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

m

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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

ll

l

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l

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

x

x

xxx

x

x

xxxx

xxx x

x

x

x

x

x

x

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

850

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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 LD DD

Log. (Control) Log. (LD) Log. (DD)

800

850

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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