volume

ellipsoid (TMVE) and trimmed minimum covariance determinant

(TMCD), respectively, estimates were obtained by applying MVE

and MCD estimators to the trimmed hard labeled image. Moreover,

we listed parameter estimates resulting from the EM-ICM algorithm

and parameter estimates used to initialize it. For the purpose of the

PV classification, intensities of background voxels were assumed to

have a normal distribution with the zero mean and the covariance

matrix 0.1R

CSF

where R

CSF

is the covariance matrix of the class

CSF. In reality, the image intensities in magnitude MR images are all

greater than zero by definition and the intensity distribution of the

background voxels is Rician. Hence, this assumption is a rough

approximation of the reality and it is made purely for convenience.

During the PV classification, pure tissue classes were WM,

GM, and CSF. Mixed tissue classes were CSF/backgro und,

CSF/GM, and GM/WM. Because nonbrain voxels were masked

off, the background class was not required. The parameter b

(see Eq. (8)) controlling the relative strength of the MRF was

set to 0.1 unless otherwise mentioned. The grid search for

solving the PVC estimation step (10) used an equally spaced

Table 1

The image sets

Image set INU (%) Voxel size Registration

101

1

1 mm succeeded

2401

1

1 mm succeeded

301

1

3 mm succeeded

401

1

1 mm failed

The abbreviation INU stands for the strength of intensity nonuniformity

field in a simulated image.

J. Tohka et al. / NeuroImage 23 (2004) 84–9790

grid G = {0, 0.01, 0.02 ..., 1} of 101 points at which the

objective function in Eq. (10) was evaluated. The value of w

i

j

a

G yielding optimal value of the objective function was then

selected as the estimate w

i

j

*

.

Error criteria

To quantitatively evaluate location estimates l

j

, the mean of the

Mahalanobis distances between the true sample mean and the

estimated mean of each pure tissue class was computed. (We name

this criterion ‘‘Mahalanobis error ’’.) The true mean and the

covariance matrix were computed from voxels that contained over

99% of a certain tissue type in the phantom image. This error

criterion was selected due to its simplicity and its applicability to

both the single and multispectral case. Direct comparison of

Mahalanobis errors obtained at different noise levels would require

normalization of the covariances used in calculation of errors.

However, this kind of normalization would make the error criterion

and its analysis more complicated.

For covariance estimates, the definition of an error criterion that

would be meaningful for our problem is more difficult. In experi-

ments, errors in location estimates usually had a greater effect to

the PV estimation accuracy than errors in estimates of covariances

R

j

. For thes e two reasons, we only describe the quality of

covariance estimates verbally and we do not attempt to evaluate

it quantitatively.

For estimates of PVCs, the following error criterion is used

E

PVE

¼

1

N

X

N

i¼1

X

M

j¼1

Aw

i

j

*

w

i

j

A; ð13Þ

where w

i

j

*

is the estimated PVC, w

i

j

is the true PVC, M is the number

of pure tissue types, and N is the number of voxels in the brain

volume. Here, M = 3. Note that the value of this criterion does not

depend on the number of the pure tissue types in the image, because

we assume that each voxel contains at most two types of tissue. The

range of this error criterion is from 0 to 2. We have selected this

criterion closely related to mean absolute error (MAE) because we

are interested in the average accuracy that can be obtained in PV

estimation. Error criteria that are based on mean squared error (MSE)

could be as well employed, but they put more weight to gross errors,

hence evaluating more robustness than accuracy.

To establish a link between Mahalanobis errors in the model

parameter estimates and the error criterion for the PVC estimates,

a simulation was performed. For the simulation, we generated

intensities of WM/GM mixed voxels with varying mixing pro-

portions. Statistical models for the required tissue classes were

obtained from the simulated images in the same manner as when

computing the error criterion for parameter estimates. That is,

parameters for the densities were computed based on voxels that

contained over 99% of a certain tissue type (WM or GM) in the

phantom image. We also randomly generated a set of erroneous

model parameter estimates yielding a fixed Mahalanobis error.

Subsequently, PVCs were estimated using Eq. (10) based on the

simulated intensity values and the erroneous location estimates.

Errors in covariance estimates were not simulated, because this

simplifies the interpretation of the simulation results. A more

detailed description of the simulation can be found in the

Appendix A.

As can be seen in Fig. 4, the relationship between the PVC

and Mahalanobis errors is approximately linear in most cases.

Only the curve corresponding to the highest level of noise in

the single-spectral case seems to be nonlinear. Based on this

curve, Mahalanobis error values above 1.35 are worse than the

values below 1.35. However, experiments with the simulated

MR images rarely gave as large as 1.35 Mahalanobis error

values with the highest noise level. Also, it can be noticed in

Fig. 4 that the PVC error increases more rapidly relative to

Mahalanobis error in the single-spec tral ca se than in the

multispectral case.

IBSR data set

Simulated images allow us to study in detail each step of the

proposed procedure. To examine the practicality of the proposed

method, it is tested on real data sets. With real data, quantitative

valuation of the PV estimation is restricted to evaluation of the

quality of the subsequent ha rd segmentations. For this, the

segmentation from the PV estimation with TMCD parameter

estimates was evaluated with the internet brain segmentation

repository (IBSR) data set. The IBSR data set comprises of the

20 normal MR brain data sets and their manual segmentations

Fig. 4. The influence on the errors in parameter estimates to the errors in

PVC estimates. The top and bottom panels show results for, respectively,

the single-spectral (T1-weighted only) and multispectral (T1-, T2-, and

proton density-weighted) cases.

J. Tohka et al. / NeuroImage 23 (2004) 84–97 91

that were provided by the Center for Morphometric Analysis at

Massachusetts General Hospital and are available at http://neuro-

www.mgh.harvard.edu/cma/ibsr. These images have been used to

evaluate the quality of several (automatic) tissue classification

methods. The quality measure used is the Tanimoto coefficient

between the tissue class in the expert segmentation and in the

automatic segmentation (cf., e.g., Shattuck et al., 2001).

The preprocessing of the images consisted of correction of

interslice intensity nonuniformity that was done (see Zijdenbos et

al. (1995)) before registering them with stereotaxic (Talairach)

space. After stereotaxic registration, the N3 algorithm (Sled et al.,

1998) was used to correct for the remaining intensity nonunifor-

mity. Images were classified for parameter estimation in the same

way as simulated images. A hard segmentation was generated

from PVC estimates by selecting the class with the largest PVC

for each voxel as its label. The dimensions for the images were

256

256

64.

Results

Simulated data

Parameter estimation

Results for the single-spectral case are presented in Table 2.

Robust estimators combined with trimming were the most reliable

among the segmentation-based parameter estimation techniques.

They were also better than parameter estimates that were used to

initialize EM-ICM and usually better than the final results of EM-

ICM. For example, with image set 1 and 5% noise, TMCD

produced a Mahalanobis error of 0.06, whereas the error resulting

from MCD was 0.19 and the error resulting from EM-ICM was

0.11. Only with the image set 4, where the initial classifications

were not accurate, the EM-ICM algorithm yielded better results

than image-based parameter estimation techniques. Without trim-

ming of the initial classification, robust estimators did well only

with the lowest level of noise. The most extreme case occurred

with image set 3 and the highest noise level, where the errors

produced by robust estimators were 10 times higher than those

produced by trimmed robust estimators. T he performance of

TMVE and TMCD did not differ much in the single-spectral

case. The best variance estimates were achieved using the

trimmed robust estimators, while the trimmed ML estimator

typically underestimated the variances and nontrimmed estimators

overestimated them, although over/underestimation was always

consistent.

In Table 2, error values typically decrease when the noise level

increases. This is because, as was explained in Error criteria

section, the values of the Mahalanobis error at different noise

levels are not necessarily comparable.

Results for the multispectral case are presented in Table 3.

These results are similar to those with single-spectral data, except

that TML estimator was almost as good as TMCD estimator and

even better than TMVE estimator. With the image set 1 and the

noise level of 5%, for example, the error of TML was 0.25, the

error of the TMVE was 0.36, and the error of TMCD was 0.23. It

remains to be studied whether poor results of the TMVE

estimator as compared to the single-spectral case were due to

the estimator itself or to the approximative algorithm used to

compute it. The failure of all image-based estimators with the

image set 4 and a 5% noise level was due to very poor initial

classifications (about two-thirds of GM voxels were labeled as

WM), causing also robust estimators to break down. The quality

of initial classifications was better with the other noise levels.

With all the image sets, the covariance estimates obtained by

trimmed robust estimators were better than the ones of the TML

estimator, and the effect of this can be seen in the quality of PVC

estimates (see Table 5).

The EM-ICM algorithm typically produced the best estimates

when the voxel size was 1 mm

3

(i.e., image sets 1, 2, and 4).

However, with the image set 4 and the lowest noise level, EM-ICM

failed in the parameter estimation (error 5.67) and this can be seen

also in the quality of the corresponding PVC estimates (error

0.783). This failure was probably because the EM-ICM algorithm

failed to converge to a strong maximum due to a poor initialization

based on the ima ge tha t was not pr oper ly reg ist ere d to the

stereotaxic space. Especially, the initial covariance estimates great-

ly overestimated the (scaling of) covariance matrices, which could

explain why EM-ICM failed particularly with the lowest noise

level. The application of the EM-ICM algorithm did not always

improve the parameter estimates when compared the parameter

estimates used for its initialization. Indeed, there are no results

Table 2

Means of Mahalanobis distances between true and estimated mean

intensities of tissue types of T1-weighted data

Image

set

Noise

level

(%)

ML MVE MCD TML TMVE TMCD INIT EM-

ICM

1 1 1.16 0.11 0.13 0.20 0.21 0.19 0.27 0.11

5 0.46 0.18 0.19 0.06 0.07 0.06 0.13 0.09

9 0.28 0.55 0.39 0.17 0.04 0.05 0.06 0.14

2 1 0.99 0.07 0.07 0.11 0.14 0.16 0.26 0.09

5 0.48 0.16 0.17 0.09 0.07 0.07 0.14 0.10

9 0.28 0.48 0.39 0.15 0.06 0.05 0.23 0.19

3 1 2.32 0.30 0.13 0.50 0.14 0.13 0.70 0.20

5 0.66 0.44 0.38 0.13 0.10 0.05 0.22 0.22

9 0.31 0.64 0.51 0.19 0.05 0.04 0.13 0.25

4 1 3.03 0.65 0.54 1.51 0.58 0.61 7.58 0.11

5 1.38 0.39 0.45 0.84 0.39 0.46 2.84 0.10

9 0.92 1.37 1.26 0.58 0.27 0.37 1.62 0.15

Names for different methods for the parameter estimation are given in

Implementation section. INIT is the initialization for the EM-ICM

algorithm.

Table 3

Means of Ma halanobis distances between true and estimated mean

intensities of tissue types of multispectral data (cf. Table 2)

Image

set

Noise

(%)

ML MVE MCD TML TMVE TMCD INIT EM-

ICM

1 1 1.57 0.52 0.33 0.32 0.40 0.37 0.52 0.30

5 0.54 0.36 0.41 0.25 0.36 0.23 0.26 0.11

9 0.49 0.37 0.44 0.33 0.24 0.31 0.14 0.13

2 1 1.36 0.44 0.32 0.27 0.49 0.30 0.60 0.19

5 0.54 0.58 0.44 0.23 0.39 0.22 0.30 0.17

9 0.51 0.41 0.48 0.33 0.25 0.33 0.23 0.20

3 1 3.26 2.49 2.30 0.61 0.43 0.25 1.05 1.25

5 1.09 1.05 0.94 0.22 0.24 0.18 0.36 0.29

9 0.63 0.67 0.61 0.19 0.21 0.18 0.19 0.26

4 1 2.26 0.52 0.30 0.76 0.43 0.37 9.93 5.67

5 2.71 2.09 1.99 2.16 1.98 1.81 3.93 0.11

9 0.91 0.92 0.87 0.37 0.36 0.34 2.38 0.13

J. Tohka et al. / NeuroImage 23 (2004) 84–9792

concerning the convergence properties of the EM-ICM algorithm

(cf. Besag, 1986). Furthermore, the convergence to a local mini-

mum (or maximum) may actually draw estimates further from the

global minimum (or maximum).

Partial volume coefficients

Errors in the PV estimation are listed in Tables 4 and 5.InFig.

5, PV estimation errors obtained by applying different parameter

estimation methods are compared with some of the image sets.

Improvements in the quality of the model parameter estimates

improved PVC estimates in most cases. In that respect, these

results were consistent with the simulation described in Error

criteria section. However, generally the errors in PVC estimates

obtained with simulated images were lower than those obtained in

the simulation of Error criteria section assuming the same value of

the Mahalanobis error. This is not surprising since in the simulated

images some voxels are classified as pure voxels that yield a PVC

error value of zero in the case of a correct classification. Similar

reasoning could be used to explain why the improvements to an

already small Mahalanobis error led ra rely to a considerably

improved PVC estimation. An example of this phenomenon can

be seen in Table 4 by comparing the results by TMCD (Mahala-

nobis error 0.05, PVC error 0.195) and EM-ICM (Mahalanobis

error 0.22, PVC error 0.196) with the image set 3 and the noise

level of 5%.

PVC estimates obtained with multispectral images were

considerably better than those obtained with single-spectral

images (see Fig. 6). Moreover, it can be seen from PV

estimation results that gain from multispectral images increased

with the noise level. The differences in the errors in PVC

estimates between single and multispectral cases increased with

the noise level. However, it should be noted that in this case,

multispectral images were perfectly registered with each other,

which is rarely the case with real data. In the multispectral

image set 4, better PVC estimates with the noise level of 9%

Table 5

Errors (13) in PV estimation with multispectral data (cf. Table 2)

Image

set

Noise

(%)

ML TML TMVE TMCD EM-

ICM

1 1 0.104 0.086 0.082 0.083 0.088

5 0.140 0.132 0.135 0.131 0.128

9 0.237 0.213 0.210 0.213 0.198

2 1 0.111 0.087 0.086 0.084 0.081

5 0.147 0.137 0.138 0.137 0.134

9 0.243 0.217 0.223 0.216 0.201

3 1 0.153 0.104 0.084 0.085 0.099

5 0.202 0.169 0.165 0.164 0.163

9 0.271 0.257 0.264 0.256 0.252

4 1 0.130 0.095 0.083 0.082 0.783

5 0.642 0.538 0.485 0.443 0.128

9 0.285 0.245 0.235 0.241 0.199

Fig. 5. Errors in PV estimation with different parameter estimation methods

and noise levels. Form top, the sets 1 and 3 of T1-weighted images and the

set 1 of multispectral images.

Table 4

Errors (13) in PV estimation with T1-weighted data (cf. Table 2)

Image

set

Noise

(%)

ML TML TMVE TMCD EM-

ICM

1 1 0.108 0.083 0.084 0.084 0.078

5 0.157 0.156 0.156 0.155 0.156

9 0.249 0.259 0.247 0.248 0.252

2 1 0.112 0.089 0.089 0.089 0.086

5 0.160 0.158 0.157 0.157 0.157

9 0.252 0.262 0.252 0.253 0.256

3 1 0.156 0.106 0.089 0.089 0.088

5 0.206 0.195 0.195 0.195 0.196

9 0.316 0.317 0.306 0.308 0.318

4 1 0.160 0.107 0.082 0.083 0.079

5 0.257 0.207 0.162 0.168 0.156

9 0.364 0.324 0.276 0.286 0.255

J. Tohka et al. / NeuroImage 23 (2004) 84–97 93

compared to those with the noise level of 5% were due to

particularly poor initial classification when the noise level was

5%.

Shattuck et al. (2001) have evaluated their very fast PV

estimation routine using BrainWeb images but using an error

criterion different from ours. Therefore, to compare our results

with theirs, we computed errors of TMCD-based PVC estimates

also using the criterion they applied. The criterion is defined as (cf.

Eq. (13) for notation)

E

MSE

j

¼

ﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃ

1

N

X

N

i¼1

Aw

i

j

*

w

i

j

A

2

v

u

u

t

; ð14Þ

for each tissue class j. Particularly, we compared results with

single- spectral images from sets 1 and 2. (In Shattuck et al.,

2001, no results with multispectral data or images corresponding

our sets 3 and 4 were available.) Results are shown in Fig. 7.As

can be seen invariably, the TMCD-based method was better of the

two. Particularly, the PVC estimates for the gray matter were

considerably better with the TMCD estimated parameters. For the

white matter, differences were smaller. Although the methods differ

in all their components, they are both based on a division of the

problem in smaller subproblems. Hence, these results are a good

indication that our paramete r est imation techniques are a real

improvement as compared to previous similar approaches. The

model by which the data were simulated is the material-dependent

noise model, but with very similar covariance for each class.

Hence, the results of the PVC estimation step are similar with

both models (cf. PVC estimation section).

Comparison with the initial hard segmentation

With image set 4, we also list the misclassification rates of the

initial hard labeling and the hard labeling derived from PV

estimation in Tables 6 and 7. For this, the PV estimations were

hardened by labeling each voxel by the most dominant tissue type.

Almost all PV estimation techniques improved the results of the

original labeling (see Fig. 8 for an example). The only exception

was EM-ICM in the multispectral case with the lowest noise level.

In this case, the poor classification result was due to poor

parameter estimates (cf. Parameter estimation section).

Computation times

The entire procedure to estimate PVCs with a single-spectral

181

217

181 image took on average about 20 min using

parameter estimation based on hard classification. Most of the time

(over 10 min) was spent to the PV classification step. Image

Fig. 6. Voxel-wise absolute errors in PVC estimates obtained with single-

spectral (top) and multispectral (center) data. In the bottom, histograms of

voxel-wise absolute errors are shown. The noise level is 5% and the voxel

size is 1

1

3 mm. The parameter estimates were obtained with TMCD

estimator.

Fig. 7. MSE error values as in Eq. (14) with BrainWeb images. PVCs

estimated with the TMCD method are compared to the ones published in

Shattuck et al. (2001).

Table 6

Misclassification rates in the brain area in percent

Noise

(%)

ORIG ML TML TMVE TMCD EM-

ICM

Image set 4 1 18.8 4.5 2.1 1.9 1.9 1.9

5 24.3 8.6 6.8 6.0 6.1 5.9

9 31.6 17.0 15.1 13.6 14.0 13.4

ORIG denotes the initial hard classification. Otherwise, abbreviations are as

in Table 2.

Table 7

Misclassification rates in the brain area in percent with multispectral data

Noise

(%)

ORIG ML TML TMVE TMCD EM-

ICM

Image set 4 1 8.2 3.2 2.9 2.6 2.6 37.8

5 38.2 32.4 25.6 19.7 18.9 4.5

9 21.7 11.4 9.9 9.8 9.6 9.0

ORIG denotes the original hard classification. Otherwise, abbreviations are

as in Table 2.

J. Tohka et al. / NeuroImage 23 (2004) 84–9794

preprocessing (hard classification and nonuniformity correction)

typically took 3 min. Parameter estimation and PV estimation were

fast, requiring about 1 min each. In the multispectral case, the total

computation time was approximately 40 min. PV estimation with

EM-ICM algorithm took 2 h in the single-spectral case and 6 h in

the multispectral case. All computation times are on a 400 MHz

MIPS R12000 processor (SGIROriginR 3800 compute server). The

algorithms were implemented in C. These running times, particu-

larly for the PV classification step, could be probably improved by

paying more attention on the efficiency of the implementation.

Results with the IBSR data set

The Tanimoto coefficients (TCs) of segmentations obtained

from PV estimations using the TMCD parameter estimates can

be found in Table 8. The mean value of the Tanimoto coefficient

was 0.6686 for the WM and 0.6760 for the GM. We experimented

the procedure also with a higher value (0.5) for the parameter b

controlling the strength of the MRF prior. The average TC values

in this case were 0.6637 (WM) and 0.6807 (GM).

We selected to evaluate our algorithm with this data set due to its

frequent use in the evaluation of MR segmentation algorithms.

Although our interest in PVE is not in improving hard segmenta-

tions by modeling of it, it is interesting to compare the results of our

method to those obtained with algorithms for hard segmentation.

Rajapakse and Krugge (1998) compared several algorithms and the

best TC values were obtained by Adaptive MAP method, and they

were 0.567 for the WM and 0.564 for the GM. A more recent

method by Marroquin et al. (2002) achieved TCs 0.683 for the WM

and 0.662 for the GM. The average running time for this algorithm

was 19.2 min with the IBSR data set, which is similar to our

methods, but no PV estimation can be obtained with this method.

Discussion

In this paper, various methods for the parameter estimation for a

statistical model of the partial volume effect have been studied. It

has been shown that it is possible to estimate parameters in a

reliable and fast way based on the initial hard labeling of the image

before the actual partial volume estimation procedure. For this,

outliers of each class in the classified image were eliminated using

a simple morphological rule, and thereafter, parameters for model

were computed by us ing robust estimators: MVE and MCD.

Parameters estimated by MCD were of better quality than those

relying on sample means and covariances as estimates. It was also

observed that the trimming of the initial classification is necessary

even when using robust estimators. The parameter estimates based

on the hard classification were almost as good as the ones obtained

by the EM-ICM algorithm for simultaneous PV classification and

parameter estimation. The EM-ICM algorithm is, however, more

time consuming. Another downside of the EM-ICM algorithm for

parameter estimation is that it is essentially a local optimization

algorithm and hence its results depend on its initialization. In our

experiments, EM-ICM failed completely in parameter estimation

and subsequently in PV estimation with one of the multispectral

images. In that case, the parameter estimates that were used to

initialize the EM-ICM algorithm were of particularly poor quality

due to the failed stereotaxic registration.

The influence of improved parameter estimates on the PV

estimation was studied. As expected, better parameter estimates

produced better estimates of partial volume coefficients. Fur-

thermore, we examined the effect of increased error in param-

eter estimation to the error in PV estimation through a

simplified simulation. The simulation showed that the relation-

ship between Mahalanobis errors in parameter estimation and

errors in PV estimation is approximately linear for a fixed level

of noise.

We have studied our parameter estimation procedures in con-

junction with the material-dependent noise model, an indirect PV

estimation algorithm and a particular method for preliminary hard

classification. But in fact, the proposed parameter estimation

methods (TMVE and TM CD) can be applied more generally,

and hence other choices could have been made as well. First,

location parameter estimates for the sampling noise model can be

obtained in the exactly same manner as for the material-dependent

noise model. However, only a single covariance matrix describing

the sampling noise is required. This issue can be solved by

considering the pooled covarianc e of the estimated covariance

for the tissue classes (Dougherty, 1990, p. 467). Secondly, as

parameter estimation is a separate step of the whole procedure, it

could be applied also with direct PV estimation algorithms.

Furthermore, the initial hard classification and correction of inten-

sity nonuniformity can be performed with other methods than those

applied in this study. The state of the art algorithms for these tasks

(such as Marroquin et al., 2002; Van Leemput et al., 1999; Zhang

et al., 2001) are however more time consuming than the methods

applied in this study. Moreover, the robustness in parameter

estimation compensates also for classification errors as was shown

with misregistered Brainweb images.

Fig. 8. The improvement of the hard classification results by using PV

model. Left: the ground truth classification. Center: the initial classification

of the misregistered image with 5% of noise. Right: the hardened partial

volume estimation with TMCD parameters of the same image.

Table 8

IBSR data set results

Image 100

_

23 110

_

3112

_

211

_

312

_

313

_

3111

_

215

_

316

_

317

_

3

GM 0.6783 0.7363 0.7063 0.7381 0.8044 0.7716 0.7765 0.6076 0.6261 0.6026

WM 0.6844 0.6841 0.6632 0.7300 0.7393 0.7550 0.7409 0.6009 0.6275 0.6609

Image 191

_

31

_

24 202

_

3 205

_

32

_

44

_

85

_

86

_

10 7

_

88

_

4

GM 0.6896 0.7106 0.7968 0.7426 0.4535 0.5876 0.6581 0.5632 0.6447 0.6261

WM 0.7399 0.7328 0.7516 0.7519 0.5399 0.5625 0.6006 0.4851 0.6632 0.6591

J. Tohka et al. / NeuroImage 23 (2004) 84–97 95

To conclude, we have presented fast and robust methods to

estimate parameters for the mixel model. These robustified param-

eter estimates were shown to improve the performance of PV

estimation as compared standard estimates and heuristics used in

Shattuck et al. (2001). Moreover, parameter estimation based on

segmented image was demonstrated to be much faster than

competing EM style algorithms (Noe and Gee, 2001; Van Leemput

et al., 2003) . Also, as demonstrated with the IBSR data set, our fast

PV estimation routine produced hard segmentations of a similar

quality than a state of the art algorithm for this task (Marroquin et

al., 2002). In summary, we recommend the use of the TMCD

estimator based on hard labeling for fast and reliable parameter

estimation for a statistical PVE model.

Acknowledgments

Fig. 1 was generously provided by Jason Lerch, McConnell

Brain Imaging Centre, Montreal Neurological Institute. Thanks to

Chris Cocosco, Jason Lerch, and Steve Robbins for help in

implementing the algorithms for this paper. J. Tohka acknowledges

financial support from the Tampere Graduate School in Informa-

tion Science and Engineering, the Academy of Finland, the

KAUTE foundation, and the Jenny and Antti Wihuri fund.

Appendix A

This appendix describes the simulation used to link the Maha-

lanobis errors in parameter estimation and the absolute errors in

PVC estimation. Only mixtures of the white matter and the gray

matter tissue types were considered. The intensities were generated

by using the material-dependent noise model and assuming param-

eters as in GM and WM classes of the simulated images. The

mixing proportions were 0.1, 0.3, 0.5, 0.7, and 0.9. The number of

samples generated per each mixing proportion were 1000.

Different Mahalanobis errors evaluated were 0, 0.05, 0.1,...,

2.5. One hundred different locatio n parameter estimates were

generated for each fixed value of Mahalanobis error. The location

parameter estimates were generated by first randomly selecting the

direction of the error for both WM and GM tissue classes. In the

single-spectral case, this is easy, since only the choice between

positive or negative direction has to be made. This is a bit more

complicated in the multispectral case, where random points lying

on the unit sphere have to be drawn (see Marsaglia, 1972). After

the selection of directions of the error, the proportion of the total

Mahalanobis error rising from the estimate of the mean of WM

class was randomly drawn from the interval [0.2, 0.8]. Thereafter,

the exact covariance and each erroneous location estimate was used

to estimate the true PVC-coefficient from each 5000 samples of

intensity values. The results of the simulation are shown in Fig. 4.

We also performed a simulation where Mahalanobis errors were

assumed to be equally distributed between tissue types, but results

were similar to the more general experiment described above.

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- "This algorithm does not require prior knowledge of the brain tissue classes and can iteratively estimate both the multiplicative bias field and the distribution of true tissue intensities for the automatic correction of intensity non-uniformity in MRI data. The resultant brain images were then automatically segmented into gray matter, white matter, cerebrospinal fluid, and background by using a partial volume (PV) classification algorithm, in which a trimmed minimum covariance determinant method was applied to estimate the parameters of the PV effect model; the parameter, b, controlling the relative strength of the Markov random field was set to 0.1 [Tohka et al., 2004]. Next, the inner and outer gray matter surfaces were automatically extracted for each hemisphere using the CLASP algorithm [Kim et al., 2005]. "

[Show abstract] [Hide abstract]**ABSTRACT:**Neurodegenerative diseases such as Alzheimer's disease (AD) have been recognized to exhibit disease-specific brain vulnerability patterns. Apolipoprotein E (APOE) ɛ4 allele imparts a high genetic risk of developing AD. Whether the APOE ɛ4 allele damages the brain when cognitive functions are still intact is important to understand, especially for possible early detection and intervention. This study aimed to examine the selective degeneration pattern associated with the APOE ɛ4 allele in the brains of cognitively normal elderly subjects. We enrolled 35 cognitively healthy ɛ4 carriers and 40 non-carriers (53 to 81 years old) to evaluate group differences in cortical thickness and brain activation during a memory-encoding task. We also assessed the functional connectivity of the brain regions with both structural and functional damages. The results from the neuropsychological tests showed that the performances of ɛ4 carriers and non-carriers were comparable. Primarily, we found that the precuneus exhibited thinner cortical thickness and decreased deactivation during memory encoding. Furthermore, the connectivity analyses show that carriers exhibited damaged connectivity of the precuneus to several regions in the default mode network and the attention/executive control network. Our study reveals the degeneration pattern of the ɛ4 allele, which could be used as a potential biomarker for early detection for possible interventions and treatments. Hum Brain Mapp, 2016.- "All T1-weighted images were corrected for bias-field inhomogeneities, then spatially normalized and segmented into gray matter, white matter, and cerebrospinal fluid within the same generative model [50]. The segmentation procedure was further extended by accounting for partial volume effects [51], by applying adaptive maximum a posteriori estimations [52], and by using a hidden Markov random field model [53]. Preprocessing the images further included affine registration and smoothing with 4-mm full-width-at-half-maximum (FWHM) Table 1. "

[Show abstract] [Hide abstract]**ABSTRACT:**In our aging society, diseases in the elderly come more and more into focus. An important issue in research is Mild Cognitive Impairment (MCI) and Alzheimer’s Disease (AD) with their causes, diagnosis, treatment, and disease prediction. We applied the Brain Age Gap Estimation (BrainAGE) method to examine the impact of the Apolipoprotein E (APOE) genotype on structural brain aging, utilizing longitudinal magnetic resonance image (MRI) data of 405 subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. We tested for differences in neuroanatomical aging between carrier and non-carrier of APOE ε4 within the diagnostic groups and for longitudinal changes in individual brain aging during about three years follow-up. We further examined whether a combination of BrainAGE and APOE status could improve prediction accuracy of conversion to AD in MCI patients. The influence of the APOE status on conversion from MCI to AD was analyzed within all allelic subgroups as well as for ε4 carriers and non-carriers. The BrainAGE scores differed significantly between normal controls, stable MCI (sMCI) and progressive MCI (pMCI) as well as AD patients. Differences in BrainAGE changing rates over time were observed for APOE ε4 carrier status as well as in the pMCI and AD groups. At baseline and during follow-up, BrainAGE scores correlated significantly with neuropsychological test scores in APOE ε4 carriers and non-carriers, especially in pMCI and AD patients. Prediction of conversion was most accurate using the BrainAGE score as compared to neuropsychological test scores, even when the patient’s APOE status was unknown. For assessing the individual risk of coming down with AD as well as predicting conversion from MCI to AD, the BrainAGE method proves to be a useful and accurate tool even if the information of the patient’s APOE status is missing.- "Here, thickness was computed using the CIVET pipeline (Zijdenbos et al. 2002). This involves an initial N3 correction for field non-uniformities (Sled et al. 1998 ), linear and nonlinear registration to the MNI152 population template (Mazziotta et al. 2001 ), tissue classification with partialvolume estimation (Tohka et al. 2004 ), and the approximation of GM/WM and GM/CSF boundaries using the constrained Laplacian anatomic segmentation using proximity (CLASP) algorithm (Kim et al. 2005; MacDonald et al. 2000). CLASP uses a deformable surface model approach to find the optimal surface mesh representing borders between tissue classes. "

[Show abstract] [Hide abstract]**ABSTRACT:**Human neuroimaging methods have provided a number of means by which the connectivity structure of the human brain can be inferred. For instance, correlations in blood-oxygen-level-dependent (BOLD) signal time series are commonly used to make inferences about “functional connectivity.” Correlations across samples in structural morphometric measures, such as voxel-based morphometry (VBM) or cortical thickness (CT), have also been used to estimate connectivity, putatively through mutually trophic effects on connected brain areas. In this study, we have compared seed-based connectivity estimates obtained from four common correlational approaches: resting-state functional connectivity (RS-fMRI), meta-analytic connectivity modeling (MACM), VBM correlations, and CT correlations. We found that the two functional approaches (RS-fMRI and MACM) had the best agreement. While the two structural approaches (CT and VBM) had better-than-random convergence, they were no more similar to each other than to the functional approaches. The degree of correspondence between modalities varied considerably across seed regions, and also depended on the threshold applied to the connectivity distribution. These results demonstrate some degrees of similarity between connectivity inferred from structural and functional covariances, particularly for the most robust functionally connected regions (e.g., the default mode network). However, they also caution that these measures likely capture very different aspects of brain structure and function.

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