Network Connectivity in Resting-State fMRI as a Novel

Biomarker in Diagnosing Alzheimers Disease

Daniel Park
Department of Bio and Brain Engineering
Korean Advanced Institute of Science and Technology
August 2nd, 2013
Abstract
This paper presents a novel algorithm for increased
performance of early detection in Alzheimers Dis-
ease (AD) patients using Neural Networks as
a classication tool, as well as reveal newly-
discovered functional pathways among various
regions of the brain that show signicant change
with the progression of the disease.
Resting-state functional Magnetic Resonance
Imaging (rs-fMRI) was used to acquire the vox-
elwise time series in 156 subjects with clinically
diagnosed AD (Clinical Dementia Rating 1.0 = 55,
CDR 2.0 = 22) and Normal (n = 79). The brains
were divided into 116 regions of interest (ROIs)
and the Pearson correlation coecients of pairwise
ROIs were used to classify these subjects (Tzourio,
Rodgers). Error estimation of the classications
was performed with the ve-fold cross-validation
method. An Articial Neural Network (ANN)
was used to classify extracted features from
correlational coecients of functional connections.
With this algorithm, the area under the receiver
operating characteristic curve (AUC) yielded
87.4% classication power, 84.4% sensitivity, and
88.6% specicity between the AD group and the
non-AD group. 25 functional pathways in the brain
that showed statistically signicant changes in AD
patients were found with the Correlation Feature
Selection (CFS) algorithm (Hall).
1 Introduction
Alzheimers Disease is a neurodegenerative disor-
der and also the most common cause of dementia
(Heron). Denitive diagnosis is dicult in clinical
settings because only an autopsy can conrm the
abnormal levels of amyloid plaques and neurob-
rillary tangles in the brain.
Because AD patients experience severe decrease
in their quality of life with the advancement of
the disease, it is imperative to diagnose it at the
earliest stage possible. There are several ways
to diagnose the disease but none yields high
accuracy, especially in the early stages. Although
the deterioration of DMN has been widely studied
among Alzheimers patients, only one study has
shown it to be an eective biomarker for diagnosis
of AD (Chen, Raichle). It is the aim of this
research to improve the performance of such
diagnosis as well as create a connectivity map of
the functional pathways that are correlated with
the disease.
Resting-state data is collected to analyze the
brains connections when a subject is not per-
forming any tasks or responding to any stimulus
during imaging. Rs-fMRI data yields new insights
into how structurally segregated and functionally
specialized brain networks are interconnected with
Blood Oxygen Level Dependent (BOLD) signals
by tracking the hemodynamic response of an idle
brain (Fries). Several studies have proposed a
new perspective on neurodegenerative diseases by
focusing on networks such as Hippocampus Net-
works (HN), the Default Mode Network (DMN),
and the Small-World Network (SWN).
With the recent rise in the use of Support
Vector Machines (SVM), the number of papers
on automated categorization of structural and
functional brain images by dierentiation of im-
ages from two groups has increased dramatically.
The pattern recognition techniques employing
1
machine learning are multivariate and take into
account various biomarkers to help categorize
scans. New rs-fMRI scans of patients can be
compared against the existing training set and can
then be classied as either positive or negative (Li).
Current studies suggest a positive correlation be-
tween the progression of AD and the deterioration
of the DMN (Palop); yet there is almost no litera-
ture on a quantitative approach to measuring the
network connectivity as a biomarker in diagnosing
AD. Utilizing functional connections as features,
the algorithm presented in the paper performs well
in the dierential diagnosis of three dierent forms
of dementia, suggesting the reliability of generaliz-
ing over bigger groups.
2 Materials and Methods
2.1 Human Subjects
Out of 156 test subjects, 79 had been diagnosed
with Subjective Memory Impairment (SMI) but
were treated as the control group and 77 were
placed into the experimental group with AD. Of
the Alzheimers group, 55 subjects had a Clin-
ical Dementia Rating (CDR) of 1.0 and 22 had 2.0.
The control group had a mean age of 67.6 with a
standard deviation of 7.41. For patients diagnosed
with CDR of 1.0, mean age was 76.60 with a stan-
dard deviation of 11.09. The last group with CDR
2.0 was 75.20 with a standard deviation of 7.17.
2.2 ROI Selection
Selecting Regions of Interest (ROI) is necessary
to dene regions which are related to AD. Inde-
pendent Component Analysis (ICA) was used as
an unsupervised clustering algorithm that can
group proximal areas of the brain that show high
correlation with other areas, yet independent. The
Default Mode Network (DMN) includes Posterior
Cingulate Cortex (PCC), Left Lateral Parietal
Cortex (LPC-L), Right Lateral Parietal Cortex
(LPC-R), Left Superior Frontal Gyrus (SFG-L),
and Right Superior Frontal Gyrus (SFG-R).
The ICA problem can be solved by maximizing
the contrast function which can be considered as
an approximate representation of the independence
among the components of the transformed data
(Ashburner). The log-likelihood contrast function
for ICA can be written as
L =
n

i=1
E[ln p
yi
(y
i
)] + ln | det B|,
where E denotes the expectation operator; y
i
is the ith component of y = Bx, i.e., y
i
= b
T
i
x
where b
T
i
is the ith row vector of B; p
yi
(y
i
) is the
probability density function of y
i
.
The ICA problem is solved by maximizing the
equation above and can be changed into the fol-
lowing equation
L
B
= E[g(B)x
T
] + (B
1
)
T
= 0
where g(B) is a column vector dened by
g(B) = [g
y1
. . . g
yi
. . . g
yn
]
T
and
g
yi
(y
i
) = p

yi
(y
i
)/p
yi
(y
i
)
where p

yi
(y
i
) stands for the derivative with respect
to y
i
. Multiplying the partial derivative equation
by B
T
yields the following gradient equation
F(B) = B
T
L
B
= B
T
E[g(B)x
T
] +I = 0
where I is the identity matrix (Lai).
After the ROIs were determined, they were la-
beled according to the Anatomical Automatic La-
beling (AAL) template from Statistical Paramet-
rical Mapping (SPM) (Tzourio-Mazoyer). Of the
116 regions, only 90 were of the cerebellum region,
and the remaining 26 in the cerebrum were dis-
carded due to their anatomical irrelevance to AD
(Greicius).
Figure 1: The brain from dierent angles colored
based on regions from the AAL template.
2.3 Pre-processing
After determining the ROIs using ICA, voxels rep-
resenting Cerebrospinal Fluid (CSF) were excluded
from the nal set of ROIs because they introduced
unnecessary noise. Chang and Glover showed that
2
when both White Matter (WM) and CSF ROIs
were regressed out of the data prior to correlation
analysis, performance increased. The assumption
underlying this method is that the time series from
WM and CSF may carry physiological uctuations
that are similar to those aecting grey matter,
while containing little contribution from neural
activity.
However, in the case of AD, results were better
when only CSF was removed; this may be due to
the fact that AD is a disorder aecting connections
among dierent regions of the brain and aecting
the WM connections. In other words, the number
and length of axons may be of signicance in de-
termining AD in a test subject. From the selected
ROIs, the voxel with the highest Pearson correla-
tion coecient was selected as the root and a mean
time series was calculated from the nearby voxels
of size 5x5x5.
Raw ROI CSF removed Both removed
Figure 2: ROI after pre-processing
2.4 Feature Extraction
Out of the 116 ROIs, 90 non-cerebellum ROIs
were put into a correlation matrix to make feature
arrays for the classication algorithm. Each of
these correlation values from the matrix was put
into an array of features but since the matrix is
symmetrical with respect to the diagonal from
top left to bottom right, there was a total of 4005
features instead of all 8100.
The Pearson Correlation ranges from -1 to
1 with the former indicating a perfect negative
correlation and the latter perfect positive cor-
relation. An absolute value of the correlation
values were taken as features as the sign of the val-
ues are insignicant when used as indicators of AD.
For variables X and Y , the coecient P can be
found with the following formula,
P(X, Y ) =
E(XY ) E(X)E(Y )
_
E(X
2
) (E(X))
2
_
E(Y
2
) (E(Y ))
2
Figure 3: Correlation matrix of the 90 cerebellum
regions.
2.5 Filtering
Out of the 4005 connections between all 90 regions
of the brain, it is clear that not all of them
will prove useful as biomarkers for diagnosing
Alzheimers Disease. With this idea in mind, it is
hypothesized that selecting and using only a sub-
set of the data will produce better results because
the others will act as noise in classication. At
rst, the subset was determined after ltering the
features below a certain threshold but because all
156 patients needed subject-specic thresholds,
this method was inecient and ineective.
The nal idea was to use a Correlation Feature
Selection (CFS) algorithm that evaluates subsets
of features on the basis that good feature subsets
contain features highly correlated with the classi-
cation, yet uncorrelated to each other. The subset
can be found with the following equation,
CFS = max
x{0,1}
n
_
_
n
i=1
a
i
x
i
_
2

n
i=1
x
i
+

i=j
2b
ij
x
i
x
j
_
where x
i
is the set membership indicator function
for the features. The size of the resulting subset
was 25, signicantly smaller than the original 4005.
All 25 were used as features for classication and
yielded higher performance than when using 4005.
3
2.6 Classication
Support Vector Machines
A Support Vector Machine (SVM) is an example
of a supervised, multivariate classication method.
SVMs are supervised because they include a
training step to learn about dierences between
groups to be classied. For this paper, a normal-
ized polynomial kernel is created from normalized
training data (Theodoridis).
Given data vectors x
i
(i = 1, 2, ..., N), the stan-
dard SVM provides an optimal separating bound-
ary (a hyperplane), to assign a label y
i
[1, 1]
to each x
i
by solving the following optimization
problem:
min
w,,b
_
1
2
|w|
2
+c

y
1
=1

i
_
subject to the constraints y
i
(w

(x
i
) + b) 1
i
and
i
0, where c is the penalty parameter.
For the classication algorithm, the following pa-
rameters were used: C = 5.0, L = 0.05, P =
1.0E
12
, N = 0, V = 1, W = 1, and K =
Normalized Polynomial Kernel. They were found
by looping through all the variables in small in-
crements until the accuracy was maximized. The
kernel was chosen in a similar fashion, with the al-
gorithm looping for each kernel and it was shown
that the Normalized Polynomial Kernel performed
the best.
Figure 4: Illustration of the concept used in sup-
port vector machines. The algorithm tries to nd
a boundary that maximizes the distance between
groups. The gure reduces the problem to two di-
mensions for the purpose of illustration only.
Neural Networks.
Articial Neural Network (ANN) is an intercon-
nected group of natural or articial neurons that
uses a mathematical or computational model for
information processing based on a connectionistic
approach to computation. In most cases an ANN
is an adaptive system that changes its structure
based on external or internal information that
ows through the network. In essence, they are
non-linear statistical data modeling or decision
making tools which can be used to model complex
relationships between inputs and outputs or to
nd patterns in data.
Neural networks work with the help of an
algorithm called back propagation in which the
original error caused by random assignment of
weights is reduced by altering the weight of the
most inuential node. ANNs are meta functions in
which the mapping functions in the hidden layer
determine its characteristic.
For the classication algorithm, the following pa-
rameters were used: B = 2, S = 6, R = 0.0,
M = 2, W = 1.004. The activation function was
chosen after looping through each function and the
Radial Basis Function performed the best.
Figure 5: Neural network with one hidden layer.
3 Results
There are two benchmark performance numbers
for the algorithm presented in this paper: the
original paper in Radiology and the diagnostic
accuracy of doctors in clinical settings. The
original paper had 87% accuracy, 85% sensitivity
and 80% specicity (Kloppel). The accuracy of
doctos in clinical settings range from 50% to
nearly 90% and there is no objective criteria for
4
denitive diagnosis (Heron).
The goal of this paper is to develop an algo-
rithm that can objectively diagnose AD from
one fMRI scan. The test was comparing SVM
against ANN, of which was further divided into
four groups, pre - CFS lter, post - CFS lter,
90 ROIs, and 116 ROIs. Sequential Minimal
Optimization (SMO) was used as the classication
algorithm for SVM and a Radial Basis Function
(RBF) was used as the activation function in ANN.
Table 1: Comparison of pre & post-lter of SMO
Data Accuracy Sensitivity Specicity
Pre 90 74.36% 0.744 0.742
Pre 116 66.02% 0.660 0.658
Post 90 82.05% 0.820 0.819
Post 116 75.00% 0.750 0.747
In the SMO group in the table above, the algo-
rithm performed best when the 90 x 90 correlation
matrix was used as features.
Table 2: Comparison of pre & post-lter of RBF
Data Accuracy Sensitivity Specicity
Pre 90 60.26% 0.603 0.600
Pre 116 58.97% 0.590 0.588
Post 90 86.5% 0.819 0.865
Post 116 84.6% 0.846 0.845
In the RBF group in the table above, the al-
gorithm again performed best when the 90 x 90
correlation matrix was used as features. In fact, it
outperformed the Radiology benchmark in speci-
city by 6.5% and equalled in accuracy and sensi-
tivity.
Table 3: Eectiveness of CFS Filter
Group x
2
x
1
% increase P - value
SMO 90 7.69% 10.34 0.0491
SMO 116 8.98% 13.60 0.0491
RBF 90 26.24% 43.54 0.0075
RBF 116 25.63% 43.46 0.0075
A look into the performance of the CFS lter
is shown in the table above. Calculations show
that they have a statistically signicant eect in
increasing the accuracy of the algorithm (Noether).
Table 4: Summary statistics before and after CFS
SMO RBF
Pre Post Pre Post
Mean 70.19 78.53 59.61 85.5
SD 5.90 4.99 0.91 1.34
SEM 4.17 3.53 0.645 0.950
The above table shows the summary statistics
before and after applying the CFS lter on both
SMO and RBF groups. It should be noted that
there were 5 times the number of subjects in this
study than Radiologys, which makes it less likely
to have been overtted and more reliable as a
diagnostic tool in clinical settings.
Table 5: Comparison of pre & post-lter of RBF
ROI # Functional Connection
1x89 Amygdala L x Rectus L
4x32 Angular R x Cingulum Post R
8x58 Caudate R x Hippocampus R
8x70 Caudate R x Olfactory R
27x51 Cingulum Ant L x Frontal Sup Orb R
28x41 Cingulum Ant R x Frontal Med Orb L
28x42 Cingulum Ant R x Frontal Med Orb R
28x56 Cingulum Ant R x Heschl R
28x97 Cingulum Ant R x Temporal Inf L
29x53 Cingulum Mid L x Fusiform L
30x53 Cingulum Mid R x Fusiform L
30x84 Cingulum Mid R x Precentral R
30x108 Cingulum Mid R x Thalamus R
35x36 Frontal Inf Oper L x Frontal Inf Oper R
35x41 Frontal Inf Oper L x Frontal Med Orb L
39x60 Frontal Inf Tri L x Insula R
39x93 Frontal Inf Tri L x Supp Motor Area L
45x104 Frontal Mid Orb R x Temporal Pole Sup R
46x101 Frontal Mid R x Temporal Pole Mid L
51x56 Frontal Sup Orb R x Heschl R
53x57 Fusiform L x Hippocampus L
53x85 Fusiform L x Precuneus L
56x98 Heschl R x Temporal Inf R
58x95 Hippocampus R x SupraMarginal L
60x105 Insula R x Temporal Sup L
The list above includes 25 features extracted
from applying the CFS lter to the raw data and
signify functional connections that are related to
the progression of AD. Aside from the Default
Mode Network, there has not been any studies
showing statistically signicant pathways in the
brain. This novel nding sheds light on new ways
of treating Alzheimers Disease by targeting only
specic networks. The list is not only statistically
signicant but also anatomically relevant, as it in-
5
cludes key areas such as the Hippocampus, Tem-
poral Lobe, and the Thalamus.
4 Discussion
Our results indicate that supervised machine
learning techniques can aid the clinical diagnosis
of AD. The analytical technique presented here
promises to distinguish disease-specic atrophy
from that of normal aging in a standard T1
weighted structural MRI scan. Furthermore, the
study provides evidence that the method can
be developed to correctly dierentiate between
dierent forms of dementia.
Further areas of improvement include increasing
the sample size and having more groups of dierent
CDR in order to increase the classication power.
We can also try dierent lters other than a CFS
on a faster computer to optimize the performance
of the algorithm.
5 Acknowledgement
I would like to thank Dr. Yong Jeong for providing
the opportunity to conduct independent research
over summer and oering helpful suggestions over
the course of the internship. Young Beom Lee was
also extremely helpful in introducing me to the lit-
erature and answering many questions about the
dierent approaches to setting up the tests. This
work was supported by the Korean Advanced In-
stitute of Science and Technology (KAIST), and
specically the Laboratory for Cognitive Neuro-
science and NeuroImaging (CNI). Finally, I would
like to thank all the members of the CNI lab for
making the internship as enjoyable as it could have
possibly been.
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6