1. Thank you: NIMH, NINDS and NICHD Simons Foundation Autism Speaks Cure Autism Now NICHD Brain Bank ATP/Harvard Brain Bank Taran Sierra

2. N EURODEVELOPMENTAL S TUDIES OF A UTISM : F ROM MRI AND F MRI TO N EURONS AND G ENES UCSD Autism Center of Excellence Eric Courchesne, Director Karen Pierce, Assistant Director

3. SIZE AGE NORMAL ASD Arrested Growth Possible Decline/Degeneration Overgrowth Three Phases of Growth Pathology in ASD Frontal Temporal Amygdala Courchesne et al 2001 Courchesne et al., 2003 Courchesne & Pierce 2005 Courchesne et al., 2007

4. 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., 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       10 30 50 70 90 -0.50.5  x x x x x x x x x x x xx x x x x x x x x x x x x x x x x x Birth 6-12 mos Dementieva et al 2005

5. Abnormal Brain Overgrowth in Autism by 2 to 4 Years of Age 900 1100 1300 1500 234 Age (years) Autism Normal Mean 1179 ml Courchesne et al., 2001 Volume (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., 2002 Carper et al 2002 Carper & Courchesne 2005 Hazlett et al., 2005 Schumann, Pierce, Courchesne in prepapration

6. Gray Matter Overgrowth in ASD * * n.s. 1. Carper et al. 2002 3.4 years * * OccipitalParietalTemporalFrontal Standard deviations from normal * p<0.05 1 2 3 4 5 * * * * * * * ç ç 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) *

7. Gray Matter Overgrowth in ASD * * n.s. 1. Carper et al. 2002 3.4 years * * OccipitalParietalTemporalFrontal Standard deviations from normal * p<0.05 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 * * *

8. (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 SIZE AGE NORMAL ASD Overgrowth Major Goals of the UCSD Autism Center of Excellence

9. What Causes Early Brain Overgrowth in ASD?

11. SIZE AGE NORMAL ASD Overgrowth Autistic (N=7) vs Control (N=6) Males Ages 2 to 15 years 68% more neurons 34% more neurons Mouton, Calhoun, Arhens- Barbeau, Courchesne

12. 68% more neurons What is the Cause of Excess Cells? What are the Resulting Cortical Defects? Gene Expression and CNV analyses Anatomic Microstructure

13. Abnormal Frontal Cortex Gene Expression at 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 Integrity DNA damage responses Cell cycle regulation Cell proliferation Apoptosis and survival Prenatal Processes Governing Patterning Left/Right neural patterning Anterior/Posterior neural patterning

14. 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 Upregulation proliferation regulators (e.g., WNT3) Abnormalities in Neural Patterning, Cellular Specification, Cell Division and Proliferation Processes Chow, Pramparo et al., in manuscript

15. Abnormal Laterality to Language in ASD Infants & Toddlers Eyler, Pierce and Courchesne R Age R Temporal cortex TYPICAL 13 to 45 months ASD 14 to 47 months Fw Bw Fw Bw L Temporal cortex 0.0 1.0 Effect Size (Eta 2 ) Age in months

16. CTGF Layer 1 - Pial Surface Layer 6 – White Matter Boundary CALB1 RORB PCP4 NTNG2