BIOMEDICAL INFORMATICS RESEARCH NETWORK: FUNCTIONAL IMAGING RESEARCH IN SCHIZOPHRENIA TESTBED S.G. P

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BIOMEDICAL INFORMATICS RESEARCH NETWORK
FUNCTIONAL IMAGING RESEARCH IN SCHIZOPHRENIA
TESTBED S.G. Potkin1 J.A. Turner1 G.G.
Brown2 G.H. Glover5 S. Heckers4 D.B. Keator1
J.S. Grethe3 FIRST BIRN6 1. Department of
Psychiatry and Human Behavior, University of
California, Irvine, CA, USA 2. Psychiatry, 3.
BIRN-Coordinating Center, University of
California, San Diego, La Jolla, CA, USA 4.
Psychiatry, Mass. General Hospital, Charlestown,
MA, USA 5. Lucas Center, Stanford University,
Stanford, CA, USA 6. www.nbirn.net
Introduction
Methods QA Calibration
Results
Preliminary analyses
ABOUT THE FUNCTIONAL IMAGING RESEARCH IN
SCHIZOPHRENIA TESTBED FIRST BIRN The FIRST
BIRN is developing and validating functional
magnetic resonance imaging (fMRI) methods to
combine data from different sites using a common
protocol, for a large-scale multi-center study of
schizophrenia. The proposal is crystallized
around a high-speed broadband network supporting
a federated database, specifically developed for
the pooling and sharing of data across sites, to
facilitate large-scale hypothesis testing and
intelligent data mining to address complex
scientific problems. Each center will also
conduct its own unique studies on the same
patients being studied by the FIRST BIRN
consortium, to provide added value. Sites
participating in the FIRST BIRN are shown in the
image to the left.
Non-human phantom scans are used to (1) perform
a one time system check to test a scanners
geometric accuracy using a specialized
cylindrical geometry phantom and (2) perform
ongoing quality assurance scans using a spherical
agar phantom to verify inter-image scanner
stability and drift. The phantoms, protocols, and
measures were developed at Stanford the phantoms
were built at UCSD the measures were made
useable across different file formats by UCI. The
data obtained from scanning the spherical agar
phantom are analyzed to measure the Signal to
Noise ratio, the drift and fluctuation over time,
and spatial correlations within the images.

• ANOVA design 2 (breathhold and sensorimotor) x 2
  (first two runs of each paradigm) x 2 (day) x 8
  (sites) using the 3 dependent measures (P, M,
  MC). The following significant effects were
  found
• Site x paradigm interaction on P (see figure
  below)
• Run x paradigm interaction on MC (not shown)
• Run effect on MC The second run showed
  consistently less head motion than the first run,
  and there was more of an effect for the
  breathholding task than the sensorimotor task
  (not shown)
• Site effect on P, M, MC (see figure below). The
  analysis was completed at UCI.

Example QA results from two different 1.5T
scanners at two different sites. Three different
measures can independently indicate the
functionality of the scanner, detecting drift and
increases in noise, as well as malfunction prior
to component failure. The collaborative efforts
in sharing this data have forced some consistency
across the sites, since the evidence regarding
each scanner is available to all. Scanner
manufacturers are using these data to improve
imaging performance.
Effect of subject x day x site
Subject 105
Subject 104
The advances of the FIRST BIRN federated database
will specifically facilitate this combining of
site-specific data with the consortium data.
This value added sharing will enhance the
FIRST BIRNs scientific discovery process. GOALS
OF THE FIRST BIRN The FIRST BIRN has two major
goals Technological development of a
distributed network infrastructure that will
support the creation of a federated database
consisting of large-sample fMRI datasets
contributed by the 10 centers. Clinical
Study brain function in schizophrenia with fMRI.
We propose to use the technology developed herein
to study changes in brain function in the
development, progression, and treatment of
schizophrenia as assessed by fMRI. We will
investigate two domains that have been
demonstrated to be dysfunctional in
schizophrenia early auditory sensory processing,
and working memory/executive functioning.
Collaborative studies will focus initially upon
first onset, chronic, and late-onset
patients. FIRST BIRN will perform a.
Standardization and calibration of equipment and
imaging activation paradigms across sites using
mechanical and human phantoms b. Collection of
imaging data using the consortium fMRI protocol
on populations of persons with schizophrenia at
different sites c. Combining of unique imaging
data collected with diverse activation methods
into the federated database. We present here the
initial progress toward the standardization and
calibration of equipment and activation paradigms
made by the FIRST BIRN over the past year.
Left Normalized areas used to compare results
across subjects and sites. Right The average F
value in the hand area on day 1 and day 2, at UCI
and UCSD, for two different subjects shows a
consistent subject x day interaction. A similar
pattern was seen in the motor and auditory areas.
(Analysis completed at UCSD.)
Methods Human Calibration

• Five male right handed subjects traveled to all
  ten scanning sites over the course of August and
  July 2003, and were scanned on two separate days
  doing the same tasks repeatedly. They served as
  human phantoms, being the same brain doing the
  same task.
• The primary tasks used were multiple repetitions
  or runs of the following
• Resting The subject laid with eyes open, 4.5
  minutes two runs per session.
• Breathholding The subject alternated between
  breathing normally and holding his breath every
  15 s, for 4.5 minutes two runs per session.
• Sensorimotor task The subject tapped his fingers
  and heard tones in time with a 3Hz flashing
  checkerboard (left), alternating with rest
  periods every 15 s, for 4.5 minutes four runs
  per session.
• This collection of multiple runs, visits, tasks,
  and scanners across a consistent set of subjects
  is a unique fMRI dataset that allows us to assess
  the relative variability introduced by each of
  these factors.

Effect of scanner strength

• The imaging data are uploaded to the SRB and
  shared with all the consortium sites. Analysis
  occurs on a site by site basis. All sites have
  access to all the human phantom data and can
  download and analyze it as they wish.
• The current goals are to assess the variability
  within the imaging data and develop methods to
  counteract it. The preliminary analyses being
  presented involve per-scan, global measures of
• Percentage of voxels activated by the task (p lt
  .0001) (P)
• The amount of head movement in mm (MC)
• The average percent signal change in all the
  active voxels (M). These global measures were
  calculated at MGH on the following sites data
  UCI (1.5T), UCSD (1.5T), MGH (3T), Minnesota
  (3T), New Mexico (1.5T), Iowa (1.5T), Duke
  (1.5T), Duke (4T).

Integration of different methods and measures
The kind of data the FIRST BIRN will be combining
across the country a) Cortical activations to a
thought or perception, from an individual b)
Measures of group differences in activations on a
partially-inflated cortical model c) The
macro-circuitry of the brain involved in
schizophrenic syndromes d) The micro-circuitry
of the cortical layers e) Areas with differences
in cortical thickness over the brain, between
patients and controls f) Data from other species
or studies regarding cell types, locations,
receptor densities, etc.
e)
c)
a)
Example EPI images from the same subject at four
different sites show the variation in image
intensities and distortions.
Left One of the subjects doing the sensorimotor
task in a 1.5T scanner Right the same subject
and task in a 3T scanner. The stronger field
strength shows the expected increase in
sensitivity to the BOLD response in the auditory,
motor, and visual areas. (Data from Duke and MGH
images from MGH.)
d)
b)
f)
The differences between sites in the overall
amount of brain which shows an activation to the
task, with the same 5 subjects doing the task in
each scanner. 1.5T scanners are shown on the
left 3 and 4T scanners on the right. Even
within the 1.5T scanners, there are consistent
site to site differences in fMRI sensitivity,
which need to be accounted for before data can be
combined.
Effect of paradigm x site
Ongoing calibration development
Example Query of Federated Database
Assess the variability Determine which global
measures reflect critical variance components ROI
measures The final calibration might be
region-specific Calculate reliability maps (e.g.,
ICCs) Model-based analysis (e.g., GLM) Bayesian
estimates of effects Correlation between the
various tasks Can the results from one task be
used to remove variance in the results from
another task? Determine correlations between
results and QA measures from a given
scanner Cognitive tasks were also performed by
the human phantoms (results to be presented)
Apply the possible calibration/correction methods
to results from the cognitive tasks as a test.
The development of calibration method is a
multi-site effort that is currently ongoing,
working with this unique dataset. The second
phase of the calibration effort will collect a
larger dataset on site-specific subjects, which
will be used to test the developed calibration
methods.
Are chronic, but not first-onset patients,
associated with superior temporal gyrus
dysfunction?
Data Integration A users query to the federated
database requires integrating the different kinds
of data shown above. The software architecture of
such integration systems consists of a two-part
middleware, called the wrapper and the mediator,
that are between the information sources and the
user. The wrapper converts the data from the
respective information source to a form that the
mediator can accept and manipulate. The
mediator converts a users query into smaller
sub-queries that are sent to each source, and to
integrate the results returned from each source.
Integrated View
Example sensorimotor results from one subject on
day 1 (upper) and day 2 (lower) from a single
site (UCI), shown overlaid on the subjects mean
image. The primary visual, sensorimotor, and
auditory areas are successfully activated, though
not identically from day to day.
Mediator
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The percent of voxels in the entire brain which
showed significant activation (p lt .0001) showed
a significant interaction between site and the
paradigm While fewer voxels overall were active
for the sensorimotor than the breatholding task,
the 1.5T scanners were more similar for the
sensorimotor task than for the breathholding
task.
PET fMRI
Clinical
ERP
Receptor Density
Structure
The integration of the returned data is directly
dependent on the ontological/semantic information
available. The FIRST BIRN group is actively
working to define the ontology describing patient
populations needed to share imaging data.
Example results from the breathholding task for
one subject, collapsed across the two runs. This
is a vascular response which activates grey
matter throughout the brain. Behavioral data
(above, collected at MGH) indicated the subject
successfully complied with the breathing
instructions.
This research was supported by the Functional
Imaging Research in Schizophrenia Testbed (FIRST)
Biomedical Informatics Research Network (BIRN,
http//www.nbirn.net), which is funded by the
National Center for Research Resources at the
National Institutes of Health (NIH).