1. Early Stimulant Exposure Impact on Later Substance Abuse: A Longitudinal Study F. Xavier Castellanos Rachel Klein Sal Mannuzza John Moulton NYU Child Study Center

2. The New York Longitudinal Sample Recruited 1970 – 1977 Lower middle class Caucasians; > 90% male Initial ages 6 to 12 y Pervasively hyperactive (included blinded in- school observations) Excluded if primarily aggressive [Main source of DSM-III criteria for ADHD]

3. Treatment of ADHD in Childhood All subjects diagnosed by Rachel Klein All psychopharmacology managed by Don Klein Free treatment – research clinic Other options essentially unavailable Methylphenidate – mean 38 mg/day –Identical to MTA titration! Duration: 7 d to 5 y; mean 2.2 y

6. Zijdenbos, Giedd, Blumenthal, Paus, Rapoport, & Evans How Do We Measure the Brain? Template brain Deformation field Atlas defined on template brain

7. Total Cerebral Volumes 700 800 900 1000 1100 1200 1300 1400 1500 0510152025 AGE (y) mL ADHD F ADHD M NV F NV M N=291; 544 scans

8. Total Cerebral Vol. Growth Curves Controls > ADHD P<.003 Castellanos, JAMA 2002

9. 1000 1020 1040 1060 1080 1100 1120 1140 1160 1180 45678910111213141516171819202122 Age (years) mL ADHD MN NV HealthyControls Total Cerebral Volume in Healthy Controls, Medicated ADHD, and Initially Unmedicated ADHD

11. N=291

12. Early Normal White Matter Development Paus et al., 2001 –Brain Res Bull

13. Normal White Matter Development - Adulthood Increases ~linearly to max at ~ age 44 N=70 men Cross-sectional Frontal, temporal WM Bartzokis et al., 2001 –Arch Gen Psychiatry

14. Enduring Stimulant Effects? Not on teacher or parent behavior ratings Sensitization of accumbal circuitry? –Predisposition to substance abuse? –Well documented in animal studies Alternatively: protective against substance abuse Mechanism? –Trophic effect on myelination?

15. NY Longitudinal Study – Next Phase Reassess outcome at middle adulthood –Mean age 39 y Interval substance abuse, psychiatric, functional outcomes Relate 3-T high-resolution structural MRI including diffusion tensor imaging to outcome –Comparison with prospective control group –Stratify by age treatment began NIDA – R01 DA-16979