2. Evaluation of the Dopamine Hypothesis of ADHD with PET Brain Imaging James M. Swanson, Ph.D. Professor of Pediatrics, UC Irvine Adjunct Professor of Psychiatry, WCM Cornell

3. DSM IV Symptoms of ADHD

5. Categorical Diagnosis of ADHD Based on “symptom count” by domain 6 or more of 9 Inattention 6 or more of 9 Hyperactive/Impulsive

7. Dimensional Adjunct for DSM V Use ratings of symptom severity along with “symptom count” criteria

8. Often fails to give close attention to detail 0 +1 +2 +3

9. Definition of ADHD as Psychopathology Increasing Symptom Severity 0 3 21 Not Present Not at AllJust A Little Quite a Bit Very Much Add up the scores and divide by the number of items used in a particular scale (SNAP, Conners, etc.) to get a Average Rating Per Item (ARI) score Example: SNAP-IV-18 score = 45 Divide 45 by the number of items (18) 45  18 = 2.5 Severity of “symptom presence” on 4-point scale: Severity of “symptom presence” on 4-point scale: “Often fails to give close attention to detail” Degree Present Example: SNAP-IV-18 score = 16 Divide 17 by the number of items (18) 16  18 = 0.9 5436 18 0

10. Continuum of Behavior Use ratings of full range of ADHD-like behavior from positive to negative

11. How does this child give close attention to detail? +3 +2 +1 0 -1 -2 -3

12. N = 656 mean = 2.13, sd = 1.46, skew =.01 N = 847 mean =.54, sd =.67, skew = 1.47 Below AverageAbove Average Average

14. Presumed Etiologies of ADHD Environmental –Fetal distress (eg, preterm birth: Lou, 1996) –Lifestyle risks (eg, smoking during pregnancy: Linnet et al, 2006) Genetic –Dopamine genes (eg, DAT and DRD4: Cook et al, 1995; LaHoste et al, 1996) –Other genes (eg, from genome scan locations)

15. Dopamine Deficit Hypothesis of ADHD SN VTA DRD2 DAT Dopamine Receptor D4 (DRD4) Dopamine Receptor D2 (DRD2) Wender, (1971); Levy (1990)

16. Positron Emission Tomography (PET) image showing the striatum of the human brain PET studies of ADHD

17. James Swanson, Gene-Jack Wang, Jacob Hooker, Tim Wigal, Scott Kollins, Jeff Newcorn, Frank Telang, Jean Logan, Wei Zhu, Yeming Ma, Chris Wong, Kith Pradhan, Joanna Fowler, and Nora Volkow

18. DA HN H H 3 11 CO 2 C C 6 H 5 H signal DA MAO A MAO B DA transporters DA receptors

19. Nora D. Volkow, M.D., Director National Institute on Drug Abuse Brookhaven National Laboratory Effects of Methylphenidate on the Brain Nora D. Volkow, M.D., Director National Institute on Drug Abuse Brookhaven National Laboratory Effects of Methylphenidate on the Brain

20. * cocaine d-methamphetamine MDMA methylphenidate modafinil amphetamine Psychostimulant Drugs

21. Positron Emission Tomography (PET) studies show that methylphenidate acts predominantly in the striatum of the human brain where it binds to DA transporters [11C]methylphenidate methylphenidate PET studies of the Site of Action of Methylphenidate in the Human Brain 11 C

22. [ 11 C]Cocaine [ 11 C]Methylphenidate 0 20 40 60 80 100 0 10 20304050607080 % Peak "High" Time (min) 0 20 40 60 80 100 0 10 20 30 40 50607080 "High" % Peak

23. Biological Bases of ADHD: The Dopamine Hypothesis RECEPTOR TRANSPORTER

24. Caudate nucleus (Attention Network) Nucleus accumbens (Motivation Network) Substantia nigra Ventral tegmental area Hypothalamus Dopamine Pathways Frontal Cortex RECEPTORTRANSPORTER

25. Dopamine Transporter Density in Patients with ADHD (Dougherty et al, 1999) “We have shown a 70% increase in age-corrected dopamine transporter density in patients with ADHD compared to healthy controls”.

27. Images Obtained with [ 11 C]Cocaine to Assess Dopamine Transporters

28. (Attention) (Motivation) (Attention) (Motivation)

29. (Attention) (Motivation) (Attention) (Motivation)

30. (Attention) (Motivation) Transporter PET Image

31. (Attention) (Motivation) Receptor PET Image

32. Chronic treatment with methylphenidate increases dopamine transporter density in patients with attention deficit hyperactive disorder. G-J Wang*, ND Volkow, T Wigal, S Kollins, J Newcorn, F Telang, J Logan, C Wong, JS Fowler, JM Swanson. Brookhaven National Laboratory, Upton, NY Mt Sinai School of Medicine, NY, NY NIAAA/NIDA, Rockville, MD UC Irvine, Irvine, CA Duke University, Durham, NC

33. Subjects ADHDFirst vs FUControlADHD vs NC First visitFollow upp valueFirst visit 5 F, 4 M 1F, 4 M Age range (yrs)18-42 29-43 Age mean (yrs)29.7±10 34.9±6.0NS Education (yrs)15.7±1.9 16±2.2NS CARRS-A Inattention/Memory Problems 73±1250±15p < 0.000339±10p < 0.00006 CARRS-B Hyperactive/restless 58±1343±8p < 0.000340±6p < 0.003 CARRS-E DSM-IV Inattentive symptoms 80±1051±15p < 0.000542±8p < 0.003 SNAP Inattentive2.1±0.90.6±0.5p < 0.00070.7±0.5p < 0.00002 SNAP Hyperactive0.6±0.70NS0.5±0.8NS

34. DAT images in the first visit Control Subjects (n = 5) StriatumCerebellum ADHD Subjects (n = 9) High Low [C-11]cocaine

35. Effect of chronic treatment (12 months) with oral methylphenidate in ADHD subjects Baseline After methylphenidate ADHD Subjects (n = 9) Baseline Control Subject (n = 5) 12 months retest (no medication) High Low [C-11]cocaine

36. ROI measures of DAT availability 23±25% p < 0.04 18±19% p < 0.03 41±31% p < 0.005

37. Summary and Conclusion This study reveals no significant difference in DA transporter availability in a comparison of stimulant- naive ADHD and control subjects. After long-term treatment of ADHD with stimulant medication, an increased DA transporter was observed, and a comparison of the two groups revealed significantly higher DA transporter density in ADHD than control subjects. Upregulation of DA transporter during chronic treatment with methylphenidate could underlie the decrease in methylphenidate’s efficacy with chronic treatment (tolerance).

39. MPH-related Decrease in Task-related Increase in Glucose Metabolism from PET ADHD- off Control-off ADHD-on Control-on

42. National Children’s Study Sample All Births in the Nation Sample of Study Locations Sample of Study Segments Sample of Study Households Sample of Study Women 105 Locations (counties) Selection of neighborhoods All or a sample of households within neighborhoods All eligible women in the households - ~1.5 million ~4 million births in 3,141 counties Sample of Study Children 105,000 births

43. Schedule of Participant Visits for 100,000 children (about 5,000 with ADHD 14 face-to-face contacts over 21 year study period Contacts most frequent early in the study Between visits: ongoing data collection by phone, PDA, etc. Enrollment 3 years 1 st Trimester 5 years 2 nd Trimester 7 years 3 rd Trimester 9 years Delivery 12 years 6 months 16 years 12 months 20 years

44. What is COPE and CUIDAR? (www.CUIDAR.net) Community Parent Education Program “Service before diagnosis” approach A 10-week parenting skills program 2 hour weekly sessions Delivered in large groups (10+ families) Non-didactic model CUIDAR offers English or Spanish

46. COPE Session outline: –Social catch up – coffee/cookies –Review homework –Watch videotape of parent making an error –Small group discussion of errors/Small group discussion of solutions –Leader modeling solution –Brainstorm homework application –Parent role play of solutions*

47. CUIDAR - COPE Topics: –Praise and Positive Attention –Planning Ahead –Transitional Warnings –Response Cost –Time Out –When-Then –Ignoring –Rewards and Star Charts –Problem Solving - PASTE

49. Alerting Task – Alert Frog Developed a developmentally appropriate task to specifically target alerting Training Alerting: Train child to wait and remain in a ready-to-respond state for increasing lengths of time, in order to rapidly respond to infrequent, brief events Alert Frog task: Child is instructed to catch as many flies as they can from a jar using the space bar, but they must follow 2 rules: 1)They can only press the space bar when the fly exits the jar 2)The children are instructed that they may hear a bell before some trials, but they must wait for the fly to exit the jar before pressing the space bar

50. Attention Training: Training of Alerting Function

52. Images Obtained with [ 11 C]Cocaine to Assess Dopamine Transporters

54. (Attention) (Motivation)

58. DA signal DA MAO A DA transporters [11C] MPH or Cocaine DA D2 receptors [11C] Raclopride PET Measures 1.DA Transporters 2.DA D2 Receptors DRD2 DAT Dopamine-Deficit Hypothesis of ADHD/HKD (based on stimulant drug site-of- action hypothesis)