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FLORIDA STATE UNIVERSITY

COLLEGE OF ARTS AND SCIENCES

STATISTICAL DATA ANALYSIS OF RESTING STATE FMRI


A STUDY OF NICOTINE ADDICTION TREATMENT

By
ANAHID EHTEMAMI

A Thesis submitted to the


Department of Scientific Computing
in partial fulfillment of the
requirements for the degree of
Master of Science

2016

Anahid Ehtemami defended this thesis on November 28, 2016.


The members of the supervisory committee were:

Anke Meyer-Baese
Professor Directing Thesis

Xiaoqiang Wang
Committee Member

Peter Beerli
Committee Member

The Graduate School has verified and approved the above-named committee members, and certifies
that the thesis has been approved in accordance with university requirements.

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ACKNOWLEDGMENTS
Firstly, I would like to express my sincere gratitude to my advisor Dr. Anke Meyer-Baese for the
incredible support of my study and related research, for her patience, motivation, and immense
knowledge. Her guidance helped me in all the time of research and writing of this thesis. I could
not have imagined having a better advisor and mentor for my research.
Besides my advisor, I would like to thank Dr. Xiaoqiang Wang and Dr. Peter Beerli for giving
me this honor and serving as my committee members.
I thank Dr. Olmo Zavala-Romero for the stimulating discussions and continuous help and support. Also, I thank my friends who have been an important part of my life for their understanding
and encouragement in all stages of my life.
Last but not the least, I would like to thank my dear mother for her endless love, support, and
encouragement without whom, I would not be able to accomplish my goals and fulfill my dreams.

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TABLE OF CONTENTS
List of Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

List of Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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List of Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii


Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . viii
1 Introduction
1.1 fMRI Background . . . . . . . .
1.1.1 The Physics of fMRI . .
1.1.2 Uses of fMRI Imaging in
1.2 Experiment Background . . . .
1.2.1 Experiment Design . . .

. . . . . . . .
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Neuroscience
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2 Methods
2.1 Preparing the Data . . . . . . . . . . .
2.1.1 Preprocessing Tools . . . . . .
2.1.2 Statistical Parametric Mapping
2.2 Region Of Interest Analysis . . . . . .
2.3 Machine Learning in Medicine . . . . .
2.3.1 Support Vector Machine . . . .
2.3.2 Decision Trees . . . . . . . . .
2.4 Cross Validation . . . . . . . . . . . .
2.5 Visualization . . . . . . . . . . . . . .

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3 Results and Discussion


3.1 Results . . . . . . . . . . . . . . . . . . .
3.2 Challenges . . . . . . . . . . . . . . . . .
3.2.1 Training Sample Size . . . . . . .
3.2.2 Reliability of Resting-State fMRI
3.2.3 Reproducability . . . . . . . . . .
3.2.4 Class Size . . . . . . . . . . . . .
3.3 Extensions . . . . . . . . . . . . . . . . .

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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Biographical Sketch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

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LIST OF TABLES
2.1

Final Matrix - Including all data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

3.1

SVM model diagnostic table using ranked features . . . . . . . . . . . . . . . . . . . . 23

3.2

SVM model diagnostic table using random features

3.3

Decision trees model diagnostic table using ranked features . . . . . . . . . . . . . . . 24

3.4

Decision trees model diagnostic table using random features . . . . . . . . . . . . . . . 24

3.5

Model Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

. . . . . . . . . . . . . . . . . . . 23

LIST OF FIGURES
1.1

When a powerful magnet is present, the atoms normal spin changes and they all align.

1.2

A radio frequency wave tips the atoms for a short period of time. . . . . . . . . . . . .

1.3

In the absence of the radio frequency wave, the atoms return to the previous alignment
but with different speeds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Hemodynamic Response - Neural activity causes the initial dip and blood is sent to
that region at a higher rate in response to the increased demand.[1] . . . . . . . . . .

fMRI Scans - Images obtained from a single subject. Horizontal planes captured with
different z values for one xy coordinate. . . . . . . . . . . . . . . . . . . . . . . . . . .

2.1

Posterior view of the brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.2

Superior view of the brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.3

Sagittal view of the brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.4

SPM GUI - Tool for preprocessing and limited visualization of fMRI images. . . . . . 10

2.5

Realignment - Using the 6 parameters spatial transformation to align the time series
of images. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

2.6

Sample image after coregistration - Using both structural and anatomical images to
increase the mutual information. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

2.7

Comparing fMRI Images after smoothing with different values for FWHM. For left
side images FWHM is set to [8 8 8] and for the right side images it is set to [2 2 2]. . 14

2.8

Brodmann areas shown in different colors - Dots are regions of interested with the
diameter of 5 mm. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

2.9

White matter of the brain. The ROIs are placed on the areas that can retrieve the
most useful information, white matter and cerebrospinal fluid. . . . . . . . . . . . . . 16

2.10

The symmetric ROI to ROI matrix of one subject after preprocessing the images. . . 17

2.11

Graphical representation of the decision tree. . . . . . . . . . . . . . . . . . . . . . . . 20

2.12

Displaying processed images for one patient using SPM - Files with .nii extension can
be used as input for spm. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

1.4

1.5

vi

LIST OF ABBREVIATIONS
fMRI
BOLD
NAC
NIfTI
SPM
PET
FWHM
ROI
SVM
CV
LOOCV
SNR

functional Magnetic Resonance Imaging


Blood Oxygenation Level Dependent
N-acetylcysteine
National Incubator Farm Training Initiative
Statistical Parametric Mapping
Positron Emission Tomography
Full-Width Half-Maximum
Region of Interest
Support Vector Machine
Cross Validation
Leave One Out Cross Validation
Signal to Noise Ratio

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ABSTRACT
Statistical analysis methods are used by neuroscience researchers to obtain information from functional magnetic resonance imaging data to learn more about brains. Machine learning, more specifically pattern recognition and classification tools are frequently used to find regularities in brain
scans of different people and/or different stages of an illnesses to understand how functional and
anatomical structures of the brain change under different circumstances. Studies have confirmed
that nicotine dependence have impacts on human behaviors such as emotions and motivations,
ability to focus, and recalling information which proves nicotine dependency alters brain networks.
This study was conducted to investigate this alterations and to test if they can be used for
fMRI data classification. The two sets of data that are used are fMRI brain scans from before and
after a nicotine addition treatment on patients. Some of the patients received placebo instead of
the real treatment and the goal is to develop a method to be able to classify new patients based on
receiving the real treatment or the placebo.
The success of the two classification methods, support vector machine and decision trees on the
processed data, was not significant and they should not be considered as reliable methods for use
in medical diagnosis. This might be due to the different challenges that are present in analyzing
fMRI data such as feature to instance ratio, signal to noise ratio and redundancy.

viii

CHAPTER 1
INTRODUCTION

Nicotine dependence has been one of the concerns of human kind for a long time because of the
severe and harmful effects that it has on people. Smoking cessation improves health and thus many
efforts has been made in order to facilitate withdrawal and prevent relapse.
In this study, statistical approaches are applied to a data set provided by Amsterdam Center
for Addiction Research with the hope of discovering more about the effects of smoking, a specific
treatment and how the treatment affects the possibility of relapse for the patients.

1.1

fMRI Background

Living brains show activity unceasingly independent of external stimuli or tasks. This activity
can be observed by Magnetic Resonance Imaging machines through a procedure called functional
MRI. Doing specific tasks such as moving fingers or more complicated cognitive tasks such as
speaking or comprehending spoken words activates different parts of the brain. This activity can
be located and measured by non-invasive method of fMRI which more commonly uses the BloodOxygen Level Dependent (BOLD) contrast. Furthermore, fMRI reveals functional connectivity
network in the brain.[2] Functional connectivity is the level of communication between different
regions of the brain.

1.1.1

The Physics of fMRI

BOLD contrast imaging is based on differences of blood flow rate in the brain. [3] The areas
with more neural activity consume more oxygen which first results in a quick decrease in blood
oxygenation level (Initial dip). The area then receives blood at a higher rate (hemodynamic response) to overcompensate the increased demand. This leads to an increase in oxyhemoglobin and
deoxyhemoglobin molecules in those areas and this phenomenon has a magnetic signature that the
machine can determine. [4] The MRI machine uses powerful static electromagnetic fields to align
the oxygen atoms.

Figure 1.1: When a powerful magnet is present, the atoms normal spin changes and they
all align.

Then radio frequency waves reorient the nuclei of the atoms (magnetic resonance).

Figure 1.2: A radio frequency wave tips the atoms for a short period of time.

When the interfering waves are stopped, atoms return to their aligned position because of the
magnetic field and release the energy that is stored in them.

Figure 1.3: In the absence of the radio frequency wave, the atoms return to the previous
alignment but with different speeds.

MRI machines pick up this energy. Oxygen rich areas can release up to 20 percent more energy
than the rest of the tissue and these differences are detected and interpreted into images. [5]

1.1.2

Uses of fMRI Imaging in Neuroscience

Functional MRI reveals the patterns of brain activity during specific tasks or just resting state
and associates different brain regions to the specific stimuli (brain mapping). Analyzing the functional networks also reveals the neural interaction in different regions which are temporarily correlated. This technology is used by researchers in different fields such as biology, neuroscience
and medicine to study the origin of different neurological or psychiatric diseases or psychological
disorders and observe their impacts on the brain and allows them to explore new treatments.

1.2

Experiment Background

Smoking tobacco releases nicotine into the blood stream and it increases neurotrasmitters in
brains. One of these neurotransmitters is Dopamine, an organic chemical that has different roles

Figure 1.4: Hemodynamic Response - Neural activity causes the initial dip and blood is
sent to that region at a higher rate in response to the increased demand.[1]

in the brain and is strongly associated with pleasure and the reward center of the brain. That
is why the main purpose of drug abuse is to boost the release rate of the naturally occurring
neurotransmitter, Dopamine. In addition to be extremely addictive, Nicotine has many other
harmful effects on human body. Disruption of natural neurotransmitters in the brain can cause
symptoms such as lightheadedness, insomnia, tremors and more. It also increases heart rate and
blood pressure which potentially can increase the risk of heart attack, stroke, and aneurysm. It
also has harmful effects on other organs such as eyes, bones and the reproductive system. [6]
It is reported by Centers for Disease Control and Prevention that the rate of mortality in
smokers in the United States is almost three times higher than people who has never smoked.
Fighting against Nicotine addiction and reducing the negative side effects on individuals as well as
nations has become one of the priorities of governments.[7] In a report released by Food and Drug
Administration, every year, millions of dollars are allocated to research studies related to nicotine
addiction.

1.2.1

Experiment Design

Test subjects of this double-blind study are 39 patients with Nicotine addiction. Patients
agreed to undergo a treatment with N-acetylcysteine (NAC), a compound with many uses including

Figure 1.5: fMRI Scans - Images obtained from a single subject. Horizontal planes captured with different z values for one xy coordinate.

treatment of psychological addictions or compulsions, for a week. Some studies suggest that NAC
can be a promising new treatment option specifically for prevention of relapse in nicotine dependent
individuals. From all patients, 20 were randomly selected to receive placebo instead of NAC.
Functional and anatomical scans were obtained from all patients before and after the treatment.
Scans were performed while patients were in resting-state to eliminate any external stimuli. Resting
state is when subject is asked to not perform any tasks and stay awake and keep their eyes closed
so fMRI can measure the level of spontaneous brain activity.
Approximately 200 images were obtained from each subject. The acquired data consists of
2 sets of T1-weighted high resolution pictures with spatial dimension of 240x240x220 and voxel
size of 1 mm and 1 temporal dimension which is used for anatomical analysis and T2-weighted

low resolution images with spatial resolution of 80x80x37 and voxel size of 3 mm for studying the
functional connectivity in the brain. For each patient, one set of images are obtained before and
one set after the treatment.
Hypothesis in this research is that machine learning methods can successfully recognize the
subjects that have been given the real treatment which not only confirms that NAC aids nicotine
withdrawal, but also proves that it impacts the functional connectivity of the brain. Studying
the impacted regions will help to understand how nicotine affects the brain and possibly assists
developing new and better treatments for it. [8]

CHAPTER 2
METHODS

Some preprocessing is necessary before fMRI data is useful for further analysis. All the steps are
mentioned and explained in chronological order.

2.1

Preparing the Data

Functional MRI data consists of images from the brain and these images are not error-free. To
be able to use machine learning methods on this type of data, images need to be processed and
converted to vectors. Statistical Parametric Mapping (SPM) are processes that apply algorithm on
voxel based images to do corrections such as realigning, coregistration, and normalization.
The data type for fMRI images is NIfTI (Neuroimaging Informatics Technology Initiative).
NIfTI files are designed to be processed by many data analysis tools and can be directly used in
MatLab, Java, R and others.
Values that remain the same throughout this analysis are:
Number of subjects = 39
Number of sessions per subject = 2
Repetition time = 2.3 seconds
Number of slices per subject = 37

2.1.1

Preprocessing Tools

FEAT is an open source tool with user interface that runs on linux and is used for high quality
model based fMRI data analysis. FEAT has set defaults for all the possible options to make it more
user friendly. It uses multiple regression to create a model of the brain activities based on the data.
FEAT is mostly used for low level analysis (analysis of data for each session) and for anything more
complicated (combining first level analyses or analysis across subjects) FLAME package should be
added. The input for FEAT should be a 4D image rather than multiple 3D images. The fourth

dimension is for the time. The other open source tool that is frequently used for medical imaging
data analysis is called SPM which will be discussed later.

Figure 2.1: Posterior view of the brain

Figure 2.2: Superior view of the brain

2.1.2

Statistical Parametric Mapping

In order to remove the noise and prepare the data for fMRI analysis, the images were preprocessed using Statistical Parametric Mapping. SPM is produced by Wellcome Department of
Imaging Neuroscience at University College London for analyzing brain images from fMRI or PET
scans and can be used in MatLab.( SPM is free but distributed under the terms of the GNU General Public License as published by the Free Software Foundation). The input format for SPM
is multiple 3D images and the support for 4D images is very limited. Noise or error might be
produced because of the unwanted head movements during the scanning process. Also every brain

Figure 2.3: Sagittal view of the brain

has a slightly different shape and size from the others. To do comparisons the images need to be
normalized first. [9] Functions that are used in first level fMRI data analysis:
spm slice timing
spm coreg
spm preproc
spm fmri design (Assembles a design for fMRI studies)
The outputs of SPM are ANALYZE files such as img and hdr. However it is also possible to
modify SPM to get outputs in NIfTI format.

%Loading and reading files


[P,filter]=spm_select(Inf,.*\.img$,Select Images);
Vols = spm_vol(P);
Images = spm_read_vols(Vols);
[Y] = spm_get_data(Vols,XYZ);%get the data
%To write data as new images
Vol = spm_create_vol(Vol, varargin)
spm_write_vol(mean_img_Real, meanMat);%meanMat is the matrix the data is written in

Figure 2.4: SPM GUI - Tool for preprocessing and limited visualization of fMRI images.

Realignment.

Functional MRI scans include several images that are obtained in specific

intervals. During the process, the subject may have involuntary movements which although are
not significant, still play a destructive role in the analysis. To counteract this, SMP can realign
the images using a least squares method and a 6 parameter spatial transformation. All images are
selected for reslicing except the first image which remains in its original place. After realignment,
a mean image is produced which will be used in coregistration and the data is saved in a text file.

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Since images are likely to have different patterns of zeros from where it is not possible to sample
the data, the whole time series should be considered for sampling voxels even if they are outside
the original images.

Figure 2.5: Realignment - Using the 6 parameters spatial transformation to align the time
series of images.

To go through all subjects, a batch is created for one subject and then is sent to a loop for 39
subjects.
clc;
clear all;
global Defaults; %Loading SPM defaults for functions
Defaults = spm_get_defaults;
spm_jobman(initcfg)
load realign_batch
matlabbatch{2}.spm.util.imcalc.outdir = {NicotineStudy\all_Data}
all_images = dir(s*.img);
for i=1:10:length(all_images)-10
for j=i:i+9
names{j,:} = [pwd / all_images(j).name];

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end
matlabbatch{1}.spm.spatial.realign.estwrite.data{1} = names;
matlabbatch{2}.spm.util.imcalc.output;
= sprintf(mask_%g.img,i);
output_list = spm_jobman(run,matlabbatch);
end
To reach each specific voxel:
Inv = inv(Vol.mat);
coordinate_in_voxel = Inv(1:3,:)*[coordinate_in_mm ;1];

Coregistration.

Coregistration is done based on the interpolation method defined by Col-

lignon et al. between structural and functional images with the mean image produced in the first
step as the reference image and structural image as the source.
There are different options for registration. To find the parameters that maximize or minimize
the objective function, suitable function must be selected. Here, Normalized Mutual Information
function is selected which is used for inter-modal registration. Also, tolerance for the differences
between successive estimates of the parameters should be set.

%Coregistration
clear matlabbatch
%Specify the reference file
matlabbatch{1}.spm{1}.coreg.estimate.ref = {["Path of the mean image"]}
%Specify files to transform
matlabbatch{1}.spm{1}.coreg.estimate.source = {["Path of the structural image"]}
%Run batch
spm_jobman(run,matlabbatch);

Due to speed-accuracy trade off and considering the large volume of data, tolerance for all parameters are set to 0.02. [10]

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Figure 2.6: Sample image after coregistration - Using both structural and anatomical
images to increase the mutual information.

Segmentation and Normalization.

This function of SPM segments and bias corrects the

images. Normalizing the images to a standard space (mapping the grey matter to a grey matter
reference) is done in order to eliminate the effects of tissues other than brain. Bayes rule uses
the priors and tissue type probability (according to the voxel intensity) to provide the posterior
probability. In this research the default template of SPM is used for the tissue probability map.
Normalization in version 12 of SPM can be done within the segmentation routine. Check reg
function was used repeatedly to make sure after the spatial normalization the images are aligned
with the template. For all voxel x y z vector of (3, 3, 3) is used. The most accurate function
considering the speed of processing the data that is used in this normalization is 4th degree Bspline, a piecewise polynomial function of degree 4 used for interpolation. Each subjects vector of
values was normalized to have 0.4 as mean and standard deviation of 1.

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Smoothing.

To blur the images and remove details and noise, smoothing function is applied

on the images. The FWHM of the Gaussian smoothing kernel for this experiment was set to be 5
millimeters which is commonly used for fMRI data. Overusing the smooth function will result in
significant data loss.

Figure 2.7: Comparing fMRI Images after smoothing with different values for FWHM.
For left side images FWHM is set to [8 8 8] and for the right side images it is set to [2 2
2].

2.2

Region Of Interest Analysis

As the dimensionality of the data set increases, the performance of classifiers are improved up to
an optimal point. After the optimal point, if the dimensionality is increased but no new instances
are added to the data set, the performance of classifiers begins decreasing. To reduce the risk of
overfitting due to the curse of dimensionality, instead of using the entire image we have to perform
dimensionality reduction either by using feature selection, or feature extraction approaches. [11]

14

Regions of interest analysis is a method of feature selection which provides a statistical map
of the images for further processing and eliminates features that are uninformative. Regions of
interest can be selected anatomically or functionally. To define the ROIs it is important to know
if the subjects are studied individually or being compared to each other. To analyze ones data
individually, it is possible and encouraged to use more complex designs such as factorial designs
based on each subjects macroanatomy such as gyral anatomy. The other method is to use a set
of predefined anatomical ROIs for all images when comparison is done across subjects. Since the
macroanatomy of each subject is slightly different from the others and therefore it is impossible to
have spatial normalization, it is very unlikely that individually defined ROIs for different subjects
completely align. [12]
In this study ROIs are selected anatomically based on Brodmann areas of the brain. In Brodmann template, brain is divided into four parts: frontal lobe, parietal lobe, temporal lobe, and
occipital lobe. In general, information is sent from the frontal parts of the brain to the backside.
That is why the frontal areas generally have lower numbers in Brodmann template and also numbers
of most of the areas with the same cognitive functions are in sequence which makes it convenient
for us to use for analyzing the functional connectivity of different regions. [13]

Figure 2.8: Brodmann areas shown in different colors - Dots are regions of interested with
the diameter of 5 mm.

15

SPM12 implements Guassian Random Field Theory for small volumes on the selected atlas
and hundreds of thousands of voxels are reduced to more manageable and tractable regions that
are placed on the white matter and cerebrospinal fluid of the brain which matter while analysis
the functional connectivity. To cover the entire images, mean BOLD time series for each patient
is extracted for 137 regions and each region is a circle with the diameter of 5mm. Therefore for
each patient we have a 137x137 matrix consisting of Pearsons correlation coefficients of each two
regions. Correlation coefficients are considered features and are used as input to the classification
methods. However, since the matrix is symmetric, only the upper-triangular matrix is used. The
sampling distribution of Pearsons r is not normal, so in order to normalize the distribution, Fisher
z-transformation is applied to the correlation coefficient matrices before using them as inputs.

Figure 2.9: White matter of the brain. The ROIs are placed on the areas that can retrieve
the most useful information, white matter and cerebrospinal fluid.

16

Figure 2.10: The symmetric ROI to ROI matrix of one subject after preprocessing the images.

%To transform images to matrices to be used in classification models


%Correlation coefficient r
%X and Y are features
%can be written as: r = corrcoef(X, Y)
%which is MatLabs predefined function for
r = cov(X, Y)./(std(X)*std(Y));
%Fishers z-transformation of r
z = 0.5*log((1+r)./(1-r));
Because of the massive number of features, it is possible to use a method for reducing the
number of features. Feature ranking is a method to find the significant features by assuming each
value is independent and compute a two way t-test. This returns the most significant features
and eliminates the rest. Then the machine learning models were trained with the ranked features.
Random featuring is another method which generates a smaller but randomized subset of the
features.

17

%Different method of feature reduction


[I, Z] = rankfeatures(trainX, tY);
[I, Z] = randfeatures(trainX, tY);
The result of running classification models with these two methods of feature reduction are
slightly different.
Description of the final matrix including all subjects:
Table 2.1: Final Matrix - Including all data

2.3

Name

Size

Bytes

Class

DOF
SE
Z
names
names2
regressors
xyz

1x39
39x137
137x137x39
1x137
1x137
1x1
1x137

312
42744
5855928
26498
26498
93960
18632

double
double
double
cell
cell
struct
cell

Machine Learning in Medicine

Researchers are trying to expand the usage of machine learning techniques on biomedical data
to build analytical models. Although, it still is very cautiously used. If the techniques are properly
developed and validated, they can be used to confirm diagnoses made by medical professionals
to reduce human error, or even fully replace the involvement of human in making near perfect
diagnoses which would significantly reduce the costs of healthcare for patients. [14] A classification
model is basically basically trained to model the relationship between features and the class label
(y = f(x)).

2.3.1

Support Vector Machine

Support vector machines is a supervised learning method that uses the training data for classification and regression analysis. Based on the training data and the model that is obtained using
SVM, new instances can be classified into the existing classes yi {-1, 1} in the training (predicting) data.[15] SVMs can process high dimensional data well so they are frequently used for
analyzing fMRI data and are proven to be working well. [16] Fitcsvm is a predefined function in
MatLab which trains and cross validates a SVM model. This function is used for moderately high

18

dimensional data and requires the features as input and a character vector assigned to the response
variable. Fitclinear function is also another classification model for binary learning but it can be
used for even higher dimensional data. [17] [18]
trainX = X(trainIdx,:);
testX = X(testIdx,:);
tY = Y(trainIdx,:);
SVMModel = fitcsvm(trainX(I,:),Y(trainIdx),BoxConstraint,1,...
KernelFunction,linear,ClassNames,{pla,nac});

2.3.2

Decision Trees

Another supervised learning method is Decision Trees which build a graph with branches (decisions) that covers all the possible outcomes. Each leaf in a decision tree is one of the possible
classes. Decision trees are not good methods to use for high dimensional data since too many
features decrease the effects of the important decisions (important features) thus the decisions will
not be accurately made. [19] Dimensionality reduction which means mapping the data to a space
with lower dimension is a common approach to this problem in which eliminating irrelevant features
makes the data more suitable.
%Define the classification tree
dtree = fitctree(trainX(I,:),Y(trainIdx));
pred = predict(dtree, testX(I,:));
%Text description
view(dtree);
%Graphical tree
view(dtree, mode, graph);
Decision tree for classification
1. if x2192<0.0848326 then node 2 elseif x2192>=0.0848326 then node 3 else pla
2. class = nac
3. if x2462<0.253133 then node 4 elseif x2462>=0.253133 then node 5 else pla
4. if x4<-0.18458 then node 6 elseif x4>=-0.18458 then node 7 else pla
5. class = nac

19

6. class = nac
7. class = pla

Figure 2.11: Graphical representation of the decision tree.

2.4

Cross Validation

Cross validation is a technique that is used to validate the results of statistical analysis. Here CV
is used to estimate the accuracy of the classification methods. To train the classifying algorithms in
this study, the entire data set is used. Leave-One-Out-Cross-Validation is a type of cross validation
in which 38 patients are considered the training data set and the testing set is the remaining patient
and this process is repeated for all patients. For k folds, the total number of subjects is divided by
k to form mutually exclusive subsets. In this study, the training data set includes: D1 ... Dk 1
and one subset is used for testing. Therefore, accuracy is the number of successful classification
attempts divided by the number of instances. Accuracy is tracked using a performance tracker in
MatLab. [20]

20

Figure 2.12: Displaying processed images for one patient using SPM - Files with .nii
extension can be used as input for spm.

cvFolds = cvPartition(nsubs, leaveout)


k = 10; %Number of folds
cp = classperf(Y); %Performance tracker
/*
Here classification method is applied for all subjects.
*/
accuracy = cp.CorrectRate;

2.5

Visualization

There are many different, open source tools that can be used for visualizing fMRI images
such as BrainNet, [21] MRIcron, and AFNI which help researches have a better understanding
of the data and can help neuroscientists discover more about the functionality of regions of the
brain. Although each tool or package may not be the ultimate tool for fMRI visualization and

21

a comprehensive package is yet to be developed. The figure of the Brodmann areas of the brain
which shows where ROIs are located is created by BrainNet Viewer. [22] For this research, the
visualizations are created using MRIcron or automatically generated by SPM.
There are several extensions for all versions of spm such as Wrap2 and Anatomy developed by
other organizations which work well for visualizing fMRI images.

22

CHAPTER 3
RESULTS AND DISCUSSION

The aim of conducting this study was to observe possible regular patterns of functional connectivity
changes in nicotine dependent patients who were treated used NAC. This could reveal more about
addiction, treatments, and their impact on brain and could potentially assist in developing new
ways for diagnosis and treatment of similar cases. However, the attempt to use the existing data
for classification of new subjects with the methods that were applied in this study, failed. There
are several possible reasons which will be discussed later in this chapter.

3.1

Results

Using the 137x137 matrix using ranking feature method for all subject as input for classifying
algorithms, I tried to classify the remaining subject. This was done 39 times, once for each subject
and the final accuracy of the model is the average of the success of all the classification attempts.
Using support vector machine algorithm, the model could only predict with 0.4615 accuracy which
is less than null hypothesis.
Table 3.1: SVM model diagnostic table using ranked features

Classifier
Output

1
0

True
1
9
11

State
0
10
9

Table 3.2: SVM model diagnostic table using random features

Classifier
Output

1
0

23

True
1
9
11

State
0
10
9

Moreover, decisions tree model was not significantly better and could only classify the subjects
with 0.5128 accuracy. Current models are not reliable to be used without further improvements.
Table 3.3: Decision trees model diagnostic table using ranked features

Classifier
Output

1
0

True
1
11
9

State
0
10
9

Table 3.4: Decision trees model diagnostic table using random features

Classifier
Output

1
0

True
1
9
11

State
0
10
9

I have tried the classifying models with different options and you can see the accuracy for each
run here.
Table 3.5: Model Performance
SVM
DT

Ranked features
0.4615
0.5128

Random features
0.4615
0.4872

All features
0.5128
0.5641

The SVM models was tested using fitclinear which trains a linear classification model for binary
learning. This function can be used on full or sparse predicting data and in high dimensions. Also,
fitcknn for the k-nearest neighbor classifier was used on the same data. However, the results did
not show any significant improvement.

3.2

Challenges

There are several possible reasons for the low accuracy of the classification models. In addition
to extremely high ratio of feature-to-instance and low SNR, there are more substantial difficulties
which I will discuss some of them here.

24

3.2.1

Training Sample Size

Determining how many training samples are required for a classifier (learning curve) depends on
several issues such as the classification method, the complexity of it, and how far the classes are from
each other. As a general rule, the accuracy of a classifier with infinite number of samples is usually
better than a classifier with n number of samples. However, it is possible to get a good model even
with a relatively small sample size. Clearly, a larger sample size means having scans done on more
subjects. This increases the cost of the experiment as well as slowing down the performance of
classification models. There are some suggestions which can help estimating the minimum required
sample size. It is suggested that the number of subjects should be at least six times the number of
features and at least three times the number of features per class. In conclusion, it is highly likely
that the sample size for this experiment is not large enough to produce a good classifying model.
However, it is not enough to only have a good classifying model. The performance of the model
also has to be validated. In case there was more data available, one could measure a small number
of new cases and observe the improvement and repeat this until desired accuracy is achieved. One
of the difficulties in this particular experiment is the massive number of features.

3.2.2

Reliability of Resting-State fMRI Data

Many studies have been conducted in order to assess the reliability of resting-state fMRI data.
One study that was done on a subject over an extended time period with several fMRI scans
suggests that there are 14 unique resting-state brain networks. Most of these networks were close
to the subjects average network and the average network of multiple subjects. However, executive
function networks and BOLD signals in executive networks have the most reproducibility among
all. Examples of executive functions include attention control and problem solving.

3.2.3

Reproducability

Reproducability is the ability to redo the entire experiment and get the same results and it is
one of the principles of the scientific method. Reproducability of an experiment cannot guarantee
that the experiment is right, but without it, the results are not reliable. Many scientists nowadays
believe that without reproducability of the data and results, the experiment cannot be trusted. [23]

25

The externally directed networks or resting state networks are the least reproducible because
of the unrestrained conditions. This means random thoughts while people are not engaged in an
attention demanding task, can affect the brain networks heavily. [24] [25]

3.2.4

Class Size

To develop an effective predicting model, most suitable features should be selected and assigned
to each class. Then the accuracy is based on the performance of the model on the test data. However, a general performance accuracy for a predicting model does not contain all the information.
It is better to have performance accuracy assessed for each class in the data set and a general error
rate can be estimated using the proportions of each class. Also, the size of the data set for each
class should be large enough to produce an effective predicting model. In a data set, it is possible to
have sufficient number of subjects for one class and only a few for another. Having a small sample
size will not give the model enough features to use. [26]

3.3

Extensions

Machine learning methods have proved to be reliable and useful in diagnostics. More specifically
SVM and fMRI which have been studied several times. One of the famous studies that has used
SVM on fMRI data of schizophrenic patients has produced a model with an accuracy of over 90
percent.[27] Even though the results that are produced by this study are not desirable, it is still very
likely that some changes improve the accuracy significantly. There are many areas of this research
that can still be developed and expanded. The primary step perhaps should be preprocessing the
images. There are many functions applied on the data set in the preprocessing stage of fMRI data
analysis by SPM in this study and this may impact the results in a negative way. Another toolbox
that is commonly used for fMRI data preprocessing is FSL [28] which can be explored. Choosing
the features is another important part of this study. I have chosen to use 137 ROIs based on
Brodmann Atlas as my features but there are other methods of selecting features for fMRI such as
spectral cluster. [29]

26

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29

BIOGRAPHICAL SKETCH
Anahid Ehtemami was born in Iran. After finishing high school, she moved to Malaysia to study
computer science - software engineering at Asia Pacific University. She then moved to the United
States to pursue graduate studies at the Florida State University with a focus in machine learning
and data mining.

30