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Thank you:NIMH, NINDS and NICHD
Simons Foundation
Autism Speaks
Cure Autism Now
Organization for Autism Research
NICHD Brain and Tissue Bank
ATP/Harvard Brain and Tissue BankTony Wynshaw-Boris & Nik Schork
Steve Glatt & Lisa Eyler & Fred Gage
Laura Schreibman & Aubyn Stahmer
Anders Dale & Clelia Ahrens-Barbeau
Cindy Carter & Melanie Weinfeld
Kathleen Campbell & Stephanie Solso
Rich Stoner & Julia Young
Jamie Desmond & Roxanna Hasin
Julia Young & Stuart Spendlove
Taran
Sierra
Karen Pierce
Tracking Infants Eventually Diagnosed as ASD
At 6 mos of age, “infant made a lot of vocalizations during play and responded to social interactions by smiling and cooing”From Pierce et al., 2008 meta-analysis of Bryson et al., (2007) & Dawson et al.,
(2000)
The great majority of several hundred biological
studies of autism have focused on the brain 10, 20
or more years
after clinical onset.
They have not shown what is abnormal in autism
during the first years of life,
at the age of clinical onset.
Only a dozen MRI studies of early brain
development in ASD
Unusual Brain Growth Trajectory
In Early Life in ASD
Courchesne et al., 2001
mmm
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0 2 4 6 8 10 12 14 16
BR
AIN
VO
LUM
E
(ml)
AGE (years)
l Normalm Autism
Abnormal Brain Overgrowth
in Autism by 2 to 4 Years of Age
ll
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900
1100
1300
1500
2 3 4
Age (years)
Autism
Normal Mean1179 ml
Vo
lum
e (
ml)
Courchesne et al., 2001
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
Bloss & Courchese 2007
Schumann, Pierce, Courchesne
2010Average Normal
Abnormal Brain Overgrowth in ASD in First Two Years of Life
10
30
50
70
90
Birth 6-12 mos
10
30
50
70
90
-0.5 0.5
xx
x
x
xxx
x
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xxxx
xxx x
x
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x
Birth 6-12 mosDementieva et al 2005Dementieva et al 2005
Courchesne et al., 2003 JAMA
Data from Webb, Dawson 2007 = *And Courchesne 2003
* *
** *
Dementieva et al., 2005Dissanayaki et al., 2005Hazlett et al., 2005Dawson et al., 2007Mraz et al., 2007Webb et al., 2007Elder et al., 2007Pierce et al in manuscript
n.s.
n.s. n.s.
*
*
OccipitalParietalTemporalFrontal
Sta
nd
ard d
evia
tions
from
no
rmal
1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6
***
*
*
*
*
**
Gray Matter Overgrowth in ASD
1. Carper et al. 2002 3.4 years
2. Bloss & Courchesne, 2007 3.8 years
3. Kates et al. 2004 7.6 years
4. Palmen et * al. 2005 11.1 years
5. Hazlett et al. 2005 n.s. 19.1 years*(left cerebrum only)
6. Schumann, Pierce et al. 2010 2 years
* p<0.05
*
Amygdala Overgrowth in Autism
by 2 to 4 Years of Age
Schumann, Courchesne & colleagues 2009
First Reported by
Sparks et al., 2002
Also reported by
Munson et al., 2006
Mosconi et al 2009
Temporal
Amygdala
FrontalAGE
SIZ
E
NORMAL
ASD
Arrested Growth
Possible Decline/DegenerationOvergrowthThree Phases of Growth Pathology in ASD
Courchesne et al 2001 Courchesne & Pierce 2005 Courchesne et al., 2007
Autism in the First Years of Life
Eric Courchesne and Karen Pierce
Neurosciences, UCSD
NIMH Autism Center of Excellence
The UCSD-ACE Prospective Study of Autism
1 Yr Well-Baby Check-Up Approach
•
•
Fast
Easy
• Investigates autism asit occurs in the population
Karen Pierce et al., in
manuscript
UCSD-ACE PEDIATRICIAN NETWORK N=150Dr. Robert Bjork, Dr. Michael Nelson, Dr. Cheryl JennettDr. Dr. John Kafa, Dr. Douglas Wilson, Dr. Crystal De FreitasDr. Martin Gilboa, Dr. Patricia Juarez, Dr. George Madany, Dr. Seven Brody, Dr. Ingrid Martinez-Andree, Dr. Irene ChangDr. Stephanie Powell, Dr. Adam Breslow, Dr. Patricia PisingerDr. Isabel Baratta, Dr. Sheila Cason, Dr. Thomas NegliaDr. Stephen Balch, Dr. Randall Metsch, Dr. David SchmottlachDr. Sonja Brion, Dr. Anna Mendenhall, Dr. Nancy ClementinoDr. Marshall Littman, Dr. Leslie McCormick, Dr. Sharon SternfeldDr. Cara Cohen, Dr. Nicholas Tsoulos, Dr. Elena FishmanDr. Hilary Bowers, Dr. Albert Martinez, Dr. Genevieve Minka
Dr. Wendy Chacon, Dr. Leon Kelley, Dr. Victor Lipps, Dr. Jeffrey Selzer, Dr. Lynn Herring, Dr. Teresa O’dea, Dr. Richard Walls, Dr. Vivian Tung, Dr. Christian Archambault, Dr. Veronique James, Dr. Stuart Cohen, Dr. Nancy Shiau, Dr. Linda Smith, Dr. Tevor Henderson, Dr. Cheryl Morrell, Dr. Josef Zwass, Dr. Lon Dubeye, Dr. Andrea Siano, Dr. Aida Martinez, Dr. Rachel Ireland, Dr. Louis Luevanos Dr. Laurie Tyrrell, Dr. John Cella, Dr. Jill Gustafson, Dr. Rosemary Page, Dr. David Steele, Dr. Carlos Quiros, Dr. Brian Chu, Dr. Kathleen Jones, Dr. James Moseman, Dr. Laurence Ashbacher, Dr. Theresa Dailey, Dr. Frederick Frumin,Dr. Nicholas Levy, Dr. Julie Snyder Block, Dr. Lori Taylor, Dr. Rosalind Dockweiler, Dr. Christine Wood, Dr. William Hitchcock, Dr. Robert Warner, Dr. Sheetal Gandhi, Dr. Suzanne Mills, Dr. Mona Sobel, Dr. Craig Duck, Dr. James Hay, Dr. Georgine Jorgensen, Dr. Richard Payne, Dr. James Quigley, Dr. Richard Buchta, Dr. Ann Marie Engfelt, Dr. Benjamin Siegel, Dr. Lori Gould, Dr. Micelle Sanford Dr. Annie Kupelian, Dr. Paula Grayson, Dr. Raha Shaw, Dr. Gary Chun, Dr. Matilda Remba, Dr. Janna Cataldo, Dr. Nicole Gorton, Dr. Bret Gerber, Dr. Denise Brownlee, Dr. Stuart Rubenstein, Dr. Peggy Manuel, Dr. Veda Wu, Dr. Michael Berent, Dr. Gargi Kubal, Dr. Norman Gollub, Dr. Teresa Hardisty, Dr. Jeanne Montal, Dr. Katrina Durkee, Dr. Kamei Tolba, Dr. Carol Hart, Dr. Dennis Butler, Dr. Howard Mehl, Dr. Marta Awdykovych, Dr. Uma Narayan, Dr. Richard McNeal, Dr. Marta Awdykovych Dr. Richard McNeal, Dr. Jennie Ou, Dr. Howard Smart, Dr. Neethi Ratnesar, Dr. Fujii, Dr. Mattson, Dr. Norman, Dr. Sauer, Dr. Gabriela Mogrovejo, Dr. Julie Keeler, Dr. Liz Hourihan, Dr. Dania Lindenberg, Dr. Dori Mortimer, Dr. Marvin Zaguli
Total Brain Volume over Time Total Brain Volume:
800
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1050
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1200
1250
1300
0.00 10.00 20.00 30.00 40.00 50.00
Tota
l Bra
in V
olu
me
(cc
)
Age (months)
Control LD DD
Log. (Control) Log. (LD) Log. (DD)
800
850
900
950
1000
1050
1100
1150
1200
1250
1300
0.00 10.00 20.00 30.00 40.00 50.00
Tota
l Bra
in V
olu
me
(cc
)
Age (months)
Control ASD singleASD multi Log. (Control)Log. (ASD single) Log. (ASD multi)
Simplex vs. Multiplex LD vs. DD
CLINICAL CHARACTERISTICS: Simplex More
Severe
VINELAND MULLEN: ELC
SIMPLEX SIMPLEX MULTIPLE
X
MULTIPLE
X
RED FLAGS of Autism Spectrum Disorder by 12- 24
Months
Reduced social interest and affect
lack of warm, joyful emotional expressions
lack of sharing emotional enjoyment or interest
lack of response to name
lack of showing and interacting
Abnormal language development
Lack of coordination of gaze, facial expression,gesture & sound during interactions
CUTE HAT
Abnormal Laterality to Language in ASD Infants & Toddlers
Eyler, Pierce and Courchesne
R
Age
RTemporal
cortex
Fw FwFw Bw Fw Bw Bw Bw
TYPICAL13 to 45 months
ASD14 to 47 months
L Temporal
cortex
-0.1
-0.08
-0.06
-0.04
-0.02
0
0.02
0.04
0.06
0.08
0 10 20 30 40 50
Left
-Rig
ht
Dif
fere
nce
in
Me
an F
ItC
oef
fici
en
t
TYPICALL > R
ASDR > L
0.0
1.0
Effect Size (Eta2)
Age in
months
RH recruitment may be advantageous in ASDReday & Courchesne, 2008
% S
igna
l Cha
nge
p<.005, cluster 640 mm3
SOCIAL ORIENTING EXPERIMENT
11 min 12 sec
40sec
SOCIAL
ORIENT
REST
NON
SOCIAL
ORIENT
LANGUAGE
CONTROLRepeat 2x
(random order)
IMAGING PARAMETERS
TR = 2.5 sec
# of TRs = 270
TE = 30 msec
Typical Toddlers > Autistic Toddlers
0.001
1e-8
L
Karen Pierce et al,
in manuscript
Early Brain Overgrowth May Be Caused By:
3 Year Old Autistic BoyS
IZE
AGE
NORMAL
ASD
Overgrowth
neurons
42% more neurons
overall in autistic boy
58%
more
spindle