Thank you:
NIMH, NINDS and NICHD
Simons Foundation
Autism Speaks
Cure Autism Now
NICHD Brain Bank
ATP/Harvard Brain Bank
Taran
Sierra
NEURODEVELOPMENTAL STUDIES OF AUTISM:
FROM MRI AND FMRI
TO NEURONS AND GENES
UCSD Autism Center of Excellence
Eric Courchesne, Director
Karen Pierce, Assistant Director
Three Phases of Growth Pathology in ASD
SIZE
Overgrowth
Arrested
Growth
Frontal
Possible
Decline/Degeneration
ASD
NORMAL
Temporal
AGE
Courchesne et al 2001
Courchesne et al., 2003
Courchesne & Pierce 2005
Courchesne et al., 2007
Amygdala
Abnormal Brain Overgrowth in
ASD in First Two Years of Life



90
70
x
x
xxxx
xxx
xx x x
x
Courchesne et al., 2003 JAMA
Dementieva et al., 2005
Dissanayaki et al., 2005
Hazlett et al., 2005
Dawson et al., 2007
Mraz et al., 2007
Webb et al., 2007
Elder et al., 2007
x
x
x

 x xxx x x
x
xx
x
x 
50
30
10
Data from Webb, Dawson 2007 = *
And Courchesne 2003
x
x
*

0.5mos
6-12
Birth
Dementieva et al 2005
*
-0.5
*
*
*
Abnormal Brain Overgrowth
in Autism by 2 to 4 Years of Age
Courchesne et al., 2001
Volume (ml)
Autism
1500
l
l
l l
l l l
l
l
l
ll l l l l l
l
l
l
ll l
l
l l
l
ll
l
1300
1100
Normal Mean
1179 ml
900
2
3
4
Age (years)
Autism case Macrencephaly
Recent MRI Studies Also
Showing Abnormal Brain
Overgrowth
in Autism by 2 to 4 Years of Age
Sparks et al., 2002
Carper et al 2002
Carper & Courchesne 2005
Hazlett et al., 2005
Schumann, Pierce, Courchesne
in prepapration
Average Normal
Gray Matter Overgrowth in ASD
Standard deviations
from normal
*
*
1. Carper et al. 2002
p<0.05
3.4 years
2. Bloss&Courchesne, 2007 3.8 years
*
3. Kates et al. 2004
*
4. Palmen et
* al. 2005
*
7.6 years
11.1 years
5. Hazlett et al. 2005 n.s.19.1 years
*
(left cerebrum only)
*
n.s.
*
n.s.
*
*
*
*
n.s.
1 2 3 4 5
1 2 3 4 5
1 2 3 4 5
1 2 3 ç4 5
Frontal
Temporal
Parietal
Occipital
ç
Gray Matter Overgrowth in ASD
Standard deviations
from normal
*
*
1. Carper et al. 2002
p<0.05
3.4 years
2. Bloss & Courchesne, 2007 3.8 years
*
3. Kates et al. 2004
*
4. Palmen et
* al. 2005
*
*
n.s.
*
*
*
n.s.
*
*
*
7.6 years
11.1 years
5. Hazlett et al. 2005 n.s.19.1 years
(left cerebrum* only)
6. Schumann, Pierce et al. 2010 2 years
*
n.s.
1 2 3 4 5 6
Frontal
1 2 3 4 5 6
Temporal
1 2 3 4 5 6
Parietal
1 2 3 4 5 6
Occipital
SIZE
Overgrowth
ASD
NORMAL
Major Goals of the
UCSD
Autism Center of
Excellence
AGE
(1) Identify the neural and genetic defects that cause
early brain overgrowth in ASD
a) theorize defects in prenatal regulation of neural
genesis and apoptosis
(2) Discover powerful and reliable behavioral and
biological markers of ASD in the first years of life
What Causes Early Brain Overgrowth in ASD?
Overgrowth
Autistic (N=7) vs Control
(N=6) Males
SIZE
ASD
NORMAL
Ages 2 to 15 years
AGE
68% more
neurons
34% more
neurons
Mouton, Calhoun, ArhensBarbeau, Courchesne
68% more
neurons
What is the
Cause of
Excess Cells?
What are the
Resulting
Cortical
Defects?
Anatomic
Microstructure
Gene
Expression
and CNV
analyses
Abnormal Frontal Cortex Gene Expression
at Young Ages (2 to 14 years) in Autism
102 differentially expressed genes
Prenatal Pathways Governing
Cell Numbers and Functional Integrity
DNA damage responses
Cell cycle regulation
Cell proliferation
Apoptosis and survival
Prenatal Processes Governing Patterning
Left/Right neural patterning
Anterior/Posterior neural patterning
Chow, Pramparo et al., in
manuscript
Abnormalities in Neural Patterning, Cellular
Specification, Cell Division and Proliferation
Downregulation
Processes
neural patterning genes (e.g., DLX4, HOXD1, NDE1, NODAL, PCSK6, GREM1) that
affect left/right asymmetry patterning processes and anterior/posterior axis
specification (p=2.63E-04)
Hum Mol Gen, 2010: PCSK6, a genetic link between cerebral asymmetry and
language disorder
Upregulation
proliferation regulators (e.g., WNT3)
Chow, Pramparo et al., in
manuscript
Abnormal Laterality to Language
in ASD Infants & Toddlers
TYPICAL
Eyler, Pierce and Courchesne
13 to 45 months
L
1.0
Effect
Size
(Eta2)
Temporal
cortex
R
Fw Bw Fw Bw Fw Bw Fw Bw
0.0
ASD
14 to 47 months
R
Temporal
cortex
Left-Right Difference in
Mean FIt Coefficient
0.08
TYPICAL
L>R
0.06
0.04
0.02
0
-0.02
ASD
R>L
-0.04
-0.06
-0.08
-0.1
0
10
20
Age
Age in
months
30
40
50
White Matter
Boundary
CTGF
NTNG2
PCP4
RORB
CALB1
Layer 1 - Pial
Surface