Thank you:NIMH, NINDS and NICHD

Simons FoundationAutism Speaks

Cure Autism NowNICHD Brain Bank

ATP/Harvard Brain Bank

Taran

Sierra

NEURODEVELOPMENTAL STUDIES OF AUTISM:

FROM MRI AND FMRITO NEURONS AND GENES

UCSD Autism Center of Excellence Eric Courchesne,

DirectorKaren Pierce, Assistant Director

SIZ

E

AGE

NORMAL

ASD

Arrested Growth

Possible Decline/Degeneration

Overgrowth

Three Phases of Growth Pathology in ASDFrontal

Temporal

AmygdalaCourchesne et al 2001Courchesne et al., 2003Courchesne & Pierce 2005Courchesne et al., 2007

Abnormal Brain Overgrowth in ASD in First Two Years of Life Courchesne et al., 2003 JAMA

Data from Webb, Dawson 2007 = *And Courchesne 2003

** ****

** **10

30

50

70

90

Birth 6-12 mos

Dementieva et al., 2005Dissanayaki et al., 2005Hazlett et al., 2005Dawson et al., 2007Mraz et al., 2007Webb et al., 2007Elder et al., 2007

◊

◊

10

30

50

70

90

-0.5 0.5

xx

x

x

xx

x

x

x

x

xxx

x

x

x

xxx

xxxx

x

x

x

x

x

x

x

Birth 6-12 mosDementieva et al 2005Dementieva et al 2005

Abnormal Brain Overgrowth in Autism by 2 to 4 Years of Age

900

1100

1300

1500

2 3 4Age (years)

Autism

Normal Mean1179 ml

Courchesne et al., 2001

Vo

lum

e (

ml)

Autism case Macrencephaly

Average Normal

Recent MRI Studies Also Showing Abnormal Brain

Overgrowth in Autism by 2 to 4 Years of Age

Sparks et al., 2002Carper et al 2002

Carper & Courchesne 2005Hazlett et al., 2005

Schumann, Pierce, Courchesne in prepapration

Gray Matter Overgrowth in ASD

*

*n.s.

n.s.

n.s. n.s.

1. Carper et al. 2002 3.4 years

*

*

OccipitalParietalTemporalFrontal

Sta

nd

ard

dev

iati

ons

from

nor

mal

*p<0.05

1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5

***

*

*

*

*

çç

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 19.1 years(left cerebrum only)

*

Gray Matter Overgrowth in ASD

*

*n.s.

n.s.

n.s. n.s.

1. Carper et al. 2002 3.4 years

*

*

OccipitalParietalTemporalFrontal

Sta

nd

ard

dev

iati

ons

from

nor

mal

*p<0.05

1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6

***

*

*

*

*

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 19.1 years(left cerebrum only)

6. Schumann, Pierce et al. 2010 2 years

*

**

(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

SIZ

E

AGE

NORMAL

ASD

OvergrowthMajor Goals of the

UCSDAutism Center of

Excellence

What Causes Early Brain Overgrowth in ASD?

SIZ

E

AGE

NORMAL

ASD

OvergrowthAutistic (N=7) vs Control

(N=6) Males

Ages 2 to 15 years

68% more neurons

34% more neurons

Mouton, Calhoun, Arhens-Barbeau, Courchesne

68% more neurons

What is the Cause of Excess Cells?

What are the Resulting Cortical Defects?

Gene Expression and CNV analyses

Anatomic Microstructure

Abnormal Frontal Cortex Gene Expressionat Young Ages (2 to 14 years) in Autism

102 differentially expressed genes

Chow, Pramparo et al., in manuscript

Prenatal Pathways Governing Cell Numbers and Functional IntegrityDNA damage responses

Cell cycle regulationCell proliferationApoptosis and survival

Prenatal Processes Governing PatterningLeft/Right neural patterning

Anterior/Posterior neural patterning

Downregulation

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

Upregulationproliferation regulators (e.g., WNT3)

Abnormalities in Neural Patterning, Cellular Specification, Cell Division and Proliferation

Processes

Chow, Pramparo et al., in manuscript

Abnormal Laterality to Language in ASD Infants & Toddlers

Eyler, Pierce and Courchesne

R

Age

RTemporalcortex

TYPICAL13 to 45 months

ASD14 to 47 months

Fw FwFw Bw Fw Bw Bw Bw

L Temporal

cortex

0.0

1.0

Effect Size (Eta2)

Age in months

CTGF

Layer 1 - Pial Surface

Layer 6 – White Matter Boundary

CALB1

RORB

PCP4

NTNG2