A review of techniques and applications of lesion identification in MRI scans

Daryl Sheppard

Abstract
Magnetic Resonance Imaging (MRI) is the favoured technique for the identification of
lesions over other available methods due to its capability to be used in a wide variety
of examinations as well as the fact it is non-invasive and doesn‟t make use of non-
ionizing radiation (Stamatakis & Tyler, 2005).

It does however; present the medical professional with the challenge of providing a
constant and reliable method of identification of lesion areas that is repeatable
across different operators as well as the need in some medical conditions to provide
fast and accurate diagnosis of the affected areas to determine an appropriate course
of treatment.

This paper will review existing research surrounding this problem. It will not focus
specifically on any lesion type or application to any particular disease but will look at
the problem in broad terms. Three main areas will be covered; section 1 will discuss
manual segmentation techniques and issues surrounding this approach, section 2 will
discuss the development of automatic segmentation techniques and section 3 will
focus on new techniques and approaches which show some promising results and
may be the attention of further future research.

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1. Introduction
Magnetic Resonance Imaging was first
discovered in the 1950s and used initially in
the field of spectroscopy.

It was not until the 1970s when work

undertaken by Lauterbur expanded the use
of Magnetic Resonance Imaging into
medical applications which then enabled
examinations of the human body in vivo
(Liney, 2005).

The technique produces the MR image

through the detection of the presence of
hydrogens (protons) within the body. The
MRI machine subjects these hydrogens to a
large magnetic field which partially
polarizes
their nuclear spins. The spins are then Figure 1 Example of a normal brain MRI image (McGill
excited using tuned radio frequency University, 2006)
radiation. Radio frequency radiation is then
detected from them as they relax from this magnetic interaction.

The frequency of the signal from the proton is proportional to the magnetic field
applied during the radiation process. Using these signals, a map of the body area
scanned is then produced which forms the magnetic resonance image. (Nave)

While the use of MRI scans has provided good insight into the pathology of the
human body, for the identification of lesions it presents some areas of concern.

Broadly speaking there are two main categories of lesions that are of interest to
medical professionals;
 white matter lesions (WML), resulting in blood-brain barrier damage
(Calabrese, et al., 2008)
 gray matter lesions (GML), resulting in demyelination of nerve fibres
(Calabrese, et al., 2008)

These lesions point towards a number of different medical conditions and their
identification is often paramount to determine treatment for the patient as well as
critical in monitoring the effects of drug therapy in clinical trials. (Van Leemput, Maes,
Bello, Vandermeulen, Colchester, & Suetens, 2000)

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 The process of segmenting the MRI
scan of patients with WML is difficult
because the characteristics of WML are
similar to those of gray matter.
Techniques such as intensity based
statistical classification potentially may
classify some WML as gray matter and
some gray matter as WML. (Warfield, et
al., 1995)

To further highlight the subtleties

involved in the process required to
segment lesions from an MRI scan, take
the images displayed in Figure 1 and
Figure 2 as an example.

These are simulated images generated

from the online BrainWeb resource
Figure 2 Example of a brain MRI image showing MS (McGill University, 2006). Both images
lesions. (McGill University, 2006) show a T1 MRI scan taken in 5 mm slices
(slice 21 displayed).

The differences between the two images are very subtle and identifying the lesion
would be a difficult task taking into account the potentially large number of images
within a standard MRI scan. Additionally, an operator examining a large number of
images in a given work day may eventually start to misidentify some of the less
apparent lesions. Add to this a level of complexity introduced due to varying type
and quality of images under review.

Due to the fact that MRI techniques were well established prior to any concept of an
automated method for analysis, the first techniques developed to assess MRI scans
were of course manual. These consisted of trained operators following a predefined
measurement scale as will be discussed in more detail later in this paper.

With advancements in the areas of computer assisted analysis and its application to
the medical profession, a number of techniques have been developed which
automate the work of the trained operators. These include two main categories; fully
automated or hybrid approach which still requires some involvement with a trained
operator

A large amount of the literature I covered throughout the course of this review
covered the application of lesion segmentation in relation to its application
specifically to the disease of Multiple Sclerosis. Certainly other lesion-causing
diseases have been covered such as Alzheimer‟s and stroke. It should also be noted

3
that in the research covered, the specificity of the application to the disease Multiple
Sclerosis by no means invalidates the application of the lesion segmentation
technique to that disease.

It is notable, and possibly can be drawn as a cause resulting from the observation
above, the majority of the lesions segmentation techniques also focus on the
segmentation of WML with potential applicability to the segmentation of GML. With
an initial belief that Multiple Sclerosis is primarily a disease of the white matter
(Kutzelnigg & Lassmann, 2005) this may have resulted in a disproportionate focus on
the segmentation of WML over GML.

This disproportion would seem to have been the focus of some attention at least
within the last ten years which has drawn conclusions that Multiple Sclerosis also has
an impact on the cause of lesions within gray matter structures (Kidd, Barkhof,
McConnell, Algra, Allen, & Revesz, 1999). Demyelination has also been noted
prominently in the gray matter of deep cerebral nuclei and the cerebral cortex.
(Kutzelnigg & Lassmann, 2005).

Where possible the approach taken in this review has been to look at the problem of
lesion segmentation divorced from any specific disease or specific lesion type. My
observations throughout the course of this review have primarily revealed that the
issue of segmentation exists across most applications of MRI technology. That said
however, the focus of the source material used within this review has a narrow focus
towards specific applications. It is conceivable that future developments within the
field of MRI technology may address some of these issues by producing images that
more clearly identify the areas of interest. However, until that stage lesion
segmentation will be a necessary area of research and development.

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2. Manual Segmentation
2.1 Introduction
The concept behind manual segmentation is fairly simple; provide a rating system,
usually numeric, and an accurate description that enables a similar result across
disparate operators and applications.

Over time and in the absence of any automated quantitative methodology to assess
MR images, operator observation techniques developed.

2.2 White Matter Lesions on CT and MRI

One such technique (van Swieten, Hijdra, Koudstaal, & van Gijn, 1990) focused on
white matter lesions within CT and MRI scans identifies in addition to the proposed
scale, three key observations that could be applied effectively to any manual rating
system. They are:
1. The scale used should incorporate anatomical distribution and severity and
provide clear definitions for each of the different categories
Any scale used should be applicable to a given anatomical area and provide a
measure of the severity of the lesion being examined

2. Simple.
Given this is a quantitative measure involving operator observation, a granular
approach to rating would increase the likelihood of variation between
operators. As such, the scale needs to remain relatively simple with clearly
defined categories that most reasonably trained operators can readily identify
against.

3. The scale should be assessed for reliability against an inter-observer study.

The key mechanism involved within this type of approach is a human element.
As a result, a number of factors can potentially be involved which may bias the
result. Aspects such as operator training, timeframe, equipment/image quality
may all play a part in producing different results across different operators.
While the human element cannot be reduced entirely, it can be mitigated by
studies that provide a statistical measure of the accuracy of observations
made against this scale.

While the paper did cover specifically the application of this scale to white matter
lesions within CT or MR images, the observations above and the principles outlined

5
in the scale could be readily applied with only minor modification and tuning to most
lesion grading requirements.

This system identified three severity categories and associated definitions

Grade Description
0 No lesion or only a single one
1 Multiple focal lesions
2 Multiple confluent lesions scattered throughout the white
matter
Table 1 Three grade rating system, (van Swieten, Hijdra, Koudstaal, & van Gijn, 1990)

During the study conducted for this paper, examinations were undertaken on both
CT and MRI scans.

For the MRI scans, twenty four images were obtained from a study of elderly
hyperintensive patients. The results from the MRI portion of the study were
calculated using kappa statistics with a weighted value of 0.78.

While this would seem a reasonable outcome, the conclusions draw within this paper
raise two main questions:
1. Is the sample size of 24 sufficient to draw this conclusions
2. The only measure of success of this methodology is a measure generated
using kappa statistics. The utility of this measure for this type of analysis is
seen as controversial with opinions differing as to its applicability (Uebersax,
2002).

2.3 ARWMC Scale

Another manual segmentation technique (Wahlund, et al., 2001) takes a very similar
approach to that identified above. This technique, the ARWMC (Age Related White
Matter Change) scale uses two four point scales divided across two different regions
of the brain.

As you can see from the scales identified in Tables 2 and 3, the three key
observations identified above are present within this scale; anatomical and severity
measurements have been identified, the scale is simple and (as the study indicates)
provides good inter-rater reliability.

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Grade Description
0 No lesions (including symmetrical, well-defined caps or bands)
1 Focal lesions
2 Beginning confluence of lesions
3 Diffuse involvement of the entire region, with or without involvement of U
fibres
Table 2 White Matter Lesion Scale from AWRMC scale

Grade Description
0 No lesions
1 1 focal lesions (≥5 mm)
2 > 1 focal lesions
3 Confluent lesions
Table 3 Basal Ganglia Lesion Scale from AWRMC scale

The observations of this study were conducted across both MRI and CT images. The
results of this study indicated good inter-rater reliability of each of the scans. It
should be noted that similar statistical measures were used to reach this conclusion
and therefore the same issues as identified by (Uebersax, 2002) could potentially
apply.

2.4 Issues
Manual segmentation was essentially born from necessity. MRI and other scanning
technologies provided insight into areas of the human body where in vivo
examination had never been able to be performed previously. While techniques were
developed to apply this type of methodology in a consistent and scientific manner,
some shortfalls could realistically never really be adequately addressed. These issues
include;

1. Generally a high-level of expertise will be required

In essence; this process will only involve two elements; the rater and the
images. There is little additional assistance provided to complete this task
2. The process is time and labour consuming
Each image needs to be carefully examined in great detail. With this
requirement and the large number of images involved in a given MRI scan,
this is a large amount of work to complete
3. The process is subjective and therefore not reproducible
While statistically, manual segmentation methods have proven to be more or
less reliable, the subjective nature of assessment cannot be eliminated entirely
(Stokking, Vincken, & Viergever, 2000)

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While the future direction of lesion segmentation rests with better and more efficient
automated processes, it should be noted that manual segmentation processes still
have a place as viable tools to validate new methodologies. A number of studies such
as those covered in later sections within this review (Anbeek, Vincken, van Osch,
Bisschops, & van der Grond, 2004); outline steps taken to perform manual
segmentation as part of the validation of the proposed automated techniques. This
highlights the need to maintain expertise within this area of study.

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3. Automatic Segmentation
3.1 Introduction
The fundamental flaw in the manual segmentation approach is the inconsistency of
the human operator. A number of factors need to be taken into account which may
result in errors during an assessment. These include:
 Training level; each operator may be at a varying level of experience and
expertise
 Time constraints; a manual segmentation approach will take time, with a
large number of MRI scans to assess an operator may not have sufficient
time to make an adequate identification
 Large lesions; if a lesions is large enough to be spread over a number of
different image slices, this may lead to the full extent of a given lesion not
being accurately assessed

To this end, studies have been devoted to producing automated methods for the
segmentation of MRI scans.

Automatic procedures will remove a number of human related issues and produce a
more consistent result across any number of operators.

A number of different methodologies have been developed to achieve this. While

each takes a unique approach, there are also a number of common elements that are
generally present within each; uniformity correction, a method used to correct for
any inhomogeneities that are present within the scan; patient movement, correction
for any inconsistencies introduce due to the movement of the patient during the
scan; isolate brain tissue; minimize the size of the problem by ensuring that the only
areas of the scan that are examined are the required areas and not areas of non-
interest such as cerebrospinal fluid (CSF) or skull

Additionally, two main approaches can be identified across the different techniques;
fully automated segmentation, a process able to be performed by an operator
untrained in image segmentation and analysis; and partially automated
segmentation, a process still requiring some image segmentation and analysis
decision making by a skilled operator.

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3.2 k-Nearest Neighbour Technique

3.2.1 Introduction
A methodology used in a number of different lesion segmentation techniques is that
of the k-Nearest Neighbour classification.

Used within the problem of lesion segmentation, this classification algorithm makes a
determination of the classification of a given voxel based upon the classification of its
neighbouring voxels and a predefined „learning‟ set of voxels provided to the system
prior to a segmentation attempt. (Statsoft Inc., 1984-2008).

The k-Nearest Neighbour (k-NN) algorithm is an example of a type of automated

machine-based learning where a given object is labelled based upon the frequency
of that label in comparison to its neighbours (Columbia University, 2007); (van den
Bosch, 2009).

During the course of this review, I found three different approaches which make use
of this classification methodology.

3.2.2 Probability Maps

In the application we see demonstrated here (Anbeek, Vincken, van Osch, Bisschops,
& van der Grond, 2004), the learning element is undertaken based upon a features
space.

This specific implementation of this algorithm makes use of five different types of
MRI including: T1-weighted (T1-w), Inversion Recovery (IR), Proton Density-Weighted
(PD), T2-Weighted (T2-w) and Fluid Attenuation Inversion Recovery (FLAIR)

The implementation of the k-NN algorithm for this study determines a feature space
based upon voxel intensity features and spatial information. The result of this
method is the generation of an image (probability map) representing the probability
on a per voxel basis of a given voxel being part of a WML. (Anbeek, Vincken, van
Osch, Bisschops, & van der Grond, 2004).

These probability maps were then evaluated using two methodologies; binary
segmentation and direct probability evaluation.

For the binary segmentation evaluation, varying thresholds were applied to the
probability map to create different segmentations of the WMLs. From this a ROC
curve analysis was taken from the True Positive Fraction (TPF) as a function of the
False Positive Function (FPF). (Anbeek, Vincken, van Osch, Bisschops, & van der
Grond, 2004)

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In addition to this, each binary segmentation were evaluated using three different
similarity measures; Similarity Index (SI), a measure for the correctly classified lesion
area; Overlap Fraction (OF), a measure of the correctly classified lesion area relative
to only the reference WML area; Extra Fraction (EF), a measure of the area falsely
classified as lesion relative to the reference WML area (Anbeek, Vincken, van Osch,
Bisschops, & van der Grond, 2004).

These measures were defined by

2 𝑋 𝑇𝑃
𝑆𝐼 =
2 𝑋 𝑇𝑃 + 𝐹𝑃 + 𝐹𝑁

𝑇𝑃
𝑂𝐹 =
𝑇𝑃 + 𝐹𝑁

𝐹𝑃
𝐸𝐹 =
𝑇𝑃 + 𝐹𝑁
(Anbeek, Vincken, van Osch, Bisschops, & van der Grond, 2004)

For the probabilistic evaluation, each result was analysed using probabilistic versions
of the similarity measures. These measures; the probabilistic similarity index (PSI),
probabilistic overlap fraction (POF) and the probabilistic extra fraction (PEF) are
defined by:

2 𝑋 𝑃𝑥,𝑔𝑠=1
𝑃𝑆𝐼 =
1𝑥,𝑔𝑠=1 + 𝑃𝑥

𝑃𝑥 ,𝑔𝑠=1
𝑃𝑂𝐹 =
1𝑥 ,𝑔𝑠=1

𝑃𝑥,𝑔𝑠=0
𝑃𝐸𝐹 =
1𝑥,𝑔𝑠=1
(Anbeek, Vincken, van Osch, Bisschops, & van der Grond, 2004)

The preparation process applied to each of these images included three steps.

Step 1 - Inhomogeneities correction; this step involved the application of a process in

which the intensity histogram of each given image is transformed into a “standard”
histogram (Nyul & Udupa, 1999). This is done in a two stage processes. Stage 1 is the
training stage where parameters of the standardizing transformation are learned
from a set of images. This stage identifies specific landmarks of a standard histogram
and is estimated from a given set of volume images. (Nyul & Udupa, 1999). Stage 2 is
the transformation stage. The image intensity scale is computed by mapping the

11
landmarks determined from the image histogram to those of the standard
histogram. (Nyul & Udupa, 1999).

Step 2 - Correction for difference due to patient movement; all patient images were
registered by rigid registration (translation and rotation) (Anbeek, Vincken, van Osch,
Bisschops, & van der Grond, 2004).

Step 3 - Reduce amount of data to be investigated; this stage uses a technique called
MBRASE (Morphology-based Brain Segmentation). This is a segmentation process
that uses a region-based growing technique. A seed pixel is selected in the given
image and neighbouring pixels are added progressively based upon their meeting
set criteria such as maintaining a particular intensity range (Stokking, Vincken, &
Viergever, 2000)

3.2.3 Results
The end result of this process is a probability map which maps against each voxel the
probability of it being a lesion. Additionally it also provides spatial and volumetric
information about the identified WML.

This classification method resulted in a high degree of accuracy for a range of

different lesion sizes. While focussing on WML for this study, the authors do
acknowledge the further possible utility of the method in the identification of other
lesion types.

Possibly a disadvantage that this method clearly brings is the need for multiple types
of MRIs to be conducted. It has been observed generally in the other papers
reviewed that an objective is to standardise the approach to lesion segmentation and
use MRIs that would have already been taken for other diagnostic reasons rather that
requiring images to be taken for this specific purpose. However, this is obviously
needed to be weighed against the relative success of this technique by comparison
to others and the situation required.

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3.2.4 Brain Atlas Method
Another study utilizing the k-Nearest Neighbour technique (de Boer, et al., 2009)
takes an approach that utilizes the registration of brain-atlases. This method is a two
staged approach using T1-weighted and FLAIR MRI.

This study identifies a fully automated methodology for the segmentation of CSF,
gray matter and white matter and WML. The technique outlines:
 The use of atlas registration to automatically train a k-nearest neighbour
classifier
 Automatic WML segmentation

Twelve brain atlases were acquired for this study. These atlases were sourced from
the Rotterdam Scan Study; a large population-based imaging study conducted
between 1995-1996 consisting of approximately 1700 subjects who underwent MRI
scan which was then manually segmented (de Leeuw, et al., 2001). This followed with
the acquisition of test data taken from the Rotterdam Scan Study conducted 2005-
2006. This study involved 215 subjects.

The segmentation process consisted of two main stages, brain tissue segmentation;
identifying gray matter, white matter and CSF, and WML lesion segmentation; the
final stage of the process.

In the first stage (brain tissue segmentation), the CSF, gray matter and white matter
are automatically segmented using the trained k-Nearest Neighbour classifier with
the T1-weighted image. The training samples for the k-NN classifier are obtained
from the subject via atlas-based registration using either one or more registrations of
atlases to the subject.

In the second stage (WML lesion segmentation), a process of thresholding is applied

to obtain the segmentation of the WML. Initially WMLs present in the image are
misclassified at gray matter with a „halo‟ of white matter (de Boer, et al., 2009). From
this image, a histogram is then created of all voxels in the image classified as gray
matter. Within this histogram, the highest peak corresponds to the true gray matter
voxels with the intensities corresponding to the WML voxels located to the right of
this peak. The histogram is then smoothed by a convolution with a Gaussian kernel
making it possible to estimate FLAIR intensity corresponding to the centre of the
gray matter peak by the histogram bin containing the most true positive gray matter
voxels (de Boer, et al., 2009).

3.2.4.1 Results
The final analysis of the results from this study showed a high degree of accuracy
that was validated by a separate and independent manual segmentation process.

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By comparison to the previously identified method as well as the method outlined in
section 3.2.5, this approach requires the least number of MRI images which would
present an advantage to time, cost and possible dual use of scans.

3.2.5 k-Nearest Neighbour and TDS +

This study expands on previous work conducted by the authors. In the previous work,
the authors developed and validated a template-driven segmentation methodology
combined with heuristic partial volume correction algorithm (TDS+). In this study, the
work has been expanded upon to develop an automated three-channel TDS (3ch-
TDS+) MRI segmentation pipeline for the identification of MS lesion subtypes (Wu, et
al., 2006).

There are five stages involved in this methodology which utilise Proton Density, T2
and contrast-enhanced T1-weighted images. These are described as follows.

3.2.5.1 Segmentation of the Intracranial Cavity

Masks of the Intracranial Cavity were generated from the Proton Density and T2
images. This was done utilising an extraction procedure combining non-parametric
intensity-based statistical (Parzen windows) segmentation and automated
morphological operations (Wu, et al., 2006). Parzen windows are similar to k-NN. The
key difference being that k-NN will look at k closest points to the designated training
data whereas with a Parzen window, a fixed distance is considered (Vawter).

Further segmentation of material not of interest was undertaken by superimposing

the masks onto the Proton Density, T2 and contrast T1 images.

3.2.5.2 Image Correction

Once the Intracranial Cavity masking was complete, EM segmentation was applied to
provide inhomogeneity correction and intensity normalisation. The EM segmenter
compensated for intra/inter-scan intensity inhomogeneities and normalised the scan
intensities.

3.2.5.3 k-Nearest Neighbour Segmentation

The k-Nearest Neighbour segmentation approach selected was developed based on
Friedman‟s k-NN algorithm (Friedman et al., 1975; Warfield, 1996) (Wu, et al., 2006).

Two stages were involved with this process. In a similar fashion as with other k-NN
based approaches, a learning phase was initially required. For this implementation,
two randomly chosen (from the full set of scans used within this study) were selected
as calibration scans. The information obtained from this process was then applied to
the remaining scans in the study.

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3.2.5.4 TDS +
TDS+ (Template Driven Segmentation and partial volume artefact correction) was
applied to correct misclassifications after the k-NN segmentation process. This
improved lesion classification by providing a priori anatomical probabilities.

3.2.5.5 Refining “Black Holes” Segmentation

The “black holes” in the MRI image previously identified in the k-NN segmentation
stage do not include areas of the white matter that are hypointense with respect to
healthy white matter but isointense with respect to gray matter (Wu, et al., 2006). To
address this, an additional classification step is taken to refine the “black holes” to
include subtly hypointense signals. To this end, a more sensitive k-NN classifier is
obtained by adding training points from mildly T1-hypointense WM regions (Wu, et
al., 2006).

3.2.5.6 Results
The results of this study when compared to manual tracing demonstrated that the k-
NN segmentation was able to identify most of the lesions.

Most notable is that three types of misclassifications were apparent. These included;
misclassification of choroid plexus and other enhancing vascular structures as
enhancing lesions, misclassifications of subtle signal abnormalities of the white
matter as gray matter and misclassification of pixels on the cortical surface as white
matter lesions (Wu, et al., 2006).

With these issues identified, it would generally appear that further examination of
this technique is required. The authors outline in their discussion on these findings
various modifications and other enhancements applied to the original methodology.

15
3.3 Gray Matter Atrophy
An algorithm developed (Nakamura & Fisher, 2009) focuses on the measurement of
gray matter atrophy in MS patients. While not specifically looking at lesion load, this
approach could be used in determining WML load as damage to the white matter
has been show to be associated with upstream gray matter atrophy (Sepulcre, et al.,
2009).

This algorithm (Nakamura & Fisher, 2009) approaches the problem by the
combination of intensity, anatomical and morphological probability maps. It uses
analysis from FLAIR and T1-weighted images as well as brain atlas information.

The intensity based probability map is generated with a modified fuzzy c-means
(FCM) clustering method to generate probability maps for each tissue type.
(Nakamura & Fisher, 2009). During the course of this study, the FCM was applied to
the T1-weighted images.

The anatomy-based probability map was derived from the Harvard Brain Atlas, a 3-D
digitized atlas of the human brain designed for use with MR image sets (Kikinis, et al.,
1996). The process at this stage involved converting the atlas to a general GM
probability map and then applying morphologic operations and Gaussian filters to
smooth the result. The converted map is then aligned with each patient‟s MRI using a
12 DF affine transformation (Nakamura & Fisher, 2009).

The individualized morphological probability map is created from morphological

models of the cortical and deep GM.

The final stage of this process creates a combined probability image which is a
product of all of the GM probability maps. The binary GM mask is then generated by
setting a threshold of 0.5 on the combined probability map. The normalized Gm
volume is defined as:

𝐺𝑟𝑎𝑦 𝑀𝑎𝑡𝑡𝑒𝑟 𝑉𝑜𝑙𝑢𝑚𝑒

𝐺𝑟𝑎𝑦 𝑀𝑎𝑡𝑡𝑒𝑟 𝐹𝑟𝑎𝑐𝑡𝑖𝑜𝑛 =
𝑂𝑢𝑡𝑒𝑟 𝐶𝑜𝑛𝑡𝑜𝑢𝑟 𝑉𝑜𝑙𝑢𝑚𝑒
(Nakamura & Fisher, 2009)

Four different tests were developed to validate the results of this method. These
included; segmentation of simulated MRI data and comparison to correct results,
segmentation of real MRI data and comparison to manual tracing results,
segmentation of scan-rescan images to determine the reproducibility of the method
and segmentation of the same image with simulated MS lesions to determine the
effects of lesions on the results.

16
Simulated MRI data was used to determine the accuracy in terms of volumetric errors
and similarity indices by comparing the segmented tissues masks to the gold
standard tissue masks. The evaluation were conducted against the results using the
similarity index defined as

2𝑇𝑃
𝑆𝑖𝑚𝑖𝑙𝑎𝑟𝑖𝑡𝑦 𝐼𝑛𝑑𝑒𝑥 =
2𝑇𝑃 + 𝐹𝑃 + 𝐹𝑁
(Nakamura & Fisher, 2009)

MRIs from three MS patients and three normal controls were used to evaluate the
segmentation accuracy of the algorithm in real MRIs. Each image was processed
through the algorithm and then the GM was manually traced in a separate process.
Analysis was conducted on each of these results.

For a separate study, MRIs were obtained from nine MS patients. Each of the images
were analysed with the reproducibility of the algorithm evaluated by calculating the
coefficient of variation of GM volumes calculated from repeated images of each
patient. (Nakamura & Fisher, 2009).

The final test measured the effect of WML in the FLAIR images. To achieve this test,
masks of segmented MS lesions were simulated within the MRI images. This test was
conducted over 18 MS patients.

The results of each of these tests are detailed in full within the study (Nakamura &
Fisher, 2009). This particular methodology brings with it a number of advantages
over other studies.

The requirements for this methodology are similar to those required for patients
undertaking normal MRI procedures. This makes this process greatly applicable to
many standard MRI tests in retrospect without the need to specialised images to be
taken for the purposes of applying this methodology only.

3.3.1 Results
Statistically the results from this methodology appear to be promising. Additionally, a
number of observations were made that provide additional benefit to the use of this
methodology.

Comparison to other GM segmentation methodologies has identified an advantage

over other methodologies such as SPM (Ashburner) and partial volume model
(Shattuck). The similarity index for this methodology was 0.938 compared to the
other methodologies reporting 0.932 and 0.893 respectively. (Nakamura & Fisher,
2009).

17
Statistically this methodology doesn‟t correlate the measurement of GM volumes
strongly to lesion volume in comparison to methodologies such as SPM. This
eliminates the need for any form of manual correction to correct segmentation errors
between the GM and lesions volumes.

An interesting point to note with this study (which is further expanded upon in
section 3) is the application of an indirect measure to achieve a result. That is, the
measurement of one element that is known can also provide information in regards
to another element that is not known. This may not seem the most direct approach
to achieving the desired segmentation, however it may provide an easier measure or
at least confirmation of a known measure.

While this study focuses on an application to MS, an application to a range of

medical conditions such as schizophrenia, HIV dementia and Alzheimer‟s disease
could also be applicable. (Nakamura & Fisher, 2009).

18
3.4 Measuring the Whole Brain Structure
An approach taken within a number of methodologies covered has been to look at
segmentation issue from the perspective of the entire brain structure and then divide
and segment into its respective classifications of matter.

This approach differs in the manner that it doesn‟t initially focus on the immediate
identification of GML or WML but addresses each component of the brain. From this
macro scale analysis, it would be possible to identify each component of the brain
eventually eliminating everything other than the area of interest by a process of
elimination if nothing else. This methodology would be particularly beneficial in
application to longitudinal studies where measurements of the course of the study
could very easily identify areas of change.

One such application of this methodology (Iosifescu, et al., 1997), implements this
approach using an atlas image and elastic matching from automatically segmented
MRI scans.

3.4.1 Automated Segmentation

The first stage in this methodology is to perform the initial segmentation of the
images. For this stage, a segmentation methodology selected was that published by
Wells and co-workers (1996). (Iosifescu, et al., 1997). This was a two stage process
initially segmenting the image into white matter, gray matter and CSF. The second
stage then further segmented the image into cortical gray matter, subcortical gray
matter, white matter and CSF. This methodology used a priori knowledge of tissue
properties and intensity inhomogeneities to correct for intensity differences in MRI
data. (Iosifescu, et al., 1997).

3.4.2 Image Correction

The next stage in this methodology was to match the atlas brain image onto the
patient brain image. This was undertaken with a linear registration program designed
to correct for differences in size, rotation and translation between the two images.
(Iosifescu, et al., 1997). The linear registration performed an alignment of the two
data sets through a combination of energy minimisation registration techniques. The
outcome of this stage was an atlas brain image linearly registered onto the patient
brain image. (Iosifescu, et al., 1997).

3.4.3 Elastic Matching

The procedures used to elastic match the source and target data (segmented atlas
and segmented patient image) was Dengler‟s regularisation procedure (Dengler et al.
1988; Schmidt and Dengler, 1989).

19
This process used a procedure that “warped” the atlas image onto the patient‟s
image. Due to the nature of the two images, a simple uniform global displacement
(translation, rotation or scaling) would not work. (Iosifescu, et al., 1997)

3.4.4 Application to Lesion Segmentation and Identification

As identified earlier, this technique is not specifically aimed at the segmentation and
identification of either WML or GML. However, it would appear to have the capability
of being applied to this problem.

The results from this study determined that the methodology outlined is able to
measure the volumes of brain structures with a very high level of accuracy. (Iosifescu,
et al., 1997).

This capability could be utilised to assist with the identification of lesion areas by the
lesion itself having an impact on overall brain structure volume. Over a long-term
study, this could be used to track the development of targeted lesion areas.

In the current implementation outlined in this study, some key disadvantages are
however identified. It was found that the most accurate matching was done with
large regularly shaped objects. This limitation would result in the application of this
method to some brain areas being less that optimum due to size.

Certainly, for general application to the issue of lesion segmentation some

modification or development to this methodology would need to be undertaken.

20
3.5 Artificial Neural Networks (ANN)
The main objective of an automated lesion
segmentation methodology is basically just that;
automation, removal of as much interaction and
manual processing as possible and the reduction of
the human-error element of any process.

This study (Goldberg-Zimring, Achiron, Miron,

Faibel, & Azhari, 1998) has applied the use of
artificial neural networks to try and achieve this
objective. The approach undertaken here has
achieved automatic detection of white matter MS
lesions in axial proton density, T2-weighted,
gadolinium enhanced and fast FLAIR brain MR
images.
Figure 3 the original Proton
Density image prior to process
being conducted (Goldberg-
Zimring, Achiron, Miron, Faibel, &
Azhari, 1998)

The general process consists of three stages. Firstly, detection and contouring of all
hyperintense signal regions within the image. Secondly, elimination of false positive
segments by size, shape index and anatomical location and thirdly, the use of an
artificial neural network (ANN) for final removal and differentiation from true MS
lesions. (Goldberg-Zimring, Achiron, Miron, Faibel, & Azhari, 1998).

This methodology outlines four basic assumptions with its processing.

1. In PD, T2-weighted, gadolinium enhanced, and FF-MR images, MS lesions
appear much brighter than the rest of the brain
2. Non-MS regions in the brain, which also produce high signal intensity,
(especially in T2-weighted MR images) such as blood vessels, and
cerebrospinal fluid within the ventricles, have either a relatively very small or
very large (in the case of the ventricles) area
3. MS lesions have a relatively circular shape
4. Most of the MS lesions occur in the periventricular white matter area, and are
rarely seen in cortical regions on MR images. Furthermore, they are typically
located asymmetrically relative to the brain
(Goldberg-Zimring, Achiron, Miron, Faibel, & Azhari, 1998).

Based upon these four assumptions, it was determined that a brain region would be
a possible candidate for an MS lesion if it has a relatively high signal intensity, is
relatively circular in shape, its size is within a predefined range and its location
complies with assumption number four. (Goldberg-Zimring, Achiron, Miron, Faibel, &
Azhari, 1998)

The algorithm itself is applied in three stages (as indicated above).

21
 3.5.1 Detection and Contouring of all Hyperintense
Signal Regions within the Image
Normalisation of the image takes place within this stage
with the application of an adaptive threshold algorithm.
The output from this stage is a set of closed contours
described by arrays of contour data points (see Figure 4).

3.5.2 Partial Elimination of Artefacts (False

Figure 4 the processed Proton
Density image after the first stage
of the algorithm. Note the
presence of artefacts (Goldberg-
Zimring, Achiron, Miron, Faibel, &
Azhari, 1998)
Positives)
The output of this stage is displayed in Figure 5. Area,
perimeter and shape index of each of the contoured
regions from the previous stage is calculated using the
following formulas.
Area: A cross-sectional area bounded by a closed
contour can be estimated by green‟s Theorem in the
plane. (Goldberg-Zimring, Achiron, Miron, Faibel, &
Azhari, 1998)

1
𝐴= 𝑥𝑑𝑦 − 𝑦𝑑𝑥
2
(Goldberg-Zimring, Achiron, Miron, Faibel, & Azhari, 1998)

Perimeter: The perimeter was estimated using

the following

𝑃𝑒𝑟𝑖𝑚𝑒𝑡𝑒𝑟 = 𝑛𝑖=1 (𝑥𝑖 − 𝑥𝑖−1 )2 + (𝑦𝑖 − 𝑦𝑖−1 )2

(Goldberg-Zimring, Achiron, Miron, Faibel, &
Azhari, 1998)

Shape Index: The resemblance of each

segmented shape to a circular shape was
evaluating using the shape index applied by
Gibson et al. (Goldberg-Zimring, Achiron, Miron, Figure 5 the process image after
Faibel, & Azhari, 1998). removal of the artefacts (Goldberg-
Zimring, Achiron, Miron, Faibel, &
Azhari, 1998)
4𝜋 ∗ 𝐴𝑟𝑒𝑎
𝑆ℎ𝑎𝑝𝑒 𝐼𝑛𝑑𝑒𝑥 =
𝑃𝑒𝑟𝑖𝑚𝑒𝑡𝑒𝑟 2
(Goldberg-Zimring, Achiron, Miron, Faibel, & Azhari, 1998)

22
 3.5.3 Final Removal of Artefacts by ANN
The Artificial Neural Network (ANN) is applied at the
final stage to remove the remaining artefacts.

An ANN is a computer algorithm that attempts to

Figure 6 the final Proton Density
image after removal of all artefacts
and final tuning stage (Goldberg-
Zimring, Achiron, Miron, Faibel, &
Azhari, 1998)
describe the biological behaviour of brain neurons
(Goldberg-Zimring, Achiron, Miron, Faibel, & Azhari,
1998). This methodology has selected the Back-
Propagation ANN which uses a form of supervised
learning in a training phase.
During this training phase a set of input patterns close
to the desired output is entered into ANN. The ANN
then adjusts its synaptic weighting to attempt to
closely match the targeted outputs.

For this implementation a set of 40 positively identified MS lesions and 40 positively

identified artefacts were taken from across 20 images. Once the training was
complete, the trained ANN was used for the final sorting of the selected images.

3.5.4 Results
A fully automated algorithm for the detection and segmentation of MS lesions is of
course a very desirable tool for this function. The ANN produces a significant result
over other automated algorithms cover so far; namely it does have the potential for
learning based upon previous experience. The more information provided during the
training phase will ultimately produce a better tool.

With this implementation however, a number of limitations can be observed. The

assumptions identified above produce constraints that may not be suitable for all
possible MRI scans. It makes the assumption that the MS lesions being examined are
brighter than the brain (Goldberg-Zimring, Achiron, Miron, Faibel, & Azhari, 1998).
This would certainly limit the use of this tool in a number of circumstances. As
identified earlier in this paper, the involvement of GML within MS which in more
recent years has been identified as playing a role within MS would not be seen by
this method.

While this implementation would seem to have some significant limitations, this
method does demonstrate the utility of ANN in terms of the lesions segmentation
problem. Further study into this methodology may identify possible future
applications for MS and other relevant medical conditions.

23
4. New Techniques and areas of further
study
4.1 Introduction
Traditional approaches to this problem have seen advancement from fully manual
processes relying on judgment by trained operators to the introduction of either fully
or partially automated techniques.

There have also been some approaches that have taken different directions with the
resolution of this problem. Some studies have been undertaken which look at the
problem of segmentation with the emphasis on determining what is known and
easily identifiable and using that to assist in the determination of the areas or items
of interest in the scan.

4.2 Brain Atrophy

A study conducted to determine if White Matter Hyperintensities (WMH) were
related with sub cortical brain atrophy (Wen, Sachdev, Chen, & Anstey, 2006) has
provided some evidence to suggest that the brain‟s WMH load can be correlated
with atrophy in other regions of interest such as gray matter volume reduction.

This study doesn‟t draw any direct conclusions on any causality to this observation;
however it does raise an interesting line of reasoning for future study or conjecture.

A more recent study (Bendfeldt, et al., 2009) has looked to establishing a stronger
link between WML and changes of gray matter volumes by means of voxel-based
morphometry (VBM).

In this study, two hypotheses are raised;

1. Regional gray matter volume reductions occur predominantly in patients with
increasing WML volumes
2. Patients with both increasing T1 and T2 lesion burden would show volumetric
GM reductions that are qualitatively similar but even more pronounced.
(Bendfeldt, et al., 2009)

The results of this study draw a conclusion that suggests that gray matter volume
reductions are directly related to increase white matter lesion volumes.

Based on the results of these two studies, a simple but potentially effective approach
to the problem of lesion segmentation may be to approach the matter with not so
24
much identifying what is unknown, but identifying what is known and working
backwards from there. It should be noted that both studies do indicate that further
long term follow-up studies are required to further support this conclusion.

4.3 Physical Impairment as a Measure

This study (Charil, et al., 2003) looks at identifying a link between lesion location and
neurological disability in Multiple Sclerosis. The author acknowledges initially that
there is generally only weak correlation between disability and the volume of white
matter lesions (Charil, et al., 2003); however the study was able to determine some
correlation between lesion location and cognitive dysfunction.

The study consisted of a large sample of 452 relapse-remitting MS patients. From

each of the patients a Proton Density, T1 and T2 MRI image were obtained.
Disabilities were measure using the Functional System Scale (FSS) and Expanded
Disability Status Scale (EDSS).

The EDSS scale takes a measurement ranging from 0 (normal) through to 10 (death
due to MS). The FSS scale looks at specific functional systems and includes pyramidal,
cerebellar, brainstem, sensory, bowel and bladder, visual, and mental. They are
graded from 0 (normal) through to 5 or 6 (maximal impairment).

4.3.1 Image Capture

Unlike other methodologies covered within this review, this particular technique
doesn‟t present a unique and specially developed image processing technique. The
technique used within this study to analyse the images from each patient in the
study was INSECT (Intensity Normalised Stereotaxic Environment for Classification of
Tissue), a fully automatic system for the mass quantitative analysis of MRI data with a
focus on the detection of Multiple Sclerosis lesions (Zijdenbox, Forghani, & Evans,
1998).

4.3.2 Data Analysis

Spearman‟s rank correlation coefficient was used to calculate the correlations
between the total lesion load and each disability score (Charil, et al., 2003). Two main
correlation measures were taken; correlation between total lesion load and disability,
and correlation between lesion location and the rate of disease progression.

4.3.3 Results
The analysis of the results from this study demonstrated that a relationship between
lesion site and type of disability does exist. It also offers an explanation for the poor
relationship between lesion load and disability shown in previous studies being a
result of lesions within restricted sites in the white mater (Charil, et al., 2003).

25
4.3.4 Impact on General Lesion Identification
While the results of this study did statistically prove a link between lesion site and
type of disability, it also presents some drawbacks from the perspective of utilising
this as a measure for identification solely for the identification of lesion load. The
measure taken for disability (the EDSS and FSS scales) are both undertaken manually.
While the scale in question and the scope of study is broader than could be
compared to the manual segmentation systems covered earlier in this study, it still
does involve potential for human interpretation and error.

4.4 Conclusion
This section of the review has looked at two techniques that have applications to
indirectly be used to address the problem of lesion segmentation.

Currently, while showing some merit, neither appeared to be entirely suitable at their
respective current stages of development to be used to address the problem as a
whole. Both would however show some suitability for a subject of further study and
research.

26
5. Conclusions
This review has identified a range of methodologies utilised to address the issue of
lesion segmentation within MR images.

While determining the most viable and appropriate methodology is outside the
scope of this paper, a few observations can reasonably be drawn from the material
reviewed.

The requirement of type and number of MR images needed for each methodology
varied. To ensure a methodology remains flexible to the majority of circumstances it
would be a clear advantage to ensure that the methodology doesn‟t require anything
over and above the type or number of images that would normally be taken in
support of patient treatment

Approaches identified that take more novel approaches may provide further scope
for study in the future. Given some of the complex issues involved in segmentation
of lesions across the gray and white matter as well as the segmentation of other
matter contained within the MRI and also taking into account the fact that all
methodologies do present (however small) some aspect of error, an approach that
uses other measures to enhance traditional methodologies may provide assistance to
reduce the level of error to further insignificant levels. Two key areas identified here
were the use of cognitive and physical deficit and the measurement of other brain
matter to help define areas of interest. While based upon the material reviewed,
neither appears to be sufficient to stand as viable lesion segmentation
methodologies by themselves, using them in conjunction with other methodologies
may be an approach to follow.

27
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Images
Figure 1 Example of a normal brain MRI image
Image generated from BrainWeb, http://www.bic.mni.mcgill.ca/brainweb/. (McGill
University, 2006)

Figure 2 Example of a brain MRI image showing MS lesions.

Image generated from BrainWeb, http://www.bic.mni.mcgill.ca/brainweb/. (McGill
University, 2006)

Figure 3 the original Proton Density image prior to process being conducted
Image taken from (Goldberg-Zimring, Achiron, Miron, Faibel, & Azhari, 1998)
Used with permission, Assoc. Prof. Haim Azhari D. Sc., Technion Israel Institute of
Technology, Israel.

Figure 4 the processed Proton Density image after the first stage of the algorithm.
Note the presence of artefacts
Image taken from (Goldberg-Zimring, Achiron, Miron, Faibel, & Azhari, 1998)
Used with permission, Assoc. Prof. Haim Azhari D. Sc., Technion Israel Institute of
Technology, Israel.

Figure 5 the process image after removal of the artefacts

Image taken from (Goldberg-Zimring, Achiron, Miron, Faibel, & Azhari, 1998)
Used with permission, Assoc. Prof. Haim Azhari D. Sc., Technion Israel Institute of
Technology, Israel.

Figure 6 the final Proton Density image after removal of all artefacts and final tuning
stage
Image taken from (Goldberg-Zimring, Achiron, Miron, Faibel, & Azhari, 1998)
Used with permission, Assoc. Prof. Haim Azhari D. Sc., Technion Israel Institute of
Technology, Israel.

31