Alterations In Functional Connectivity Of Neural Networks In Adolescents With Autism Spectrum ...

128 Pages·2009·2.14 MB·English

by  University Library

ALTERATIONS IN FUNCTIONAL CONNECTIVITY OF NEURAL
NETWORKS IN ADOLESCENTS WITH AUTISM SPECTRUM DISORDERS

by

Shih-Jen Weng

A dissertation submitted in partial fulfillment
of the requirements for the degree of
Doctor of Philosophy
(Psychology)
in The University of Michigan
2009

Doctoral Committee:

Assistant Professor Christopher S. Monk, Chair
Professor Kent C. Berridge
Professor Israel Liberzon
Professor Catherine Lord
© Shih-Jen Weng
All rights reserved
2009
DEDICATION

To Pa and Ma,
Who brought me into this world to learn, to love and to laugh…

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ACKNOWLEDGEMENTS
I extend my greatest thanks to Dr. Chris Monk who has given me the opportunity
to be a graduate student in his lab these past 2 years and who has always set aside time to
mentor me in my research. I have learnt a great deal from him not only in terms of
neuroimaging research involving clinical populations, but also in terms of planning out
my future goals. His attitude to research and dedication as a mentor has been a source of
great inspiration. My appreciation also extends to all the past and present members of
Chris’s lab, without their support and expertise; I would not have been able to make it
this far.
I would also like to thank the rest of my committee members and past mentors in
graduate school - Dr. Cathy Lord, for her support during the difficult time in my third
year, for fueling my interest in autism research from a clinical perspective and for giving
me the opportunity to lead social groups. I am also incredibly grateful to Dr Israel
Liberzon and Dr Kent Berridge for their insights on affective cognitive neuroscience and
for their valuable feedback especially during my prospectus defense. I thank them for
their patience and for supporting me every step of the way. Last but not least, I thank Dr
Jeff Hutsler, who first sparked my interest in autism research and encouraged me to
pursue a PhD.
Lastly, I thank the friends that I have made during my years in Michigan. The
ones who covered me with prayers, the ones who help shape and support my research
goals, the ones who made me laugh and smile and the ones who warmed my heart.
Finally, I thank my family, for believing in me and for being my pillar of strength.

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TABLE OF CONTENTS
DEDICATION .................................................................................................................... ii 
ACKNOWLEDGEMENTS ............................................................................................... iii 
LIST OF TABLES .............................................................................................................. v 
LIST OF FIGURES ........................................................................................................... vi 
ABSTRACT ...................................................................................................................... vii 
CHAPTER I ........................................................................................................................ 1 
INTRODUCTION .......................................................................................................... 1

CHAPTER II ..................................................................................................................... 10 
DISTURBANCES OF FUNCTIONAL CONNECTIVITY BETWEEN THE
AMYGDALA AND CORTICAL NETWORKS THAT UNDERLIE EMOTIONAL
FACE PROCESSING IN AUTISM SPECTRUM DISORDERS ................................ 10

CHAPTER III ................................................................................................................... 65 
DISTURBANCES OF INTRINSIC FUNCTIONAL CONNECTIVITY IN THE
DEFAULT NETWORK IN ADOLESCENTS WITH AUTISM SPECTRUM
DISORDERS ................................................................................................................ 65

CHAPTER IV ................................................................................................................. 104 
CONCLUSIONS......................................................................................................... 104

APPENDIX ...................................................................................................................... 111 

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LIST OF TABLES
2.1 Subject characteristics for fMRI face study…………………………………….. 45
Functional MRI face task performance and reaction time measures across
2.2 emotion …………………………………………………………………………. 46
Emotional recognition task performance and reaction time measures across
2.3 emotion …………………………………………………………………………. 47
2.4 Activation within the left and right amygdala in the ASD and control group.….. 48
3.1 Subject characteristics for resting-connectivity study………………………....... 88
Functional connectivity between the PCC and other regions of the default
3.2 network where group differences were found…………………………………... 89
Correlations between symptom severity scores and functional connectivity
between the PCC and each of the areas of the default mode in the ASD
3.3 group…………………………………………………………………………….. 91

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LIST OF FIGURES
2.1 Temporal display of the fMRI face paradigm ……………………………………. 49
2.2 Bilateral amygdala activation in the control and the ASD group ………………... 50
Controls relative to ASDs showing greater positive coupling between the left
2.3 amygdala and the right middle temporal gyrus to fearful vs. baseline ………….. 51
Controls relative to ASDs showing greater positive coupling between the right
2.4 amygdala and the right middle temporal gyrus to sad vs. baseline………………. 52
Controls relative to ASDs showing a trend for greater positive coupling between
2.5 the left amygdala and the right middle temporal gyrus in happy vs. baseline……. 53
Controls relative to ASDs showing greater positive coupling between the left
2.6 amygdala and the right inferior frontal gyrus to sad vs. baseline…………........... 54
Controls relative to ASDs showing a trend for greater positive coupling between
2.7 the right amygdala and the left inferior frontal gyrus to sad vs. baseline ………. 55
ASDs showing a negative correlation between degree of social impairment and
functional connectivity within the right middle temporal gyrus in the happy vs.
2.8 baseline condition………………………………………………………………… 56
ASDs showing a negative correlation between degree of social impairment and
functional connectivity within the right middle temporal gyrus in the fearful vs.
2.9 baseline …………………………………………………………………………. 57
3.1 Connectivity map of an ASD case and a control case …………………………… 94
Controls showing tighter coupling within the right superior frontal gyrus relative
3.2 to the ASDs ……………………………………………………………………… 95
ASDs showing tighter coupling within the right superior temporal gyrus relative
3.3 to the controls ……………………………………………………………………. 96
Controls showing tighter coupling within the right parahippocampal gyrus
3.4 relative to the ASDs………………………………………………………............. 97
Controls showing tighter coupling within the retrosplenial region relative to the
3.5 ASDs ………………………………………………………................................... 98
ASDs showing a positive correlation between adaptive behavior and functional
3.6 connectivity within the left angular gyrus ………………………………………. 99

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ABSTRACT
ALTERATIONS IN FUNCTIONAL CONNECTIVITY OF NEURAL NETWORKS IN
ADOLESCENTS WITH AUTISM SPECTRUM DISORDERS
by
Shih-Jen Weng
Chair: Christopher S. Monk

The present set of studies sought to examine functional connectivity in
adolescents with autism spectrum disorders (ASD) using functional magnetic resonance
imaging (fMRI). In Chapter II, functional connectivity was examined in the context of a
social task with emotional faces. The task was designed to control for attention
differences between groups as well as to elicit robust amygdala activation in both groups.
Using a psychophysiological interaction (PPI) analytic technique, we examined
relationships between the amygdala and various cortical structures associated with face
processing. The results showed that although behavioral performance did not differ
between groups, adolescents with ASD relative to controls, showed weaker positive
amygdala-cortical connectivity within the temporal and frontal regions when viewing
emotional faces relative to baseline. In addition, weaker positive connectivity was
associated with the degree of social impairment in the ASD group. The findings suggest
that adolescents with ASD show a disruption in functional connectivity in the neural
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networks involved in face processing and that these disruptions relate to social
impairment, and are not driven by behavioral differences in emotion recognition. In
Chapter III, functional connectivity within the default network was examined using a
seed in the posterior cingulate cortex (PCC) in the absence of a cognitive task (subjects
lay in the MRI and viewed a cross on a screen). The default network is of interest as
others have identified it as the brain’s intrinsic activation, important in maintaining the
equilibrium between excitatory and inhibitory neuronal inputs and low-level monitoring
of the external surroundings. The results of the resting connectivity study revealed that
relative to controls, adolescents with ASD showed weaker connectivity between the PCC
and a majority of areas within the default network, with the exception of tighter
connectivity between the PCC and the right superior temporal gyrus. Moreover, poorer
adaptive behavior was related to weaker connectivity between the PCC and left angular
gyrus in adolescents with ASD. To summarize, the present set of studies show evidence
for widespread reduced connectivity and isolated areas of increased connectivity in
adolescents with ASD relative to controls.
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CHAPTER I
INTRODUCTION
Autism spectrum disorders (ASD) are neurodevelopmental conditions
characterized by deficits in social and communicative functioning, in the presence of
restricted and repetitive behaviors and interests (RRBs). Afflicting as many as 1 out of
166 children, ASD has a devastating impact on the individual, family and society
(Charles, Carpenter, Jenner, & Nicholas, 2008). Although ASD can only be defined
behaviorally, neuroimaging research has made strong contributions to identifying specific
brain regions that are implicated in ASD. One region that has received considerable
attention is the amygdala. Its involvement in social and emotional processing has
spearheaded models that link impairments seen in ASD to dysfunction within the
amygdala (Baron-Cohen, et al., 2000; Schultz, 2005). The field of ASD is now advancing
beyond localized models into examining neural networks that are disturbed within ASD
(Muller, 2008). Recently, there have been a growing number of studies that emphasize
that disruption in ASD is a function of abnormal connectivity rather than dysfunction
within a specific region of the brain (Belmonte, et al., 2004; Wickelgren, 2005).
Therefore, examining interrelationships between brain regions using functional
connectivity methods can provide useful information about how activity in one region
correlates to another in the presence of a cognitive task or during resting state.
To date, there remains no conclusive evidence for specific biological markers that
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