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Investigation of the neural mechanisms of sensorimotor integration in children with autism

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Investigation of the Neural Mechanisms of Sensorimotor
Integration in Children with Autism

By Stefanie Bodison OTD, OTR/L

A thesis submitted in partial fulfillment for the degree of

Master of Science in

Clinical, Biomedical, and Translational Investigations

Keck School of Medicine of the University of Southern California
May 2017

Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 2
Table of Contents

Chapter 1: Introduction ............................................................................................................... 3
Chapter 2: Candidate’s Background .......................................................................................... 5
Chapter 3: Career Goals and Objectives ................................................................................. 10
Chapter 4: Career Development/Training Activities .............................................................. 12
Chapter 5: Training in the Responsible Conduct of Research (RCR) ................................... 17
5.1. Prior Training Experiences in RCR ...................................................................... 17
5.2 Proposed Formal Training Experiences in RCR ................................................... 18
5.3 Proposed Informal Training Experiences in RCR ................................................ 18

Chapter 6: Specific Aims ........................................................................................................... 19

Chapter 7: Research Strategy .................................................................................................... 23
7.1. Significance ........................................................................................................... 23
7.2 Innovation .............................................................................................................. 25
7.3 Approach ............................................................................................................... 26
7.4 Research Benchmarks ............................................................................................ 36
7.5 Preliminary Data .................................................................................................... 37

Chapter 8: Description of Institutional Environment ............................................................. 40
References ..................................................................................................................................... 43

Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 3
Chapter 1: Introduction
I am an occupational therapy researcher whose goal is to become an independent scholar
conducting multidirectional translational research in children with neurodevelopmental
disorders. My overarching career goal is to carry out randomized controlled trials (RCTs)
evaluating the efficacy, effectiveness, and cost-effectiveness of rehabilitation interventions for
children. To do this, I believe it is essential to develop the knowledge and skills necessary to
investigate the neural mechanisms that undergird many of the developmental processes
hypothesized to be impacted by clinical rehabilitation interventions. To this end, I am proposing
a Career Developmental grant (K01) through the National Institutes of Health that would afford
me the time and mentoring necessary to achieve my goal of research independence.
The mentored research project to be completed during this K01 award involves children
with Autism Spectrum Disorder (ASD). To date, research suggests that 80-94% of children with
ASD have some kind of sensory abnormality and/or suffer from motor delays when compared to
typically developing children. These motor delays are often expressed as deficits in gross motor
skills and/or the inability to imitate the motor actions of others. One theory suggests that these
associated motor delays result from the child’s incapacity to integrate, or combine, sensory and
motor information in the brain. To date, there have been few scientific experiments to verify this
assumption. Despite this fact, the theory of disordered sensorimotor integration has inundated
the clinical community and dominates the intervention choices made by therapists offering
rehabilitation services to children with ASD. To more precisely inform the development of safe
and effective interventions, it is critical that we understand how the brain integrates sensory and
motor information and examine whether these underlying neural mechanisms are associated with
behavioral sensorimotor skills and subsequent differences in functional abilities. Therefore, the
Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 4
goals of the proposed research study are to: 1) document connectivity between known sensory
and motor regions of the brain in 6-8 year old children with ASD, and their typically developing
peers; and 2) elucidate whether observed sensorimotor and functional differences can be directly
linked to this neural architecture of sensorimotor integration. Using advanced multimodal
imaging techniques and a novel fMRI paradigm involving motor imitation, we will compare the
structural and functional neural mechanisms of sensorimotor integration between 30 children
with ASD and 30 typically developing children. In addition, we will behaviorally assess each
child’s sensory and motor function, as well as their ability to successfully complete daily
functional tasks. We will then investigate correlations between the brain mechanisms of
sensorimotor integration and the behavioral sensorimotor and functional abilities of all children.
We hypothesize that for the children with ASD, disordered neural patterns of sensorimotor
integration will significantly correlate with behavioral differences in sensorimotor abilities and
poorer functional performance in daily life activities.
The research proposed here is significant for two reasons. First, it seeks to translate a
basic science understanding about the mechanisms of sensorimotor integration directly to
behavioral outcomes of imitation and motor skill, and the potential impact on functional
performance. Second, the research will provide me with the pilot data necessary to develop an
R01 application aimed at investigating the role of intervention on improving the daily lives of
children and families with ASD.

Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 5
Chapter 2: Candidate’s Background
I spent the first 18 years of my career embedded in clinical practice as an occupational
therapist providing direct services to children and families with a variety of special needs,
including Autism Spectrum Disorder, learning disabilities, neurological impairments, sensory
integrative dysfunction, and delays in the attainment of feeding, eating and swallowing abilities.
Master clinicians who were trained by the originators of some of the theories that underlie
specific rehabilitation techniques aimed at improving sensory and motor function in children
mentored me. Throughout my clinical career, I kept up on continuing education experiences and
the research literature to hone my evaluation techniques and clinical reasoning to help me make
the best possible choices about rehabilitation interventions for my clients, grounded on existing
scientific evidence. I became a leader in the field, teaching nationally and internationally about
interventions to improve the sensory processing of children with a variety of
neurodevelopmental disorders. However, I became increasingly more frustrated over time in
clinical practice and teaching with the realization that my ability to rely on the scientific
evidence to inform my clinical decisions was hindered by the slowly developing, traditionally
relied upon, “bench-to-bedside” discoveries. My clinical practice, while very positive, became
one where I often applied rehabilitation techniques “hoping” that the foundation upon which
they were built was truly sound. I saw change in my clients over time, but it was, and continues
to be, difficult to predict who is the most appropriate for which intervention, and why. Theories
to guide these choices and predict change exist, but many have yet to be empirically tested.
To alleviate my own frustration and begin the necessary work to become a clinician-
scientist capable of the transformative change needed in occupational therapy, I returned to
school to obtain a clinical doctorate. During my first three months of study, I developed a clear
Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 6
picture of the path I would need to take to gain the knowledge and skills to be successful, and
identified the possible funding mechanisms to assist me in this quest. As depicted in Figure 1, I
have completed ½ of my clinical translational science journey, and the procuring of this K01 is
the next step towards my research independence. I have been developing a strong science
foundation on which to build the next level, and believe that my clinical irritations continue to
serve me well in identifying the type and intensity of training required. During my doctorate, I
took graduate courses in neuroscience, research design, quantitative and qualitative
methodologies, and statistical analyses. In collaboration with my mentor, Erna Imperatore
Blanche, PhD, OTR/L, my research project centered on the development of a clinical assessment
of proprioception, and I collected data on over 50 typically developing children and those with
autism. I was responsible for
managing the IRB process,
recruiting and consenting
subjects, testing them using
this behavioral measure, and
working with Dr. Blanche and
her research team to analyze
the data. The culmination of
this doctoral work was 2 co-
authored publications related
to the findings of this clinical
tool.

Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 7
Upon completion of my clinical doctorate, I applied for and received a USC NIH T32
Training in Rehabilitation Effectiveness and Efficacy Trials Postdoctoral Fellowship, where I was
mentored by Terence D. Sanger, MD, PhD. While working with Dr. Sanger from 2011-2013, I
developed a research tool to analyze the contribution of vision, touch and proprioception to
motor control. This tool, called the Test of Hand Gestures (TOHG), requires the child to imitate
pictures of hands with and without vision. During development of this tool, I searched the
literature to provide the basis for my items; took the pictures of the hands for each of the items;
piloted the measure on 15 typically developing adults; secured the IRB; tested 60 typically
developing children and those with autism and dyspraxia; and worked with Dr. Sanger to
analyze the findings. The culmination of this work was a first-authored publication that has
recently been accepted and the foundation for the development of a novel fMRI paradigm that I
piloted during my recently completed KL2 award. Following my T32 experience, I was hired
by the USC Chan Division of Occupational Science and Occupational Therapy as a Research
Assistant Professor.
In 2013, I competed for and received a KL2 Mentored Research Career Development
Award from the Center for Education, Training, and Career Development at the Southern
California Clinical and Translational Science Institute (NIH/NCRR/NCATS KL2 TR000131).
During my KL2, I was mentored by Elizabeth Sowell, PhD, at Children’s Hospital Los Angeles,
and I completed courses towards the MS Degree in Clinical, Biomedical, and Translational
Sciences, while receiving hands-on training in foundational neuroimaging procedures. The
courses I completed for the MS degree during my KL2 award included seminars on translational
science, biostatistics, two courses related to neuroimaging techniques (one related to fMRI), and
one course on learning statistical platforms such as SPSS and r. The training that the MS degree
Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 8
has afforded me has furthered my understanding of team science, and the need to work
collaboratively. During my MS degree courses, I was often partnered with medical students,
physician clinician-scientists, and social scientists, and we often found the need to spend the first
few moments of our time working together describing our different disciplines and recognizing
the power that each could offer the collaboration. It has been a truly rewarding experience and
energized my desire to continue obtaining advanced training in neuroimaging so that I can
transform my profession and collaborate in a transdiciplinary fashion.
My training in neuroimaging techniques occurred under the guidance of Dr. Sowell and
in collaboration with her research team. My first task was to take the work from my KL2 on the
TOHG and convert some of the items into an fMRI paradigm to assess the neural mechanisms
involved in transforming sensory data into a motor response. To do this, I learned ePrime, and
tweaked the timing and sequencing of the images to develop a viable task. With this task in-
hand, I then piloted it on 10 healthy adults in the scanner, for which I received pilot funds from
Children’s Hospital Los Angeles. After carefully analyzing these pilot scans, we were
encouraged that the areas of interest were responding the way we hypothesized, and we further
tweaked the timing and instructions for clarity. I then began gathering data on the typically
developing children and those with autism. During this data-gathering phase, I managed the
IRB, consented and tested all the children, and worked with Dr. Sowell and her team to perform
the data analyses on the findings. I have presented some of this work at national and
international conferences via poster presentations, and now have 1 first-authored manuscript
related to the fMRI paradigm in-press, and 3 more in preparation. The neuroimaging skills I
gained over the 2 years of my funded KL2 include the following: 1) development of fMRI tasks
using ePrime; 2) safely placing children and adults into the MRI scanner; 3) managing the
Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 9
scanning acquisition software to capture stable images; 4) completing quality control procedures
on captured images prior to processing; 5) preprocessing of images using brain extraction tools
and FSL software; 6) processing of structural and functional images using FSL and BrainSuite;
7) analysis of neuroimages based on processed data. Additionally, I have begun to learn the DTI
analysis techniques related to FA statistics, and will continue to hone these skills over the next
6-months without specific funding support to do so.
In summary, I believe that the research experiences I have gained have provided
me with a solid foundation on which to continue building towards research independence. I
have the desire, talent, and drive to carve out a unique niche in rehabilitation science by
combining my clinical expertise and knowledge in human growth and development, with
expanded expertise in neuroimaging to transform the way we understand our rehabilitation
interventions. The time is ripe to gain greater clarity on why we do what we do in rehabilitation.
Many of our interventions hypothesize to alter specific neural mechanisms, but in most cases,
we have yet to show if this is true. I believe I have designed the ideal training and assembled the
most knowledgeable mentorship team to help me develop the skills to help answer this question.

Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 10
Chapter 3: Career Goals and Objectives
The primary aim of this K01 grant proposal is to accelerate my development as an independent
scholar conducting multidirectional translational research in children with neurodevelopmental
disorders. My overarching career goal is to carry out randomized controlled trials (RCTs)
evaluating the efficacy, effectiveness, and cost-effectiveness of rehabilitation interventions with
children. To do this, I believe it is essential that I develop the knowledge and skills necessary to
investigate the neural mechanisms that undergird many of the developmental processes that we
hypothesize are impacted through intervention. My past T32 and KL2 experiences have laid a
solid foundation on which to enhance my understanding of these complex neural processes, and I
have assembled an exceptional interdisciplinary team of scholars who are leaders in their
perspective fields to guide me as I excel in this proposed 3-year plan towards independence. I
have developed this K01 with my mentors to enhance my career across four specific areas, for
which I have identified four career goals. It is through the achievement of these career goals that
I will become an independent investigator capable of establishing my own research laboratory,
with the ultimate aim of evaluating the efficacy, effectiveness, and cost-effectiveness of
rehabilitation interventions for children with neurodevelopmental disorders.

Career Goal 1: Building Neuroimaging Competency
To increase my ability to: 1) develop MRI paradigms targeting specific neural functions; 2)
appropriately acquire brain scans using all MRI techniques; 3) correctly preprocess imaging data;
4) adeptly use a variety of analysis techniques and software to interpret neuroimaging findings;
and 5) collaborate and communicate effectively with neuroimaging experts, I will successfully
Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 11
complete all the Training Activities I have outlined in the Career Development/Training
Activities section of this K01.

Career Goal 2: Establishing Research Independence
To increase my research independence, I will investigate the neural mechanisms of sensorimotor
integration using advanced multimodal imaging techniques by successfully recruiting, enrolling,
testing, and analyzing 30 typically developing children and 30 children with ASD, following the
Research Plan set forth in this K01.

Career Goal 3: Dissemination of Research Findings
To improve my ability to effectively disseminate research findings, I will enhance my written
and oral communication skills through the development of five first-authored manuscripts and
six scientific posters over the 3-year K01 period.

Career Goal 4: Cultivation of Grant Acquisition Skills
To cultivate my grant acquisition skills, I will receive mentoring on identifying appropriate
funding opportunities, effectively communicating with stakeholders and program officers, and
conceptualizing and writing an NIH R01 for submission during the 2
nd
year of this K01.

Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 12
Chapter 4: Career Development/Training Activities
My overarching career goal is to carry out randomized controlled trials (RCTs) evaluating the
efficacy, effectiveness, and cost-effectiveness of rehabilitation interventions with children. To do
this, I believe it is essential that I develop the knowledge and skills to investigate the neural
mechanisms that undergird many of the developmental processes that we hypothesize are
impacted through intervention. In collaboration with my mentorship team, I have identified
specific learning activities in each of the following areas to provide me with an exceptional
opportunity to succeed (see also Table 4A).

Training Area 1: Enhancement of Neuroimaging Skills. While I have had the
opportunity to learn a set of basic neuroimaging skills related to the acquisition of data,
preprocessing, and analysis using FSL, I seek to increase my repertoire of neuroimaging abilities.
Specifically, I intend to become competent in the use of the open sourcewear Analysis of
Functional NeuroImages (AFNI). To do this, I have developed a 3-pronged approach. First, I
will attend a weeklong “bootcamp” offered by the NIH within the first 3 months of this K01
award. Second, I will work directly with Dr. Sowell and her team with hands-on experiences
analyzing existing data with AFNI. Third, I will work directly with Dr. Wallace, both during my
visits to his lab and via SKYPE. Dr. Wallace’s lab uses AFNI to analyze much of the data related
to multisensory processing in humans, so I intend to gain as much experience as possible
working in-person on his existing data. In addition to my training in AFNI, when I visit Dr.
Wallace’s lab for 3-weeks each year, I will also receive training on a behavioral task he has
developed to assess the ability of individuals to perceive auditory and visual input, known as the
“Audiovisual Simultaneity Judgement Task (SJ)”. With Dr. Tjan’s assistance, I will adopt some
Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 13
of the advanced MRI and fMRI protocols (e.g. volumetric navigators for prospective motion
correction and sub-second-TR EPI to minimize inter-slice motion, simultaneous multi-slice
acceleration to shorten diffusion-weighted acquisitions) and post-acquisition data processing
techniques (e.g. machine-learning based motion-artifact removal from task- and resting-state
data) to the children in my study. Finally, two times each month, I will attend the CHLA
Pediatric Neuroimaging Journal Club, where neuroimaging faculty, postdocs, and students
discuss techniques to address data collection and analytic confounds (ie. motion, comorbidity) in
pediatric clinical studies.

Training Area 2: Expanded Experiences Collecting and Analyzing Imaging Data on
Children. I have had the opportunity to collect pilot data on typically developing children and
those with ASD, primarily to aid in the development and feasibility testing of a novel fMRI
paradigm. In order to increase my research independence, I seek expanded experiences with a
moderately sized research study with children. Specifically, I am eager to develop recruiting
processes, participate in screening procedures, regularly assess 2-3 children per month, and
adequately preprocess and analyze imaging data to answer specific research questions. Through
the hands-on experiences outlined in my Research Plan, twice-monthly meetings with Dr.
Sowell, and participation in weekly lab meetings, I will receive expanded training on the 1)
development of effective recruitment strategies; 2) ways to trouble-shoot issues regarding data
collection and quality assurance; 3) analytical methods of structural, functional, and DTI analysis
with my own data; and 4) ways to deal with confounds such as movement, sex differences, and
comorbidity. Additionally, to aid in my continued awareness of ethical considerations in
research, I will annually attend the Keck School of Medicine’s one-week, in-person course on
Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 14
the Responsible Conduct of Research. This course offers interactive learning experiences and
intimate small-group discussions about topics related to scientific integrity, misconduct and fraud
in science, data acquisition and management, protection of human subjects, and professionalism
in scientific relationships.

Training Area 3: Augmentation of Knowledge in the Neuroscience of Multisensory
Integration. While I have a strong foundation in neuroscience and the clinical manifestations
of sensory processing problems in children, I seek to augment my knowledge in the neuroscience
of multisensory integration to better understand the foundations of motor performance. During
the first year of my K01, I will enroll in two courses at USC, one per semester. The first course,
Neuroscience 408: From Synapses to Perception, offers insight about the functional organization
of the sensory and motor systems in the brain, from micro-circuitry of neural circuits to global
processes such as perception. The second course, Biokinesiology 550: Neurobehavioral Basis of
Movement, provides an in-depth review of information processing, and detailed examination of
the neural basis of perception/action, motor systems, and higher cognitive function and behavior.
Together, these two courses will assist in broadening my understanding of the specific neural
circuits involved in sensorimotor control and the accompanying behavioral and perceptual
outputs. Additional augmentation of my knowledge will occur through a directed reading course
on multisensory integration taught by Dr. Wallace that includes seminal literature on
multisensory integration in single neurons of the midbrain, cortical mechanisms of multisensory
integration, multisensory representations of space in the posterior parietal cortex, the
development of multisensory integration in humans, and functional imaging evidence for
multisensory integration processes.
Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 15
Training Area 4: Refinement of Academic and Professional Skills. Throughout my K01, I
will continue to develop and refine the academic and professional skills necessary to become an
independent investigator. Within the first year, I will complete a formal training offered by
Children’s Hospital Los Angeles (CHLA) titled Leadership and Team Management. This course
is specifically designed for new faculty to help them build and maintain their own research
programs, including personnel. This course will teach me important leadership and team
management skills that are not only pertinent to this project, but are vital for me to effectively
and efficiently lead my own research team in the near future. In addition, over the three years of
my K01 period, I will complete at least 3 seminars offered by USC’s Southern California
Clinical and Translational Science Institute (SC CTSI). The seminar topics include grant
writing, student mentoring, biomedical advancements, enhancing the peer-review process,
among others. Towards the end of my first year of this K01, I will participate in a 5-day
workshop on Training in Grantsmanship for Rehabilitation Research (TIGRR). This workshop
provides participants with an opportunity to receive mentored grant writing experience and
feedback from experts who regularly review NIH grant submissions as members of NIH Study
groups. The TIGRR workshop will provide me with a rich learning opportunity and direct
feedback about my ideas in preparation for submission of my R01. Additionally, I will submit
abstracts for consideration at each of the following conferences annually: the Organization of
Human Brain Mapping (OHBM), the International Meeting for Autism Research (IMFAR), the
American Occupational Therapy Association (AOTA), and the Occupational Therapy (OT)
Summit of Scholars. My intent is to hone my skills in the dissemination of scientific findings by
presenting posters at 2 of these conferences each year. Finally, every 6-months I will meet with
all 3 of my mentors to provide an update about my research and training progress. At one of
Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 16
these meetings each year, I will give a formal presentation of my work so that my mentors can
provide me with feedback on my presentation skills and ability to communicate scientific
findings.
Table 4A: Timeline for Completion of Learning Activities Within Each Training Area
Year 1 Year 2 Year 3
1. Enhancement of Neuroimaging Skills
Attendance at week-long neuroimaging workshop on AFNI
Hands-on training on AFNI in both Sowell and Wallace Labs
Hands-on training 3-weeks each summer in Wallace Lab
Twice-monthly participation in Dr. Tjan’s lab meetings; monthly mentor meeting with Dr. Tjan
Twice-monthly Pediatric Neuroimaging Journal Club at CHLA
Monthly mentor meeting via SKYPE with Dr. Wallace
2. Expanded Experiences Collecting and Analyzing Imaging Data on Children
Hands-on data collection with moderately sized cohort of typically developing children and ASD
Hands-on analysis of data including structural, functional, and DTI techniques
Annual attendance at USC’s Responsible Conduct of Research course
Twice-monthly mentor meetings with Dr. Sowell
Weekly participation in Sowell Lab journal club and lab meetings
3. Augmentation of Knowledge in the Neuroscience of Multisensory Integration
USC Coursework: Systems Neuroscience - From Synapses to Perception
USC Coursework: Neurobehavioral Basis of Movement
Directed reading course on multisensory integration by Dr. Wallace
3. Refinement of Academic and Professional Skills
Complete CHLA Faculty Development Series on Leadership
Attend 1 seminar/year on grant writing, student mentoring, and biomedical advancements through
USC SC CTSI

Attend TIGRR grant writing workshop
Present scientific posters annually at rehabilitation and neuroimaging conferences
Write and submit R01
Biannual presentation and review of K01 progress with Drs. Sowell, Tjan and Wallace

Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 17
Chapter 5: Training in the Responsible Conduct of Research (RCR)

5.1. Prior Training Experiences in RCR
During both my T32 Postdoctoral Fellowship and my CTSI funded KL2 award, I participated in
a variety of formal and informal training experiences in RCR. During my T32 Postdoctoral
Fellowship, I attended monthly in-person training sessions with other T32 fellows led by the
directors of the T32 program to discuss issues related to scientific integrity; data acquisition,
management and analysis; conflict management in scientific labs; and responsible practices in
dissemination of scientific findings. During my KL2 award, I completed two 4-unit courses
graduate courses in Clinical Translational Research where a discussion related RCR occurred
during every weekly class meeting. Finally, as is mandated for all neuroscience and clinical
researchers at USC, I completed a variety of on-line trainings in RCR related to Good Clinical
Practices (last completed in 10/13); conflict of interest (last completed in 12/15); and the
responsible conduct of research in human clinical trials (last completed 12/15). In addition to
these formal training experiences, during both my T32 and KL2 I was consistently instructed by
mentors on good scientific practices including the handling of patient data, subject
confidentiality, and professionalism in scientific relationships. The most fruitful informal
opportunities for this training occurred during supportive weekly mentorship meetings and bi-
weekly lab meetings where contentious discussions on topics of concern were openly discussed.

Additionally, last fall I completed the formal Responsible Conduct of Research Course provided
by CHLA and The Saban Research Institute. The format of the course consisted of 6 classes (1.5
hours each) on various topics of ethical issues in science taught by CHLA/USC faculty members
(Drs. Bogenmann, Driscoll, Gomperts, Keens, Lew & Detterich). The course was designed to
Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 18
meet the educational requirements in scientific integrity and the responsible conduct of research
outlined in “NOT-OD-10- 019” (NIH, 2009). Topics included: introduction to ethical issues,
responsible authorship, conflicts of interest, animal research ethics, pragmatics of research, and
human research subjects. A faculty member presented each topic for the first hour, followed by
scenario-based discussions among trainees and staff.

5.2 Proposed Formal Training Experiences in RCR
The Keck School of Medicine of USC offers a one-week in-person course on the responsible
conduct of research. The format of this face-to-face interactive learning experience revolves
around a large-group lecture, followed by intimate small-group discussions expanding on the
content. Lecture and topic discussions include scientific integrity, misconduct and fraud in
science, data acquisition and management, collaborative research, responsible authorship,
conflicts of interest, innovation advancement and patents, animal welfare, human subjects,
mentor/mentee responsibilities and professionalism in scientific relationships. I plan to complete
this formal training experience at USC during the first six-months of the proposed K01 training
award period, and every year thereafter.

5.3 Proposed Informal Training Experiences in RCR
It is anticipated that informal training in the responsible conduct of research will come as a result
of informal interactions with my mentors as well as during my supervision of the specialized
Research Assistant proposed for this award. It is anticipated that topics on RCR will arise during
my weekly and bi-weekly mentorship meetings, and I look forward to open discussions to learn
how my mentors have handled similar situations in the past. It is anticipated that specific points
Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 19
of RCR discussion will center on the development of mentor/mentee responsibilities, the
establishing of my own lab and training of lab personnel, the responsible dissemination of
scientific findings, and the management of human subject data.

Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 20
Chapter 6: Specific Aims

Research has well documented that 80-94% of children with Autism Spectrum Disorder (ASD)
have some kind of sensory abnormality and/or suffer from motor delays. While most of the
research related to sensory and motor delays in children with ASD has been conducted in
isolation, little is known about the link between the two, or sensorimotor integration.
Sensorimotor integration, which we define as the brain’s ability to successfully transform
sensory data into a motor response, is hypothesized to be disordered in children with ASD,
causing delays in the ability to learn new motor skills and participate fully in daily
activities. While this theory of disordered sensorimotor integration in ASD has limited empirical
support, it has pervaded the clinical community for over 20 years and dominates the intervention
choices often made by clinicians when offering rehabilitation services to children with ASD. In
an effort to inform the development and refinement of future interventions, it is imperative
that we understand the brain structural and functional connectivity of this population, and
examine the extent to which the observed differences in this neural architecture are
actually related to behavioral performance in the world. While the sensory and motor
differences noted in ASD are not hallmark features of the disorder, we know from established
animal models that the integration of sensory and motor information serves as a foundation for
increasingly more complex, higher-level cognitive, motor, and social functioning. Therefore, the
goal of the proposed research study is to document connectivity between known sensory and
motor brain regions in 6-8 year old children with ASD and their typically developing peers, and
elucidate whether observed sensorimotor and functional differences can be directly linked to this
neural architecture.
Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 21
Aim 1: To characterize the structural and functional neural mechanisms of sensorimotor
integration in 6-8 year old children with ASD, compared to age and gender-matched
controls. For the first time, I will measure the brain circuits underlying the integration of
sensory and motor information in children. These are known neural circuits in animal models
that contribute significantly to development. This work will lay the necessary groundwork about
basic neural circuitry in children that surprisingly, has not yet been done before.
Hypothesis 1: I believe that children with ASD, when compared with gender-matched
controls, will have disordered neural connectivity across the brain regions associated with
sensorimotor integration including the primary visual cortex (V1), the visual region
associated with the recognition of movement (V5), the posterior parietal cortex, the pre-
motor area, and the primary motor cortex.
Approach 1: Using structural imaging (MRI), diffusion tensor imaging (DTI), and a newly
developed functional MRI (fMRI) paradigm of imitation, we will compare the structural and
functional neural mechanisms of the aforementioned brain regions in 6-8 year old children
with ASD and typically developing controls.
Aim 2: To investigate associations between behavioral sensorimotor skills, functional
abilities, and the neural mechanisms of sensorimotor integration in 6-8 year old children
with ASD, compared to gender-matched controls. Here I aim to investigate whether the
neural differences in sensorimotor integration are functionally significant. In clinical practice
and research, behavioral measures are routinely used to say something about the brain. These
measures are reflective of real world performance, but do they truly associate in meaningful
ways with the neural mechanisms they are hypothesized to be measuring?
Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 22
Hypothesis 2: I believe that in 6-8 year old children with ASD, disordered neural patterns of
sensorimotor integration will significantly correlate with behavioral differences in
sensorimotor and functional abilities, when compared to typically developing gender-
matched controls.
Approach 2: The sensorimotor skills of all children in this study will be behaviorally
assessed using a reliable and valid standardized clinical tool of sensorimotor integration, and
the Motor and Sensation Domains of the NIH Toolbox. Functional abilities in daily life will
be assessed using standardized, clinical measures. Between-group correlations will be
conducted to examine the relationships among behavioral sensorimotor skills, functional
abilities, and the neural architecture of sensorimotor integration.

To date, there is little empirical data examining associations between brain mechanisms of
sensorimotor integration and the behavioral sensorimotor and functional abilities of children with
ASD. This innovative study will provide significant insight about brain-behavior
relationships and ultimately inform the development of future interventions aimed at
improving the lives of children with ASD. In addition, the research conducted here will
provide me with opportunities to receive expert mentorship to enhance my skills and abilities
towards becoming an independently funded clinician-scientist and leader in translational science.

Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 23
Chapter 7: Research Strategy

7.1. Significance
Description of Autism Spectrum Disorder. According to the fifth edition of the Diagnostic and
Statistical Manual of Mental Disorders
1
, Autism Spectrum Disorder (ASD) is clinically defined
by impairments in communication, reciprocal social interactions, and repetitive behaviors and/or
restricted interests. These symptoms are present early in development, often co-occur with other
symptoms
2,3
and can significantly impact the child’s ability to successfully engage in meaningful
occupations that contribute to the child’s overall growth and development. According to a
published report by the CDC on March 30, 2012,
4
the prevalence of ASD within a group of 14
US communities known as The Autism and Developmental Disabilities Monitoring (ADDM)
Network estimates the occurrence of ASD to be 1 in 88. ASD affects males 4 to 5 times more
frequently than females, and some of the most commonly co-occurring symptoms or disorders
include gastrointestinal issues, sleep disturbances, poor motor coordination, and sensory
abnormalities.
3,5,6,7,8

Sensory Differences in Children with ASD. It is now well documented that between 80-94% of
children with ASD have some kind of sensory abnormality.
3,5,6,7,8
And while there is little
consensus regarding the pattern of these sensory deficits, it is theorized that children with ASD
fail to properly develop the ability to integrate, or bind together, multisensory inputs causing the
environment to “become a much more complex and confusing space”.
9
Indeed, there is a
growing body of multisensory integration research documenting the neural differences
individuals with ASD experience when integrating multimodal sensory information, especially
those related to visual and auditory inputs
10,11,12
.

Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 24
Insight About Brain Structure and Function in ASD from MRI Investigations. The bulk of
neuroimaging research in individuals with ASD has focused on neuroanatomical and
neurophysiological differences related to brain volume
13,14,15
, under-connectivity or over-
connectivity between various brain regions
16,17
, disordered brain systems sub-serving social
perception
18,19
, and the contentious theory of “broken” (or “unbroken”) mirror neurons in an
action-observation network
20,21,22
. Surprisingly however, there is limited research investigating
the link between sensory differences in children with ASD and the subsequent motor delays
often seen in this population. In addition, a recent systematic review of the neuroimaging
findings in children with ASD
23
revealed that only a small number of MRI research studies on
children exist, with a mean age of 8 years old and under (n=9).

Interventions for Children with ASD. The available non-pharmacological interventions for
children with ASD vary widely, and often focus on the development of specific behaviors,
communication, social skills, motor skills, living skills and/or academic abilities. The
complexity of ASD suggests that no single type of intervention will be beneficial for all children,
and while many therapies have shown positive results, there continues to be a need for further
research on the efficacy and effectiveness of all non-pharmacological interventions available to
children with ASD
24
. One commonly utilized intervention with children with ASD focuses on
remediating the noted behavioral deficits in multisensory integration. This intervention, which is
often provided by occupational and physical therapists trained in Ayres Sensory Integration,
25,26
is based on several theoretical assumptions, the foundations of which suggest that the neural
mechanisms of sensorimotor integration are altered in children with ASD, and that by
emphasizing environmental enrichment with a strong sensory and sensorimotor approach, the
Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 25
child’s ability to integrate, or bind together, multisensory inputs will be improved. To date
however, all of the effectiveness studies on the remediation of multisensory deficits in children
with ASD have relied solely on behavioral measures of change. In an effort to inform the
development and refinement of future interventions, it is imperative that we understand the brain
structural and functional connectivity of this population, and investigate how these underlying
neural mechanisms are associated with behavioral sensorimotor skills and the subsequent
differences in functional abilities often noted.

Therefore, the goal of the proposed research study is to document connectivity between
known sensory and motor brain regions in 6-8 year old children with ASD and their
typically developing peers, and elucidate whether observed sensorimotor and functional
differences can be directly linked to this neural architecture.

7.2. Innovation.
The proposed research study is innovative for two reasons. First, it marks one of the initial
attempts to explore the link between the sensory and motor neural architecture of children with
ASD and typically developing (TD) children. Second, this research study will contribute to the
much needed neuroimaging work in young children below the age of 8. As is well accepted in
clinical intervention, the earlier appropriate interventions can be applied, the more positive the
impact on normalizing developmental trajectories. In order to assist in the future development of
interventions, it is imperative that scientists gain a greater understanding of the underlying neural
mechanisms of sensorimotor integration in young children so that clinicians have the empirical
data needed to inform decisions about the type, duration and intensity of their interventions.
Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 26

7.3. Approach.
Study Design. In the proposed research study, 30 children with ASD and 30 typically
developing (TD) controls will receive a battery of assessments that include advanced MRI
imaging techniques, behavioral sensorimotor assessments, and the measurement of adaptive
behavior using reliable and valid clinical tools. The testing conducted during this study will
occur over three separate, 3-hour visits to Children’s Hospital Los Angeles (CHLA). As detailed
in Figure 12A, upon contact with interested families, each child will initially be screened for
eligibility during a telephone interview with their parent/caregiver, where questions related to
diagnosis, language abilities, and sound sensitivity will be assessed. This study will specifically
screen for language
abilities and sound
sensitivity as the
collective previous
experiences of the
researchers
scanning young children and those with ASD have informed success rates based on the child’s
ability to follow a minimum of 3-step verbal directions, and tolerate a moderate level of loud
sounds. Following telephone screening, eligible children will be scheduled for their first 3-hour
visit for behavioral assessment of sensorimotor skills and, for the children with ASD, verification
of the diagnosis using the Autistic Diagnostic Observation Schedule-2
nd
Edition (ADOS-2).
Upon successful completion of visit one, eligible children will be scheduled for the remaining
two 3-hour visits to complete a battery of neuropsychological tests, assessment of functional
Figure 12A. Study Schema
Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 27
abilities, and the MRI imaging assessments. A detailed description of the assessment procedures
proposed for this study, listed in order of their administration, is provided below.
Verification of the Diagnosis of Autism: Each child with ASD who enters the study will
need to provide documentation of a diagnosis of ASD as identified by a physician, psychologist,
neurologist, or psychiatrist. During the first visit of the study, the diagnosis of ASD will be
verified using the Autistic Diagnostic Observation Schedule-2
nd
Edition (ADOS-2)
27
. The
ADOS-2 is considered the “gold standard” assessment for autism symptomatology and is a semi-
structured standardized observational method used for assessing communication, reciprocal
social interaction, play and the presence of restricted or repetitive behaviors or interests in
individuals of all ages. The ADOS-2 can be used on individuals from 12 months – adulthood,
and takes approximately 30-45 minutes to administer. During her KL2, Dr. Bodison received
training in administration and interpretation of the ADOS-2 from the primary authorship group at
the Center for Autism and the Developing Brain at the Weill Cornell Medical College in New
York. She is considered to be research reliable in the use of the ADOS-2 to verify the diagnosis
of ASD of participants in research studies and will conduct the verification of the diagnosis of
ASD in all ASD participants in this study.
Behavioral Sensorimotor Assessments: The sensorimotor abilities of all participants in
this study will be assessed via two methods: a standardized, norm-referenced, observational
clinical tool, and the Motor and Sensation Domains from the NIH Toolbox. The Sensory
Integration and Praxis Tests (SIPT)
28
consists of a battery of 17 subtests designed to assess the
tactile, proprioceptive, vestibular and praxis abilities of children 4 to 8 years of age. This
standardized, norm-referenced tool takes approximately 2 hours to complete, and will be
administered and scored by Dr. Bodison. The NIH Toolbox is a multidimensional set of brief
Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 28
measures assessing cognitive, emotional, motor and sensory function from ages 3 to 85, and is
designed to meet the need for a standard set of measures that can be used as a “common
currency” across diverse study designs and settings (ref -
http://www.nihtoolbox.org/Pages/default.aspx). For the purposes of this study, we will use the
Motor and Sensation Domains of the NIH Toolbox to assess a variety of motor and sensory
functions. The tests that we intend to use will take approximately 30 minutes to administer, and
will be performed by both Dr. Bodison and the proposed specialized Research Assistant.
Neuropsychological Assessment: All children in the study will be assessed during the
second visit using the Wechsler Intelligence Scale for Children - 5
th
Edition (WISC-5)
29
. The
WISC-5 is a standardized, norm-referenced observational measure designed to provide insight
about the child’s full scale IQ, verbal comprehension, visual spatial abilities, fluid reasoning
skills, working memory, and processing speed. It can be administered in approximately 45-65
minutes, and is meant to give some insight into the child’s cognitive abilities. The WISC-V will
be administered to all children and scored by the proposed specialized Research Assistant, who
will be trained and monitored in its use by both the psychology faculty member who is a part of
Dr. Elizabeth Sowell’s laboratory, and Dr. Sowell herself. The primary purpose for gathering
information on participant cognitive abilities is to document similarities between the groups of
children with ASD and those who are TD controls. Based on Dr. Bodison’s previous work
during her KL2, it is anticipated that there will be no statistically significant differences in the
cognitive abilities of the two groups of participants in this study.
MRI Imaging Assessments: Prior to full brain imaging procedures, each participant will
undergo several sessions in CHLA’s “mock scanner” to become familiarized with MRI scanning
procedures. Participants who are unable to tolerate mock scanning after 3 sessions will be
Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 29
excluded from the full brain imaging procedures. This “mock scanning” procedure will limit the
potential loss of subjects due to invalid scans because of subject movement or subject
unfamiliarity with the scanning procedures. All MRI images will be acquired for each
participant using a 3-Tesla Philips Achieva scanner at CHLA. The entire set of multimodal
imaging protocols described below is divided into two 30 minute sessions that are completed
over two separate days of testing. Structural MRI: One high resolution, whole-brain T1-
weighted MPRAGE sequence is obtained (TR = 6.7 ms, TE = 3.1 ms, flip angle = 8º, FOV =
256x240x204, voxel = 1mm
3
). Functional MRI (fMRI): Using T2*-weighted echo planar
imaging, eight minutes of whole-brain BOLD functional imaging is collected while subjects
participate in the fMRI activation paradigm described in this proposal (TR = 2500 ms, TE = 30
ms, flip angle = 75º, FOV = 256x256, no gap, voxel = 3mm
3
). Diffusion Tensor Imaging (DTI):
A whole-brain scan is acquired using a high-angular resolution, echo-planar imaging diffusion
sequence (TR = 9000 ms, TE = 91 ms, flip angle = 90º, FOV = 240x240, 60 slices, voxel =
2.5mm
3
). Diffusion weighted gradients are applied 30 directions with a b-value of 1000s/mm
3
,
along with the collection of a non-weighted (b0) reference image. All MRI images will be
acquired and analyzed by Dr. Bodison, with assistance from the proposed specialized Research
Assistant.
Measurement of Adaptive Behavior: The adaptive behavior of all participants in this
study will be assessed via two methods: a standardized, norm-referenced observational clinical
tool and a parent-completed questionnaire. The Goal-Oriented Assessment of Lifeskills
(GOAL)
30
is a standardized, norm-referenced assessment designed to evaluate the functional
motor abilities needed for daily living. The GOAL is based on small units of easily observable
functional behaviors that are measured during seven childhood activities. The child’s
Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 30
performance is rated on accuracy of skill, speed of completion, and independence in completing
the activity. The GOAL takes approximately 45 minutes to administer, and will be completed
and scored by the proposed specialized Research Assistant under the guidance and supervision of
Dr. Bodison. In addition to the GOAL, the adaptive behavior of each child will be assessed
using the Vineland Adaptive Behavior Scales – 2
nd
Edition (Vineland-II)
31
. The Vineland-II is a
caregiver completed rating measure of adaptive functioning and produces age-adjusted scores on
a composite scale across five subscales: Communication, Daily Living Skills, Socialization,
Motor Skills, and Maladaptive Behaviors. This parent questionnaire takes approximately 30
minutes to complete and will be scored and recorded by the specialized Research Assistant.

Description of fMRI Activation Paradigm. During the fMRI imaging, children will be asked to
imitate a series of hand gestures that they see one-at-a-time through MRI-graded goggles that
they wear while in the scanner (see Figure 12B). Orientation to this fMRI paradigm will occur
during the “mock scanning” procedures using a practice series of hand images, so that the child
will see novel images of hand gestures during the fMRI acquisition procedures. This fMRI
activation paradigm was developed and piloted by Dr. Bodison during her KL2. The fMRI
paradigm is a block design
consisting of two tasks:
an imitation condition and
a control condition.
There are 4 blocks of each
condition, with 10 images
or stimuli per run. During
Figure 12B. fMRI Activation Paradigm
Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 31
the imitation condition, the child is shown a picture of a left-hand performing a meaningless
gesture. The child is then required to imitate the same gesture with the same hand before the
presentation of the next image (approximately 4 seconds per image). Following each block of
imitation items, the child fixates on a cross to “rest”. During the control condition, the child is
presented a picture of either an up-arrow or a right-arrow. When the up-arrow appears, the child
is required to simply raise the left thumb. When the right-arrow appears, the child is required to
simply put the left first finger up as in a display of “#1”. The purpose of the control condition is
to provide a stimulus that requires the child to perform a motor response that does not need
imitation, or the transformation of a visual representation of a hand into a motor response. This
paradigm, as piloted during Dr. Bodison’s KL2, appears to provide the right kind of stimulus to
show varying levels of cortical activation across the brain regions associated with sensorimotor
integration in ASD versus TD children.

Study Population and Recruitment. Males and females 6 years to 8 years of age who are either
TD or have a diagnosis of ASD, will qualify for inclusion. For each child with ASD, the
diagnosis will be confirmed by administration of the Autistic Diagnostic Observation Schedule-
G (ADOS-G). To qualify for inclusion, the child must not have medical co-morbidities (e.g.,
significant heart problems, blindness, deafness, cerebral palsy, Fragile X or Down Syndrome,
tuberous sclerosis, g-tube, NG tube, head injury with loss of consciousness, or contraindications
for MRI such as non-removable metal in the body). Given the 4:1 ratio of boys to girls in the
prevalence rates for ASD in the United States, we plan to recruit 14 girls and 46 boys for this
study.
Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 32
Participants will be recruited from clinics within the Los Angeles area. At each site,
recruitment will be initiated through either: (a) personal contact (i.e., with parents or guardians)
by study site personnel who are working with the child either on an ongoing basis or at the point
of program entry; (b) a presentation of the project delivered at local meetings involving parents
of children with ASD; or (c) flyer notification (made available at community ASD events, in the
schools, in doctors’ offices, and on ASD-related websites) that contains a description of the
research opportunity along with study personnel contact information.

Sample Size & Power Calculations. Based on the power calculation described below, we have
estimated that we need 26 children in each group to show a difference in the brain regions
associated with sensorimotor integration between children with ASD and those who are TD.
However, given Dr. Bodison’s experience gathering the preliminary data using the novel fMRI
paradigm described here, we estimate that approximately 86% of the children to be enrolled will
produce useable scans. This means that we need to anticipate a 14% failure rate for reasons such
as too much participant movement during scanning or the inability to successfully tolerate
scanning procedures. Therefore, our target number of children to be recruited for this study is
60, with 30 children in each group.
We calculated our sample size based on the preliminary data from the fMRI imitation
task gathered during Dr. Bodison’s KL2 award. The comparison of children with ASD (n = 6)
versus TD children (n = 4) yielded a t-value of 5.0519. Calculating effect size using Cohen’s d
statistic (t = 5.0519; df = 7), our preliminary data found a large effect size (d = 3.8188; r =
.87255). Given the size limitation of our preliminary data set, we based our power calculation
for this research study on Cohen’s recommended value for large effect size of d = .80
31
rather
Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 33
than the effect size we computed. Using G*Power 3
32
, we calculated our sample size to be 26
children in each group assuming a 2-tailed difference in means at 80% power, with α = .05.
While we acknowledge that this study may be underpowered to find smaller effects between
ASD and controls, the data obtained can provide the basis for additional power calculations for
future studies, including Dr. Bodison’s R01 to assess the efficacy of intervention on the neural
architecture of sensorimotor integration.

Data Analysis Plan – MRI Imaging Data
DTI and along-tract statistics: These preprocessing steps have been previously published
in detail by Dr. Sowell’s laboratory
33
.
Illustration of this method can be seen
in Figure 12C. Raw diffusion
weighted data for each subject will be
preprocessed according to standard
protocols available in FSL (http://www.fmrib.ox.ac.uk/fsl) and TrackVis
(http://www.trackvis.org). Affine registration to the b=0 volume will be used to correct for head
motion and eddy-current distortions. A six-parameter tensor model of diffusion will then be fit to
the raw data to give voxelwise maps of the 3 principle diffusion directions, as well as the
magnitudes of diffusion along these three axes. Composite fractional anisotropy (FA) maps will
be generated. Whole-brain brute-force tractography will be performed using the Fiber
Assignment by Continuous Tracking (FACT) algorithm
34
, which has been extensively validated
in the literature
34,35,36
. This process generates deterministic streamlines by iteratively moving
from voxel to voxel along the direction of maximal diffusion, while using the following
Figure 12C. Overview of along-tract methods for the uncinate
fasciculus as published in Colby et al., 2012
33
.
Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 34
constraints: 1) a whole-brain mask, 2) an FA threshold of 0.2 to prevent spurious fibers, and 3) a
tract-dependent turning angle threshold of 35 or 60 degrees, to prevent biologically implausible
fibers. Importantly, the FACT algorithm can be used to delineate a number of key white matter
tracts
Gray matter volumetric preprocessing: Imaging analysis procedures and their validation
have been previously reported in detail elsewhere by Dr. Sowell and others, but are briefly
explained below.
37, 38
For each subject at T1 and T2, Freesurfer software will be used in
conjunction with previously published methods for automatic segmentation and measurement of
surface area and thickness of the cortical sheet based on T1-weighted MRI volumes
39
.
Specifically, 1) brain volumes will be warped into standardized 3D coordinate space using a
linear, automated image registration algorithm; 2) images will be automatically segmented into
gray matter, white matter, and cerebral spinal fluid; 3) nonbrain tissue (scalp) will be removed
and hemispheres will be separated; 4) the cortical surface will be extracted from subcortical brain
regions; 5) the cortical surface will be deformed outwards to obtain an explicit representation of
the pial surface; 6) the surface will be divided into distinct cortical units using Freesurfer’s
automated parcellation procedure that incorporates information from a manually trained
probabilistic atlas, local curvature information, and contextual neighborhood information; and 7)
the thickness and surface area of PFC regions and volume of the a priori subcortical
(hippocampus and amygdala) parcellation units will then be calculated within each labeled
region for each subject’s T1 and T2 structural image data.
fMRI methods: Functional images will undergo standard functional MRI and connectivity
preprocessing as previously published
40
. Basic functional MRI preprocessing will include 1)
removal of central spike, 2) slice-timing correction, 3) correction for head movement within and
Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 35
across the time series, 4) within-run intensity normalization to 1000, 5) transformation to
standardized space, 6) resampling into 3mm
3
voxels. Additional connectivity-specific processing
steps will then be performed to remove nuisance variance, including 1) spatial smoothing (6 mm
full width at half maximum), 2) temporal band-pass filter (.009 Hz< f < .08 Hz), 3) removal (via
regression) of the 6 motion parameters, average whole-brain signal, ventricular signal, white
matter signal, and the first derivative of the whole-brain, ventricular, and white matter signals
41
.

Data Analysis Plan – Behavioral Sensorimotor Assessments and Adaptive Behavior. Prior to
conducting statistical hypothesis tests: (a) data for all variables will be described via frequency
distributions and summary statistics; and (b) normalizing transformations will be applied as
necessary. We will evaluate correlations among the neuroimaging and behavioral data using
longitudinal linear effects models, which will allow for the use of all data, not just complete data.
We will test the assumptions of our liner effects model prior to full-scale analysis, making
adjustments by transforming data as necessary.

Limitations. This study has two primary limitations. First, the children with ASD may not
tolerate the MRI environment in the same way as the TD children. In effort to circumvent this
problem, we will use mock-scanning procedures to help the children with ASD become familiar
with the imaging environment and have an opportunity to practice remaining still. The second
limitation has to do with the limited availability of norm-referenced, standardized tools available
to behaviorally assess sensorimotor functions and adaptive behavior. The purpose of this study
is to elucidate the link between the neural mechanisms of sensorimotor integration and possible
influence of this architecture on sensorimotor skills and adaptive behavior. It is quite possible
Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 36
that the limited tools available to behaviorally measure these constructs may make it difficult to
find correlations.

7.4. Research Benchmarks.
The timeline for the proposed research project and the specific benchmarks to be achieved are
outlined in Figure 12D. Assuming a start date of December 1, 2016, IRB approval for the project
will be in place by February 1, 2017. Recruitment and testing of children will occur from March
2017, through June 2019, with data entry and preprocessing of MRI scan data occurring
simultaneously. It is anticipated that data analysis of MRI and behavioral data will take
approximately four months, from June 2019 through September 2019. First-authored manuscripts
as detailed in the career development plan of this proposal will be developed and submitted
throughout years 1, 2 and 3. The data collected during the proposed research project will serve as
pilot material to inform the development of Dr. Bodison’s NIH R01 grant application to be
submitted June 2018. As needed, this NIH R01 grant proposal will be re-submitted in March
2019, 9 months before the completion of this K01 award period in December 2019.

Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 37
7.5. Preliminary Data.
To date, very little data exists exploring the structural or functional connectivity of sensorimotor
integration in children, adolescents, or adults, or the link between these neural mechanisms and
behavioral sensorimotor integration. Therefore, we will present preliminary data from Dr.
Bodsion’s KL2 demonstrating feasibility of the fMRI paradigm, and a recent published study
from Dr. Sowell’s lab.

Neural Substrates of Sensorimotor Integration in Children with ASD: Using the fMRI
described in this research proposal, we examined the neural substrates of sensorimotor
integration in typically developing children (TD; n=4) and those with ASD (n=6) between the
ages of 6-8 years. As depicted in Figure 12E, after correcting for multiple comparisons (p <
0.05), the results showed that the TD children and the ASD children in this pilot study recruited
various regions of the brain during each of
the fMRI tasks differently. Specifically,
the TD children primarily recruited areas
in the motor cortex during the control
condition, while the visual cortices,
cingulate gyrus, pre-motor and pre-frontal
areas were recruited during the imitation
condition. In contrast, the children with
ASD recruited nearly identical brain
regions for both control and imitation
conditions, including the visual cortices,
Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 38

Figure 12F. Cross-sectional DTI results for the relationships between
a) puberty and b) puberty-by-sex interaction and white matter
microstructure (FA) in adolescents. Corrected at p < .01.

right parietal, bilateral pre-motor areas, and right pre-frontal cortex area. These findings suggest
that for children with ASD, both a simple motor task and an imitation of a hand gesture requires
extensive thinking and planning, while the simpler motor task comes more automatically to TD
children. Further investigation of the differences in the neural mechanisms between these two
groups is warranted, and there is positive support that the fMRI paradigm described here is
sensitive enough to capture these differences.
Puberty and sex relate to white matter microstructure in adolescents: To illustrate our
ability to collect and analyze brain structure in children and adolescents, we present below a
recently completed DTI cross-sectional study. Tract-based spatial statistics (TBSS)
42
was
employed to examine the relationships between FA and sex, puberty, and their interaction, while
controlling for age, in 77 subjects between the ages of 10 to 16.
25
Results showed that sex,
puberty, and sex-by-puberty related to FA in this cross-sectional sample (Figure 12F). These
findings suggest that brain structure may show unique relationships with markers of puberty.
However, it remains to be determined if these sex differences are consistent or dynamic across
pubertal development. In collaboration with Dr. Sowell, a newly funded research study is
ongoing to more fully characterize the relationships between puberty and structural brain
development using a within-subject design.

Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 39

Summary of Preliminary Findings: The above data illustrates our ability to collect and analyze
structural and functional neuroimaging data in children and adolescents with a variety of
neurodevelopmental disorders, including ASD. In collaboration with Drs. Sowell, Tjan and
Wallace, the current study will give Dr. Bodison formal training and experience on how to
implement all of these techniques to answer some of the most important questions related to
sensorimotor integration in children with ASD.

Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 40
Chapter 8: Description of Institutional Environment
The University of Southern California (USC) offers an outstanding training
environment for young scientists. USC is one of a small number of premier research institutions
on which the nation depends for a steady stream of new knowledge. USC has nearly $646
million in annual research expenditures, and has ranked among the top 10 private universities in
federal supported research activity. The USC Health Sciences Campus is home to the Chan
Division of Occupational Science and Occupational Therapy, and is adjacent to the Los Angeles
County-USC (LAC+USC) Medical Center, the largest public healthcare system in the country.
In service to the safety net population of Los Angeles County, LAC+USC generates over one
million patient visits annually.
The USC-based Southern California Clinical and Translational Science Institute
(CTSI), funded by an NIH Clinical Translational Science Award (CTSA), offers abundant
educational and scientific opportunities for career development. This includes access to a wide
array of core resources including statistical consultation, access to secure data storage using the
REDCap database; pilot and bridge funding opportunities; faculty consultation to identify
community-based research collaborators, and a translational research seminar series. The CTSI is
particularly invested in accelerating the research careers of current and former KL2 awardees
(including the PI of the proposed study) through resources such as pre-submission reviews of
research grants, and bridge funding to support the transition from mentored research to
independent research careers.
The Statistical Consultation and Research Center (SCRC) is an organized research
unit within the USC Department of Preventive Medicine which integrates statistical,
epidemiological and computing resources and offers them to professionals conducting clinical
Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 41
trials and biomedical research. The SCRC consolidates professionals in study coordination,
medical database development and management, and biostatistics and epidemiology into a
unified center with the purpose of effectively coordinating single-site and multi-site clinical
research. Dr. Christianne Lane, director of the SCRC, has agreed to collaborate with the PI of the
proposed study to support the statistical analyses of this innovative, and highly significant
research project.
The USC Division of Occupational Science and Occupational Therapy (OS/OT)
ranks #1 among graduate schools of occupational therapy in the US News and World Report. It
is an internationally recognized program dedicated to occupational science, the study of human
activity, and occupational therapy, a health profession aimed at preventing disability and
promoting adaptation to life changes. The program is known for its integration of theory and
practice, innovation in research, and leadership in interdisciplinary research. Our Division has
attracted over $15 million in extramural funding, primarily from NIH, over the past 20 years.
Core research domains include rehabilitation science; health disparities; community integration
and social participation; activity and neuroscience; and ethics, society and social justice. An
interdisciplinary faculty including occupational therapists, neurobiologists, health services
researchers, psychologists, and epidemiologists provides a rich theoretical and practice-driven
environment.
Children’s Hospital Los Angeles (CHLA) has an established track record of high
quality, patient-oriented research and has been the recipient of numerous extramural awards,
including those from the National Institute of Health (NIH). CHLA is one of the largest
children’s hospitals in the United States. It is a private, non-profit teaching hospital, affiliated
with the Keck School of Medicine of the University of Southern California (USC) and is an
Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 42
active partner in the USC Southern California Clinical and Translational Science Institute (SC
CTSI). CHLA is ranked 8th in NIH funding for children’s hospitals and was named one of the
Nation’s top five best children’s hospitals in the U.S. News and World Report. Research MRI
scanning is conducted on the first floor of CHLA in the Clinical Trial Unit (CTU) on a research-
dedicated Philips 3T scanner.
The Developmental Cognitive Neuroimaging Laboratory (DCNL), directed by Dr.
Elizabeth Sowell, is located at Children’s Hospital Los Angeles. The DCNL focuses on the
assessment of brain structure and function during normal and abnormal development. The
laboratory is actively involved in the conceptual development of new structural Magnetic
Resonance Image (MRI) analysis tools and is currently applying them in collaborative studies of
normally developing children, adolescents and young adults, and children with
neurodevelopmental disorders such as Fetal Alcohol Syndrome, dyslexia, Tourette syndrome,
ASD, ADHD, and obsessive compulsive disorder. Additionally, the lab is pursuing new studies
using a combination of functional and structural MRI and neurobehavioral assessments in both
normally developing children and adolescents, and in children with prenatal exposure to alcohol
or methamphetamine. The DCNL lab space is over 1700 sq. feet, and houses all of the
computers, software, and data storage elements needed to analyze and confidentially store all
information collected during the variety of research studies conducted here, including Dr.
Bodison’s proposed research project.

Investigation of Neural Mechanisms of Sensorimotor Integration in Children With Autism 43
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Abstract (if available)

Abstract I am an occupational therapy researcher whose goal is to become an independent scholar conducting multidirectional translational research in children with neurodevelopmental disorders. My overarching career goal is to carry out randomized controlled trials (RCTs) evaluating the efficacy, effectiveness, and cost-effectiveness of rehabilitation interventions for children. To do this, I believe it is essential to develop the knowledge and skills necessary to investigate the neural mechanisms that undergird many of the developmental processes hypothesized to be impacted by clinical rehabilitation interventions. To this end, I am proposing a Career Developmental grant (K01) through the National Institutes of Health that would afford me the time and mentoring necessary to achieve my goal of research independence.

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Asset Metadata

Creator Bodison, Stefanie (author)

Core Title Investigation of the neural mechanisms of sensorimotor integration in children with autism

School Keck School of Medicine

Degree Master of Science

Degree Program Clinical, Biomedical and Translational Investigations

Publication Date 02/23/2019

Defense Date 05/01/2017

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag autism,fMRI,OAI-PMH Harvest

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Sowell, Elizabeth (committee chair), Blanche, Erna (committee member), Cermak, Sharon (committee member)

Creator Email bodison@usc.edu

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c40-342609

Unique identifier UC11258225

Identifier etd-BodisonSte-5095.pdf (filename),usctheses-c40-342609 (legacy record id)

Legacy Identifier etd-BodisonSte-5095.pdf

Dmrecord 342609

Document Type Thesis

Rights Bodison, Stefanie

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the a...

Repository Name University of Southern California Digital Library

Repository Location USC Digital Library, University of Southern California, University Park Campus MC 2810, 3434 South Grand Avenue, 2nd Floor, Los Angeles, California 90089-2810, USA