This document describes a study investigating structural-functional correlations in the default mode network and other networks in schizophrenia patients compared to healthy controls. The study uses structural MRI to generate gray matter maps and independent component analysis of fMRI data to identify functional networks. Correlation analysis is then performed to examine the relationship between structural and functional maps across the whole brain. Results show weaker structural-functional linkage in schizophrenia patients, particularly in the default mode network, suggesting disrupted brain connectivity in the disorder.

1. Ding Nie
A Method to Investigate Structural-Functional
Correlations in the Default Mode and other
Networks: Applied to Schizophrenia
12/16/2009 1/22

2. Overview
Motivation
Default mode network
Methods
Computing structural gray matter maps
Computing functional maps using ICA
Correlation analysis
Results
ICA maps of interest
Histogram of correlations
Spatial map results
Discussion
Future work
12/16/2009 2/22

3. Motivation
Structural magnetic resonance imaging (sMRI) and
functional magnetic resonance imaging (fMRI)
analyses are typically performed separately
Previous studies only examine the localized
correlation between sMRI and fMRI
Previous research do not explore inter-correlations
of structural & functional data across the whole brain
In our recent study we introduced methods to
explore structural-functional correlations across the
whole brain [1]
[1] A. Michael, S. Baum, T. White, O. Demirci, N. C. Andreasen, J. M. Segall, R. E. Jung, G. D. Pearlson, V. P. Clark, R. L. Gollub, S.
C. Schulz, J. Roffmann, K. O. Lim, B. C. Ho, H. J. Bockholt, and V. D. Calhoun, "Does Function Follow Form?: Methods to Fuse
Structural and Functional Brain Images Show Decreased Linkage in Schizophrenia," NeuroImage, In Press.

4. Main Result from that Study
In this study we investigated
the interconnection of task-
related fMRI data and gray
matter volumes across the
whole brain
Used GLM method to construct
the task related functional
activation map
From the histogram of
structural-functional correlations
it was seen that linkage between
strucure and function was
weaker in schizophrenia patients
(SZ) than healthy controls (HC)
In this study we are interested
in the structural linkages to the
default mode network (DMN)
-1 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1
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Correlation
#ofCorrelations
Gray Matter Correlation with Sensory Motor Task (HC - SZ)
-1 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1
0
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x 10
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Correlation
#ofCorrelations
Gray Matter Correlation with Sensory Motor Task
HC
SZ
-1.0 -0.8 -0.6 -0.4 -0.2 0.0 +0.2 +0.4 +0.6 +0.8 +1.0
Correlation
3x108
2.5
2.0
1.5
1.0
0.5
0.0
6x106
2.0
-2.0
-4.0
#ofCorrelations
(a)
(b)
HC - SZ
-1 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1
-10
-8
-6
-4
-2
0
2
4
6
8
x 10
6
Correlation
#ofCorrelations
Gray Matter Correlation with Sensory Motor Task (HC - SZ)
-1 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1
0
0.5
1
1.5
2
2.5
3
x 10
8
Correlation
#ofCorrelations
Gray Matter Correlation with Sensory Motor Task
HC
SZ
-1.0 -0.8 -0.6 -0.4 -0.2 0.0 +0.2 +0.4 +0.6 +0.8 +1.0
Correlation
3x108
2.5
2.0
1.5
1.0
0.5
0.0
6x106
2.0
-2.0
-4.0
#ofCorrelations
(a)
(b)
-1 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1
-10
-8
-6
-4
-2
0
2
4
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8
x 10
6
Correlation
#ofCorrelations
Gray Matter Correlation with Sensory Motor Task (HC - SZ)
-1 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1
0
0.5
1
1.5
2
2.5
3
x 10
8
Correlation
#ofCorrelations
Gray Matter Correlation with Sensory Motor Task
HC
SZ
-1.0 -0.8 -0.6 -0.4 -0.2 0.0 +0.2 +0.4 +0.6 +0.8 +1.0
Correlation
3x108
2.5
2.0
1.5
1.0
0.5
0.0
6x106
2.0
-2.0
-4.0
#ofCorrelations
(a)
(b)
-1 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1
-10
-8
-6
-4
-2
0
2
4
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8
x 10
6
Correlation
#ofCorrelations
Gray Matter Correlation with Sensory Motor Task (HC - SZ)
-1 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1
0
0.5
1
1.5
2
2.5
3
x 10
8
Correlation
#ofCorrelations
Gray Matter Correlation with Sensory Motor Task
HC
SZ
-1.0 -0.8 -0.6 -0.4 -0.2 0.0 +0.2 +0.4 +0.6 +0.8 +1.0
Correlation
3x108
2.5
2.0
1.5
1.0
0.5
0.0
6x106
2.0
-2.0
-4.0
#ofCorrelations
(a)
(b)
HC - SZ
12/16/2009 4/22

5. Default Mode Network (DMN)
Comprises regions more active during rest than during tasks
Thought as task-independent components and decreases in
activity while the brain engages in a task
In this study we explore if structural-functional correlations
differences exist between HC and SZ in the DMN
[2] Marcus E. Raichle, Ann Mary MacLeod, Abraham Z. Snyder, William J. Powers, Debra A. Gusnard, and Gordon L. Shulman, " A
default mode of brain function," Proc. Natl. Acad. Sci. U. S. A. 98, 676–682.

6. Methods
Participants
Four different sites: IA, MA, MN, NM
sMRI Image Acquisition
fMRI Image Acquisition
n Age Education SES
HC 70 (50m, 20f) 34 ± 11 yrs 15 ± 3 yrs 2.4 ± 0.7
SZ 70 (57m, 13f) 35 ± 11 yrs 13 ± 3 yrs 2.7 ± 1.1
Scanner TR TE FOV Voxel
Siemens 1.5 T 12ms 4.76ms 161mm 0.63x0.63x1.5 mm3
12/16/2009 6/22
Scanner TR TE FOV Voxel Gap
Siemens 3 T 2s 30ms 22cm 3.4x3.4x4 mm3 1 mm

7. sMRI Preprocessing
sMRI Images brain tissue distribution
Gray matter (GM) White matter (WM) CSF
Template
SmoothNormalize
SPM used for preprocessing
12/16/2009 7/22

8. Find default mode
Motion Correction
1 2
Functional Images
Time 1 2 … 3
(secs)
Phase Fix
1
23
0s .66s .33s
Normalize
Template
Smooth
fMRI Preprocessing
group ICA used for preprocessing
Group ICA
84 81 78 75 72 69 66 63
60 57 54 51 48 45 42 39
36 33 30 27 24 21 18 15
12 9 6 3 0 -3 -6 -9
-12 -15 -18 -21 -24 -27 -30 -33
-36 -39 -42 -45 -48 -51
RL
5.8
0
7.2
0
7.3
0
8.5
0
10 20 30 40 50 60 70 80 90 100 110 120
-0.4
-0.2
0
0.2
0.4
Scans
SignalUnits
IC 11
-0.4
-0.2
0
0.2
0.4 IC 12
-0.2
0
0.2IC 17
-1
0
1
IC 18
29 24 20 15
11 6 2 -3
-8 -12 -17 -21
-26 -30 -35 -39
RL
0
7.6
Scans
12/16/2009 8/22

9. fMRI Task
Novel (complex sound)
OFF (16s)
200ms
Standard (1 kHz)
Mean ISI = 1200ms
Target (1.2 kHz)
(a) AOD
LEARN 53 619
4 *7*9
* *3**
3 2 8 …
3
6
1
9
+3
Encode (6s) Recognize (38s) Fixate
2s 1s
Or
1.1s 0.6-2.4s
4-20s
ON(38s)
(b) SIRP
ON (16s) ON
Pitch
0.2s
0.5s
(c) SM
Novel (complex sound)
OFF (16s)
200ms
Standard (1 kHz)
Mean ISI = 1200ms
Target (1.2 kHz)
(a) AOD
LEARN 53 619
4 *7*9
* *3**
3 2 8 …
3
6
1
9
+3
Encode (6s) Recognize (38s) Fixate
2s 1s
Or
1.1s 0.6-2.4s
4-20s
ON(38s)
(b) SIRP
ON (16s) ON
Pitch
0.2s
0.5s
(c) SM
fMRI  Independent components of a sensorimotor task
Sensorimotor: A motor response for a sensory stimulus
Sensory stimuli
Auditory tones
Eight different pitched tones
Ascending and descending
Motor response
Right thumb button Press
On-Off blocks (16s)
Sensorimotor Task Time Course
12/16/2009 1/22

10. Group ICA
Evaluate time course of the functional data
Use multiple regression to show the beta weights of each subject on each
component and on the task time course
: time course for individual subjects
: time course for each component
Save the beta values in two 70×1 matrices of HC and SZ for each
component of interest
[3] D. Kim, D. Mathalon, J. M. Ford, M. Mannell, J. Turner, G. Brown, A. Belger, R. L. Gollub, J. Lauriello, C. G. Wible, D. O'Leary, K.
Lim, S. Potkin, and V. D. Calhoun, "Auditory Oddball Deficits in Schizophrenia: An Independent Component Analysis of the fMRI
Multisite Function BIRN Study," Schizophr Bull, vol. 35, pp. 67-81, 2009.
12/16/2009 10/22
iy
ix

11. Beta-Structure Correlation Analysis
How all voxels from sMRI correlate to each functional component
Threshold 91×109×91-voxel sMRI data using mask to exclude CSF, skull and
non-brain region, reducing the number of voxels to N 199k voxels
The correlation matrix RSF is 1×N, N: # of brain voxels
Interpret the correlation matrix using histogram and spatial map
Compare this with previous results
RSF
cov( , )
i
i
i
X B
X B

 

Voxels (N)
SubjectsSubjects
Structure (S)
Structure Voxels (N)
Beta Value (B)
i SF correlationiX
12/16/2009 11/22

12. sMRI-fMRI Correlation Histogram
For each component of interest, draw the histogram of RSF for HC and SZ to
show the difference in each component
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N correlations
RSF
12/16/2009 12/22

13. sMRI-fMRI Correlation Spatial Map
Each RSF contain number of elements equal to N (# of voxels)
Can be used to build a spatial map to see the spatial distribution of correlation
Compare the region with ICA results show the difference between HC and SZ
50
100
150
200
250
N correlations
RSF
12/16/2009 13/22

14. 50
100
150
200
250
50
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250
50
100
150
200
250
Task-Related Component
HC SZ HC-SZ -2.0
-1.0
0.0
+1.0
+2.0
Correlation with
task time Course
HC: p<1.2e-26
SZ: p<6.4e-25
-1 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1
0
2000
4000
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HC
SZ
X0.2

15. 50
100
150
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250
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150
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250
50
100
150
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250
Default Mode 1
-2.0
-1.0
0.0
+1.0
+2.0
Correlation with
task time Course
HC: p<3.2e-14
SZ: p<8.6e-09
HC SZ HC-SZ
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
HC
SZ
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X0.2

16. 50
100
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250
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Default Mode 2
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-2.0
-1.0
0.0
+1.0
+2.0
Correlation with
task time Course
HC: p<3.2e-07
SZ: p<5.9e-04
HC SZ HC-SZ
0
2000
4000
6000
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10000
12000
14000
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18000
HC
SZ
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17. 50
100
150
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250
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Another Component of Interest
-2.0
-1.0
0.0
+1.0
+2.0
Correlation with
task time Course
HC: p<1.6e-06
SZ: p<1.4e-08
HC SZ HC-SZ
0
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4000
6000
8000
10000
12000
14000
16000
18000
HC
SZ
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X0.2

18. Discussion: Histogram of Correlations
Individual histograms: HC & SZ, difference in all four
components
Difference histogram
More negative correlations in SZ than HC; more positive
correlations in HC than SZ:
Task-related component
Default mode 1
Another component of interest
Linkage between Gray matter and functional activity higher in
HC than SZ :
Default mode 2
12/16/2009 18/22

19. Discussion: Spatial Map Results
Spatial map shows HC has more positive regions than SZ in all
four components
Regions in the cerebellum show more positive correlation in HC
than SZ in three components:
Task-related component
Default mode 1
Another component of interest
The hot region in HC-SZ map does not overlap with functional
brain region
12/16/2009 19/22

20. Preliminary Results: Brain Regions
Task-Related
Component
Default Mode
Component 1
Default Mode
Component 2
Other Component of
Interest
HC-SZ>0
Cerebellum Posterior Cerebellum Middle Parietal Lobe Anterior Cerebellum
Middle Occipital
Lobe
Posterior Frontal Lobe Middle Frontal Lobe Posterior Cerebellum
Middle Frontal Lobe Anterior Temporal Lobe Posterior Occipital Lobe
Middle Temporal
Lobe
Anterior Parietal
HC-SZ<0
Middle Cerebellum Middle Cerebellum Middle Temporal Lobe Middle Cerebellum
Middle Frontal Lobe Posterior Parietal Lobe Anterior Frontal Lobe
Posterior Frontal Lobe
12/16/2009 20/22

21. Future Works
Explore the effects of outliers in the subjects:
Bootstrap
Compute statistical significance of results
Identify differential brain regions and implication to
schizophrenia
Identify correlations with white matter
12/16/2009 21/22

22. Thank you!