Core 3.2 Activities University of California, Irvine

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Core 3.2 Activities University of
California, IrvineBrain Imaging CenterSteven
Potkin, Padhraic Smyth, James FallonUniversity
of TorontoNeurogenetics Section, Center for
Addiction and Mental Health James Kennedy
Aristotle Voineskos

• http//www.bic.uci.edu

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Overview

• Genetics Activities
• Circuitry and other statistical analyses
• Anatomical Accuracy for shape analysis and
  cortical and subcortical segmentation
• DTI Activities

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Datasets Available

• (1) Toronto genetic data on 300 schizophrenic
  patient and matched controls
• (2) Vancouver, 47 first episode schizophrenia
  patients with structural MRI scans, cognitive
  testing, and genetic and
• (3) Irvine 25 schizophrenic patients with fMRI,
  PET, EEG and 100k SNP genetic data.
• Issues with the NAMIC Toolkit

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Genetics and Neuroimaging in Schizophrenia Update
James L Kennedy MD, FRCPC
IAnson Professor of Psychiatry and Medical
Science Head, Neurogenetics Section, Clarke
Division, Director, Department of Neuroscience
Research Centre for Addiction and Mental Health
(CAMH), University of Toronto SG Potkin, A
Voineskos, D Mueller, M Masellis, N Potapova, F
Macciardi
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Genetics Summary

• SNAP25 gene associated with schizophrenia in
  Potkin sample, and Toronto sample
• BDNF gene candidate for grey matter vol and fxn
• Serotonin transporter gene for amygdala function
• DISC1 gene for cortical thickness
• NMDA, GRIN1 and 2B genes for grey matter
• Newest data MOG gene associated with total brain
  white matter (as hypothesized in grant app)
• Relational database developed for organizing
  genetic clinical imaging data
• Training available in genetics
• National Alliance for Medical Imaging and
  Computing
• NAMIC www.na-mic.org

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Molecular Genetic Approach
Pharmacogenetics
Gene Expression
Pharmacology
Neurobiology
Phenotype (Neuroimaging)
Endophenotype
-Psychophysiology
Sub-pheno
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EXTRACTING DATA FOR ANALYSIS
Data are returned in a format suitable for
association-type studies (m-link or
case-control). Additional formats may be designed
as needed (such as vertical haplotypes
). Data may be transcribed and
converted to document formats supported by the
analysis program (tab de-limited text, etc).
1 2 2 1 1 2 2 2 2 1 1 1 2 2 1 1
With access to source codes, or by invoking
special features in downstream applications, the
database can include automated running of
analyses or transfer of data to other
spreadsheets/databases.
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Cytoarchitectural abnormalities
Control
Comparison of hippocampal pyramids at the CA1 and
CA2 interface between control and
schizophrenic. Cresyl violet stain,
original magnification X250 Conrad et
al. (1991) Arch Gen
Psychiatry
Schizophrenia
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DISC-1 Gene Knock-Down (mouse)
DISC1 gene knock down with inhibitory RNA in
mouse cortex Result migration of neurons from
ventricular zone during fetal development is
impaired by DISC1 knockdown. Morphology resembles
schizophrenia pathology Marginal Zone Cortical
Plate Intermediate and SubVentricular Zone
Strongest inhibition
Ventricular side
Kamiya et al, Nature Cell Biol 2005
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DISC1(Leu607Phe) Genotype in Schizophrenia vs
Controls
Chi-sq 0.61 df2 p0.74
Potkin sample
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Will the Brain Derived Neurotrophic Factor (BDNF)
Gene Predict Grey Matter Volume?
BDNF-1 SNP BDNF-2 BDNF-3 BDNF-4
Exon 11
Val-66-met
(GT)n repeat (function? mRNA stability)
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BDNF val66met MRI functional brain imaging (Egan
et al, Cell 2003)
The red/yellow areas indicate brain regions
(primarily hippocampus) that function differently
between val/val (n8) and val/met (n5) subjects
while performing a working memory task. Subjects
with the met allele had more abnormal function.
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Haplotype TDT BDNF (GT)n repeat val66met in
schizophrenia

HTDT for 170-val66 c2 7.11 1 df p
0.007 Muglia et al, (2002)
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BDNF(val66met) Genotype in Schizophrenia vs
Controls
Chi-sq 0.59 df2 p0.74
Potkin sample
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HTTLPR (ins/del) in Schizophrenia (following
Hariri et al 2002 gt predicts 25 of amygdala fxn)
Note L LA, and LG functions as S so grouped
together under S
Chi-sq 3.3 df2 p0.19
Potkin sample
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Mochida, 2000
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SNAP25 Genotype in Schizophrenia vs Controls
Not for distribution
Chi-sq 9.4 df2 p0.009
Potkin sample
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Myelin Oligodendrocyte Glycoprotein (MOG)

• may function as
• a cellular adhesion molecule
• a regulator of oligodendrocyte microtubule
  stability
• a mediator of interactions between myelin and
  the immune system, particularly as an activator
  of the classical complement cascade via
  activation of C1q (Johns and Bernard, 1997).
• The 2 polymorphisms examined are
• a dinucleotide repeat MOG-(CA)n located
  upstream from the MOG transcription start site
  (Roth et al., 1995 Barr et al., 2001).
• a tetranucleotide repeat MOG-(TAAA)n located
  in the 3 untranslated region (Roth et al., 1995
  Malfroy et al., 1995).

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Location of MOG Gene in 6p21.3 Region (MHC Region)
Class I
Class III
Class II
C4A, C4B, C2, factor B, 21-OHase
GABABR1
LMP/TAP
NOTCH4
Histone Family
DTNBP1
HLA-F
HLA-G
HLA-A
HLA-C
HLA-B
MOG
SCA1
TNF
DM
DR
DQ
DO
DN
DP
?
?
telomere
centromere
(CA)n
(TAAA)n
2.6 Mb
Figure 2. Human MHC region and genes within the
region.
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Hypothesized Autoimmune Mechanism in Schizophrenia
Antibodies
B-Lymphocyte
Inflammation
Mast Cell
Chemokines
Illustration taken from www.phototakeusa.com.
Autoantibodies cross-react with neuronal proteins
(eg myelin?) during fetal brain development,
causing subtle damage to the CNS, leading to SCZ
in early adulthood (Swedo, 1994).
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Prefrontal fMRI activity myelin reduced in
schizophrenia Core 3.1
Figure 31-4 Statistical parametric maps of the
fractional anisotropy (FA) (left) and Magnetic
Transfer Ratio (MTR) (myelin) (right) group
comparison. Similar areas in yellow on both maps
correspond to the location of both the internal
capsule and prefrontal white matter, and indicate
smaller values of FA and myelin in schizophrenia
patients (n14) compared with controls (n15).
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Will MOG gene variants predict white matter
abnormalities?
(CA) repeat
(TAAA) repeat
C1334T C10991T
Start codon
Promoter region
Coding region
(diagram not to scale)
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MOG in Toronto Schiz sample

• TDT and Haplotype Samples
• 113 schiz proband small nuclear families from
  Toronto gt MOG-(CA)n MOG-(TAAA)n
• Statistics
• TDT/S-TDT and haplotype analysis using TRANSMIT
• Results negative for diagnosis of schizophrenia

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Haplotype Analysis of MOG polymorphisms in SCZ
Haplotype analysis between MOG-(CA)n and
MOG-(TAAA)n.
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MOG vs Total Brain White Matter

• Sample Dr. Honer UBC 47 schiz, 24 cont
• Phenotype automated output from standard
  structural MRI total grey and white matter
• MRIgt 3D SPGR
• FOV 26cm
• TE 11.2ms TR 2.1ms
• Matrix 256 x 256
• Thickness 1.5 mm
• Angle - perpendicular to AC-PC line
• Acquisition time - 6 minutes
• C1334T marker genotype associated with white
  matter volume (P0.003)
• Other MOG markers negative
• All MOG markers negative for total grey matter
  volume

Not for distribution
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Dopamine System GenesPresented by Aristotle
Voineskos MD

• COMT Catechol-O-methyl transferase
• DRD3 Dopamine receptor (D3)
• DRD2 Dopamine receptor (D2)

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COMT Gene

• Principal metabolizer of dopamine in frontal
  cortex
• Functional genetic variant val vs. met
• Val reduces dopamine levels
• Val associated with poorer working memory
  (Wienberger group)
• Ultimate hypothesis cortical efficiency (fMRI)
  impaired in val carriers

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COMT (val158met) Genotype in Schizophrenia vs
Controls
Chi-sq 2.6 df2 p0.27
Potkin sample
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DRD3 Gene

• Upregulation of D3 receptors and D3 mRNA
  following antipsychotic in rat brain
• Gly vs Ser variant reveal differences in affinity
  for dopamine
• Gly variant leads to increased striatal activity
  following haldol administration (Potkin et al
  03)
• Preliminary gly variant incr in schizophrenia

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Brain Metabolism Following Haloperidol Treatment
by D3 Genotype (FDG, n14)
Gly-Ser Ser-Ser (n9)
Haloperidol (5wks)
Baseline
Baseline
Gly-Gly (n5)
(UCI Brain Imaging Centre Potkin, Kennedy
Basile, 2003)
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Dopamine D3 Receptor GenePotkin sample N25
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Intro to Dopamine D2 Receptor

• D2 gene is the most established candidate gene
• All antipsychotic meds bind to D2 receptor these
  meds treat positive sx successfully
  (hallucinations, delusions)
• D2 receptor should be involved at some level in
  pathophysiology of disease

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D2 Linkage Disequilibrium in Caucasians
(Haploview)
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DRD2 (-141C ins/del) Genotype in Schizophrenia vs
Controls
Chi-sq 0.61 df2 p0.74
Potkin sample
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Genetics Summary

• SNAP25 gene associated with schizophrenia in
  Potkin sample, and Toronto sample
• BDNF gene candidate for grey matter vol and fxn
• Serotonin transporter gene for amygdala function
• DISC1 gene for cortical thickness
• Dopamine genes predict cortical striatal fxn?
• Newest data MOG gene associated with total brain
  white matter (as hypothesized in grant app)
• Relational database developed for organizing
  genetic clinical imaging data
• Training available in genetics
• National Alliance for Medical Imaging and
  Computing
• NAMIC www.na-mic.org

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Can Alleles Predict Circuitry?

• Need for anatomical accuracy
• D1 alleles predictions in schizophrenia
• Clinical response to clozapine
• Circuitry used in working memory task

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Core 3.2 and Core 1 Anatomical Accuracy

• Sternberg task
• Five Two

Five items compared to Two
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COMT Genotype and Cortical Efficiency During
fMRI Working Memory Task
Val-valgtval-metgtmet-met use more DLPFC to do same
task, SPM 99, plt.005
Egan et al PNAS 2001
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Statistical Parametric Map - GE-2048
Resolution Mai et al Human Atlas, 2001
??
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Improved Circuit Specification
Motor Circuit (BA6)
Orbital Cortex
Amygdala
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Potkin et al ,2003
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Circuitry via Path Analysis PLS

• Circuitry in a Working Memory task (5-2 load) by
  DRD1 genotype in schizophrenia

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Spatial fMRI Activation Patterns

• Padhraic Smyth, UC Irvine

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fMRI Activation Surface Modeling

• Model activation response surface (beta-maps,)
• Analyze variability of the features

A 2-dimensional slice of right precentral gyrus
at z53
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Subject 3

• Estimated parameters for activation centers

4 runs within visit 1 O 4 runs within
visit 2
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Detecting Spatial fMRI Activation Patterns
Activation patterns estimated by mixture model
(Kim, et al, 2005)
Thresholded voxels (plt0.05)
beta map fBIRN phantom sensorimotor task z30
slice
Not for distribution
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Core 1, 2, and Core 3.2 Activities

• Anatomical Accuracy and Flexibility for
  Integration of Imaging Modalities (e.g. MRI, DTI,
  fMRI, PET and EEG) and statistical analyses
• Slicer development in tractography Alpha and
  Beta testing.
• Development of new visualization techniques and
  visual analytics.
• Bug reporting and tracking.
• Prototype testing.
• Feature requests.
• Participants
• Core 1 Allan Tannenbaum lab (GT), Guido Gerig
  lab (UNC)
• Core 2 Ron Kikinis and Steve Pieper labs
• UCI Jim Fallon, Martina Panzenboeck, Vid
  Petrovic, Falko Kuester

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Cytoarchitectonics- Brodmann areas
Blumenfeld Fig 2-15 pg 32
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Classical Approaches to Cytoarchitectonic Mapping
of Human Prefrontal Cortex
All pictures/drawings are from Rajkowska, G.
Goldman-Rakic, P.S. (1995). Cerebral Cortex
5323-337.
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Central
Precentral
Idealized sulci
Postcentral
Intraparietal
Parieto- occipital
Superior frontal
Inferior frontal
Orbital
Superior temporal
Middle temporal
Inferior temporal
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Critical samples in BOLD
DMPFC
7
Frontal pole
Heschls
DLPFC
Occip
STG
IFG
LOF
ITG
VMPFC
CB
Fallon
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Critical samples in BOLD
DMPFC
7
Frontal pole
Heschls
DLPFC
Occip
STG
IFG
LOF
ITG
VMPFC
CB
Fallon
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DMPFC
DLPFC
ACd
IFG
ACv
25
LOF
VMPFC
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Cases from Rajkowska Goldman-Rakic's (1995)
series showing individual variability of gyral
and sulcal anatomy as well as spatial variations
in cytoarchitectural dispersion. Variations will
be seen more clearly on the succeeding slide of
two different cases.
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20 (10mm)
40 (20mm)
DLPFC
20mm
50 mm
Tip temporal lobe
Tip frontal pole
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Case 1
Anterior View
Anterior-Inferior View
Case 7
Case 12
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cx
wm
Thumbs
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beta map fBIRN phantom sensorimotor task
Thresholded voxels (plt0.05)
Activation patterns mixture model (Kim, et al,
2005)
Add 20 gutter region around each strictly
defined area (eg DLPFC) to capture rogue
functional activations in different subject and
patient PopulationsDLPC PLUS
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BA 7
DLPFC BA 46
SLF-2
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McCarthy, 2004
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Core 5 and Core 3.2 Activities

• Contributed to training material.
• Participated in training sessions both as trainer
  and trainee.
• Hosted one-on-one advanced training sessions.
• Training in neuroanatomy and circuitry and
  genetics.
• UCI Jim Fallon UT James Kennedy, Fabio
  Macciardi
• At NAMIC meetings, UCI, GA Tech and UNC.

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Publications

• Ramsey Al-Hakim, James Fallon, Delphine Nain,
  John Melonakos, and Allen Tannenbaum. A
  Dorsolateral Prefrontal Cortex Semi-Automatic
  Segmenter. Proc SPIE Medical Imaging, 2006.
• Kim, S. Smyth, P., Stern, H., Turner, J., FIRST
  BIRN. (2005) Parametric response surface models
  for analysis of multi-site fMRI data. Proceedings
  of the 8th International Conference on Medical
  Image Computing and Computer Assisted
  Intervention (MICCAI). Lecture Notes in Computer
  Science, Springer-Verlag, Berlin Heidelberg New
  York, 3749, .
• Turner, J., Smyth, P., Fallon, J.F., Kennedy,
  J.L., Potkin, S.G., FIRST BIRN (2005). Imaging
  and genetics in schizophrenia. Neuroinformatics,
  in press
• Keator, D Gadde, S Grethe, J Taylor, D FIRST
  BIRN Potkin, S. A. (2005). General XML Schema
  and Associated SPM Toolbox for Storage and
  Retrieval of Neuro-Imaging Results and Anatomical
  Labels.  Neuroinformatics, in press.
• Martucci L, Wong AHC, De Luca V, Likhodi O, Wong
  GWH, King N, Kennedy JL. NMDA receptor subunit
  gene GRIN2B in schizophrenia and bipolar
  disorder. Schizophrenia Research (in press).

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Post-doc Position at UCI

• Computer Science Department working on Brain
  Imaging
• Speak to P Smyth