i NETWORK THEORY ANALYSIS OF ETHANOL SELF-ADMINISTERING NONHUMAN PRIMATES ...

163 Pages·2013·5.54 MB·English

by  Qawi Telesford

NETWORK THEORY ANALYSIS OF ETHANOL SELF-ADMINISTERING NONHUMAN
PRIMATES

BY

QAWI K. TELESFORD

A Dissertation Submitted to the Graduate Faculty of

WAKE FOREST UNIVERSITY GRADUATE SCHOOL OF ARTS AND SCIENCES

In Partial Fulfillment of the Requirements

for the Degree of

DOCTOR OF PHILOSOPHY

Biomedical Engineering

December 2013

Winston-Salem, North Carolina

Approved By:

Paul J. Laurienti, M.D., Ph.D., Advisor/Chair

James B. Daunais, Ph.D., Co-Mentor

Robert A. Kraft, Ph.D.

V. Paúl Pauca, Ph.D.

Christopher L. Wyatt, Ph.D.
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DEDICATION

For Rufus and Ominia

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ACKNOWLEDGEMENTS

I would like to thank several people for their support and guidance over the course of my
graduate career. I would like to thank Paul Laurienti for his help and guidance throughout my
graduate career, but most importantly for his advice on how to approach scientific inquiry. I
would also like to thank James Daunais for his help and direction on this project. I would also
like to thank Robert Kraft for his early mentorship and help throughout this project. I want to
thank my committee members, Paúl Pauca and Christopher Wyatt for taking the time to serve
and advise me on my dissertation work. Graduate level research is an arduous process, so I am
thankful for working in a fun environment that has kept me engaged over the years. I would like
to thank my lab members, past and present, particularly Debra Hege for her undeniable support
and help with grant preparation. I would also like to thank Satoru Hayasaka for providing me the
extra support to present my work at conferences around the world. A special thanks to Sean
Simpson for collaborating with me on several projects. I also wanted to thank Robin Wilkins and
Paige Roseman for keeping me company during late night work sessions. Lastly, I would like to
thank my friends and family for their support during this process.

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TABLE OF CONTENTS
Acknowledgements ........................................................................................................................ iii
Table of Contents ........................................................................................................................... iv
List of Illustrations ........................................................................................................................ vii
List of Abbreviations ..................................................................................................................... ix
Abstract ......................................................................................................................................... xii
1 Introduction ................................................................................................................................ 2
1.1 Graph theory and network science ...................................................................................... 2
1.2 The role of complexity ........................................................................................................ 4
1.3 Network science and the brain ............................................................................................ 5
1.4 Nonhuman primates as a research tool ............................................................................... 6
1.5 Achievements ...................................................................................................................... 8
1.6 Overview of Dissertation .................................................................................................. 11
2 Applying network science to the brain ..................................................................................... 14
2.1 Early studies in the brain................................................................................................... 14
2.2 Network construction ........................................................................................................ 15
2.2.1 Nodes and links ........................................................................................................... 16
2.2.2 Network threshold ....................................................................................................... 18
2.3 Information flow in a network .......................................................................................... 20
2.4 Graph centrality ................................................................................................................ 22
2.5 Community structure ........................................................................................................ 25
2.6 Network comparison ......................................................................................................... 29
2.7 Null models ....................................................................................................................... 33
2.8 The brain as a complex system ......................................................................................... 34
2.9 Figures and Tables ............................................................................................................ 38
3 Developing a nonhuman primate brain network model ........................................................... 45
3.1 Nonhuman primate ethanol self-administration study design .......................................... 46
3.1.1 Animals ....................................................................................................................... 46
3.1.2 Animal self-administration protocol ........................................................................... 46
3.2 Imaging protocol ............................................................................................................... 48
3.2.1 Animal preparation ..................................................................................................... 48
3.2.2 Scanning protocol ....................................................................................................... 48
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3.3 Image Processing .............................................................................................................. 49
3.3.1 Vervet atlas ................................................................................................................. 49
3.3.2 Image preprocessing ................................................................................................... 50
3.3.3 Coregistration and skull stripping anatomic data........................................................ 50
3.3.4 Skull stripping procedure ............................................................................................ 51
3.3.5 Functional data preprocessing..................................................................................... 51
3.4 Network construction ........................................................................................................ 52
3.5 Graph metric analysis ....................................................................................................... 53
3.6 Figures and Tables ............................................................................................................ 55
4 Default mode network and acute ethanol challenge in the nonhuman primate brain network 58
4.1 Introduction ....................................................................................................................... 59
4.2 Methods............................................................................................................................. 61
4.2.1 Animals ....................................................................................................................... 61
4.2.2. Scanning protocol ....................................................................................................... 62
4.2.3 Data analysis ............................................................................................................... 63
4.2.4 Network analysis ......................................................................................................... 63
4.2.5 Graph metric analysis ................................................................................................. 65
4.2.6 Community structure analysis..................................................................................... 65
4.3 Results ............................................................................................................................... 66
4.3.1 Within animal graph metric analysis and hub structure in the rhesus macaque ......... 66
4.3.2 Network comparison across an animal population ..................................................... 67
4.3.3 Changes in nonhuman primate brain network following acute ethanol intoxication . 67
4.4 Discussion ......................................................................................................................... 68
4.4.1 Hub structure in the NHP brain .................................................................................. 68
4.4.2 Graph metric reproducibility ....................................................................................... 70
4.4.3 Measuring changes in brain organization due to alcohol ............................................ 70
4.4.4 Limitations .................................................................................................................. 71
4.5 Conclusion ........................................................................................................................ 73
4.6 Acknowledgements ........................................................................................................... 73
4.7 Figures and Tables ............................................................................................................ 74
5 Chronic ethanol exposure in the nonhuman primate brain network ........................................ 82
5.1 Introduction ....................................................................................................................... 83
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5.2 Methods............................................................................................................................. 85
5.2.1 Animals ....................................................................................................................... 85
5.2.2 Scan preparation.......................................................................................................... 86
5.2.3 Scanning protocol ....................................................................................................... 87
5.2.4 Data analysis ............................................................................................................... 87
5.2.5 Network analysis ......................................................................................................... 88
5.2.6 Graph metric analysis ................................................................................................. 89
5.2.7 Community structure analysis..................................................................................... 89
5.3 Results ............................................................................................................................... 90
5.3.1 Average graph metric analysis after chronic ethanol self-administration .................. 90
5.3.1 Hub map analysis after 12 months of ethanol self-administration ............................. 91
5.3.2 Region of interest analysis of altered brain regions .................................................... 91
5.3.3 Regional connectivity analysis ................................................................................... 92
5.3.4 Community structure analysis..................................................................................... 93
5.4 Discussion ......................................................................................................................... 94
5.4.1 Changes in brain network organization due to chronic ethanol use ........................... 94
5.4.2 Impact of ethanol on functional systems .................................................................... 95
5.4.3 Limitations .................................................................................................................. 97
5.5 Conclusion ........................................................................................................................ 98
5.6 Acknowledgments............................................................................................................. 99
5.7 Figures and Tables .......................................................................................................... 100
6 Discussion and future direction .............................................................................................. 111
6.1 Brain networks in nonhuman primates ........................................................................... 112
6.1.1 Post-induction changes in nonhuman primate brain networks ................................. 113
6.2 Network analysis of brain networks ............................................................................... 115
6.2.1 Weighted network analysis ....................................................................................... 117
6.2.2 Comparison of weighted and binary networks ......................................................... 121
6.3 Conclusion ...................................................................................................................... 122
6.4 Figures and Tables .......................................................................................................... 125
7 References .............................................................................................................................. 132
8 Curriculum Vitae .................................................................................................................... 145

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LIST OF ILLUSTRATIONS
Chapter 2

Figure 2.1. Network analysis schematic ....................................................................................... 38
Figure 2.2. Patterns of information flow ....................................................................................... 38
Figure 2.3. Hierarchical clustering tree ......................................................................................... 39
Figure 2.4. Modularity analysis .................................................................................................... 40
Figure 2.5. Overlapping communities in a network ..................................................................... 41
Figure 2.6. Functional cartography maps ..................................................................................... 41
Figure 2.7. Connections originating from the highest degree node .............................................. 42
Figure 2.8. Network null models with corresponding degree distribution ................................... 43

Chapter 3

Figure 3.1. Nonhuman primate operant drinking panel ................................................................ 55
Figure 3.2. Study timeline for alcohol self-administration study ................................................. 55
Figure 3.3. Nonhuman primate preprocessing pipeline schematic ............................................... 56

Chapter 4

Figure 4.1. Schematic of network and analysis ............................................................................ 74
Figure 4.2. Graph metric reproducibility in rhesus macaque ........................................................ 75
Figure 4.3. Hub maps of top 20% of nodes of highest degree in rhesus macaque ....................... 75
Figure 4.4. Binary hub maps for two fMRI runs across thresholds .............................................. 76
Figure 4.5. Binary hub maps for two fMRI runs across thresholds .............................................. 76
Figure 4.6. Overlap map across 10 vervet monkeys ..................................................................... 77
Figure 4.7. Average graph metrics across vervet monkey cohort................................................. 77
Figure 4.8. Average graph metrics pre- and post- ethanol bolus .................................................. 78
Figure 4.9. Network changes in rhesus macaque brain following ethanol challenge ................... 79

Chapter 5

Figure 5.1. Schematic of network and analysis .......................................................................... 100
Figure 5.2. Regional connectivity map schematic ...................................................................... 100
Figure 5.3. Ethanol intake pattern of drinking cohort of vervet monkeys .................................. 101
Figure 5.4. Comparison of average graph metrics after 12 months of ethanol self-administration
..................................................................................................................................................... 102
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Figure 5.5. Hub maps of top 15% of highest degree nodes in drinking/non-drinking vervet
cohorts ......................................................................................................................................... 103
Figure 5.6. ROI locations for ANOVA analysis ......................................................................... 104
Figure 5.7. Mean degree comparison of ROIs in vervet groups ................................................. 105
Figure 5.8. Neighborhood maps of precuneus ROI .................................................................... 106
Figure 5.9. Neighborhood maps of anterior cingulate ROI ........................................................ 107
Figure 5.10. Community structure comparison after 12 months of ethanol self-administration 107
Figure 5.11. Community structure consistency in vervet groups ............................................... 108
Figure 5.12. Consistency of precuneus module .......................................................................... 109
Figure 5.13. Mean SI values for precuneus module in vervet groups ........................................ 109

Chapter 6

Figure 6.1. Average graph metrics and community structure analysis of animal cohort ........... 125
Figure 6.2. Community structure consistency post-induction .................................................... 126
Figure 6.3. Consistency of precuneus module post-induction .................................................... 126
Figure 6.4. Comparison of hub maps in binary and weighted network ...................................... 127
Figure 6.5. Degree/Strength distribution for single animal from baseline scan ......................... 127
Figure 6.6. Comparison of unweighted and weighted clustering coefficient in single animal ... 128
Figure 6.7. Analysis of unweighted and weighted clustering coefficient distribution ............... 129
Figure 6.8. Gaussian fit histogram for percent change of graph metrics from binary to weighted
network ....................................................................................................................................... 130
Figure 6.9. Gaussian fit histogram for percent change of degree to strength over varying
thresholds .................................................................................................................................... 131

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LIST OF ABBREVIATIONS
AAL : Automated Anatomical Labeling
AC/PC : anterior commissure/posterior commissure
A : adjacency matric
ij
ANOVA : analysis of variance
BOLD : blood oxygen level-dependent
C : clustering coefficient
Cw : weighted clustering coefficient
CPM : Clique Percolation Method
CSF : cerebrospinal fluid
d : edge density
d : distance matrix
ij
DTI : diffusion tensor imaging
e : edges
EEG : electroencephalography
E : global efficiency
glob
E : local efficiency
loc
EPI : echo-planar imaging
ER : Erdős-Rényi
ERGM : exponential random graph model
EtOH : ethanol
FLIRT : FMRIB's Linear Image Registration Tool
FMRIB : The Oxford Centre for Functional MRI of the Brain
FOV : field of view
FSL : FMRIB Software Library
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i : vertex/node
K : degree
L : path length
MATLAB : Matrix Laboratory
MCFLIRT : Motion Correction using FMRIB's Linear Image Registration Tool
MEA : multielectrode array
MEG : magnetoencephalography
N : number of nodes
NA-MIC : National Alliance for Medical Image Computing
NBS : network-based statistic
NIAAA : National Institute on Alcohol Abuse and Alcoholism
NIH : National Institutes of Health
NITRC : Neuroimaging Informatics Tools and Resources Clearinghouse
NHP : nonhuman primate
p : probability
pc : participation coefficient
pk : within-module degree probability
Q : modularity
R : correlation coefficient
ROI : region of interest
S : threshold
s : strength
SI : scaled inclusivity
SPGR : spoiled gradient echo
SPM : Statistical Parametric Mapping
TE : echo time
x