ADHD vs. ADD: Neurobiological Differences and Treatment Implications

1. I have hypothesized that • ADD is a different disorder from ADHD. They have…. • different cognitive & behavioral profiles, • different patterns of comorbidities, • different responses to medication, and • different underlying neurobiologies.

2. In ADHD there is a primary problem in the striatum I hypothesize that in ADD there is a primary problem in PFC (in the PFC-parietal network)

3. The best mechanism from clearing away released dopamine is by dopamine transporter proteins. Dopamine transporter is abundant in the striatum but sparse in prefrontal cortex.

4. The dopamine receptor subtype, DRD4, is present in prefrontal cortex in humans, but not in the striatum (Meador-Woodruff et al., 1996)

5. Polymorphisms in the DAT1 gene are more strongly linked to ADHD and the striatum the 7-repeat allele polymorphism of the DRD4 gene is more strongly linked to ADD and prefrontal cortex

6. ADHD ADD Striatum Prefrontal Cortex DAT1 DRD4

7. ADD (ADHD without hyperactivity), a neurobiologically and behaviorally distinct disorder from ADHD (with hyperactivity) Adele Diamond (2005) Development and Psychopathology, 17, 807-825

8. Levels of hyperactive-impulsivesymptoms are correlated withthe number of DAT1high-risk alleles but levels of inattentivesymptoms are not (Waldman et al., 1998)

9. DAT binding specifically in the striatum has been found to be related to motor hyperactivity but not to inattentive symptoms (Jucaite et al., 2005)

10. A link between the DRD4 gene and ADD is consistent with the finding of Auerbach et al. (2001) Significant relation between individual differences in sustained attention & working memory and polymorphism of the DRD4 gene in normal infants (those with the 7-repeat-allele performing worse)

11. A role for polymorphisms of the DAT1 gene in ADHD is consistent with the efficacy of methylphenidate in treating ADHD, as methylphenidate acts directly on DAT function (Dresel et al., 2000; Seeman & Madras, 1998; Shenker, 1992; Volkow et al., 1998)

12. Methylphenidate’s mechanism of action The dopamine transporter normally moves dopamine from the synapse back into the sending neuron. Methylphenidate blocks the dopamine transporter, causing an increase in dopamine concentration at the synapse. Synapse Dopamine Dopamine receptor

13. Most children with ADHD (as high as 90%) respond positively to methylphenidate (Ritalin). Over two-thirds respond positively to methylphenidate in moderate to high doses. Consistent with… … methylphenidate acting directly on DAT, … DAT being particularly important in the striatum, and … the striatum being the site of the primary disturbance in ADHD.

14. On the other hand, a significant percentage of children with ADD are not helped by methyl-phenidate and those who are helped often do best at low doses. (Barkley et al., 1991; Barkley, 2001; Milich et al., 2001; Weiss et al., 2003)

15. Recent research suggests that low doses of MHP (dosages likely to be effective in treating ADD) preferentially release DA & NE in the rat brain (Ishimatsu, Kidani, Tsuda, & Akasu, 2002). Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses. (Berridge et al., 2006)

16. Implications… For ADD: Amphetamines, not methylphenidate, and if latter, then low doses – Doctor should do dose-response curves Studies that combine ADHD-IA & ADHD-C are combining 2 different disorders into one group “Attention deficit disorder” is a misnomer – problems with motivation and with working memory

17. By focusing on early stages in the development of executive functions rather than trying to remediate deficits at later ages, it might be possible to reduce the incidence or severity of mental health disorders of executive function, such as ADHD, addictions, or conduct disorder.

18. How can young children be helped to develop these critical EF abilities?

19. The Tools of the Mind program is based on theories of Vygotsky and Luria Elena Bodrova & Deborah Leong

20. Vygotsky: Engagement in mature make-believe play is the major mechanism for developing self-regulation in young children.

21. During social pretend play, children must hold their own role and those of others in mind (working memory) • inhibit acting out of character (employ inhibitory control), and • flexibly adjust to twists and turns in the evolving plot (cognitive flexibility) • -- all three of the core executive functions thus get exercise.

22. Deb and Elena tried EF activities as a module, added onto a curriculum. They found that children improved on what they practiced in the module, but the benefits did not transfer to other contexts or other EF skills.

23. They found that for benefits to generalize to other contexts and other EF skills, supports for, training in, and challenges to EF needed to be embedded in all aspects of the school day.

24. Buddy Reading

25. vs. what teachers usually do: - avoid problem situations - provide external control - scold for lack of control

26. In evaluatingTools we specifically chose EF measures completely different from anything any of the children had ever done before. To see a difference by condition, the children would have to TRANSFER their training in EF to utterly new situations.

27. HEARTS & FLOWERS Congruent Incongruent Push Left Push Right Push Right Push Left

29. Flanker Task

30. Reverse Flanker attend to the flankers

31. Flanker Effect for Single-Task Block vs. Mixed Block Non-Switching Trials Only 300 250 200 msec 150 100 50 0 Large Inside Large Inside Small Inside Small Outside Large Outside Small Outside Large Outside Small Inside Block 1 Block 3 (Mixed) Regardless of stimulus size, or whether a trial has an Inside or Outside target, The Mixed block always shows a significantly greater Flanker Effect.

32. Both conditions involved… • new programs, instituted at the same time. • the same books, classroom set-up, toys, & materials. • the same amount of in-classroom coaching support, same # of professional development hours, and same teacher stipends for attending workshops. • the same curricular content and covered the same topics. Teachers & assistants were randomly assigned to condi-tion by level of education (half of those w/ AA degrees & half w/ BAs were randomly assigned to each condition).

33. The conditions differed in some approaches to instruction but primarily in that the Tools condition included EF-promoting activities interwoven in all school activities throughout the day.

34. All children came from the same neighborhood and were randomly assigned to Tools or district-curriculum classrooms.

35. 1 or 2 Yrs of 1 Yr of 2 Yrs of District Curr. Tools Tools Mean age in years5.145.15 5.12 Percent Hispanic9391 91 Percent Male5541 51 % w/ family income <$25,000/year 7671 86 Avg yrs of mother's ed 1212 12 Ns per group6232 63 all were poor & at risk. all tested in their 2nd yr of presch.

36. HEARTS & FLOWERS Congruent Incongruent Push Left Push Right Push Right Push Left

37. Percentage of Correct Responses on the Incongruent Block of Hearts & Flowers Task 90 85 80 75 70 65 Percent Correct 60 55 50 45 40 35 30 No Tools 1 Year Tools 2 Year Tools

38. Mixed Block (Hearts & Flower Trials Intermixed) Percent of Children who Passed Criterion for Testing Almost 2x as many in Tools passed practice Percent Passing

39. Reverse Flanker attend to the flankers

40. Percentage of Correct Responses on Reverse Flanker 90 85 80 75 70 65 Percent Correct 60 55 50 45 40 35 30 No Tools 1 Year Tools 2 Year Tools

41. Whether children were in Tools of the Mind or not accounted for more variance in EF than did age or gender.

42. Our finding of better performance on these objective, behavioral measures is consistent with findings that on questionnaire measures, parents and teachers rate children in Tools as higher on EF (Bartnett et al. 2007).

43. The more EF-demanding the task, the more highly the task correlated with academic performance.

44. Correlation of Percentage of Correct Responses on the Hearts & Flowers Task with Academic Performance Measures Note that the greater the degree of cognitive control (EF) required by the condition of the Dots task, the greater the size and number of significant relations with academic performance.

45. November 30, 2007

46. Superior academic performance in children who have been through Tools has been replicated in other Tools of the Mind programs with other children and other teachers, in other schools and states, and with different comparison conditions.

47. Take-home Message #1: EF skills can be improved even in children as young as 4-5 years by regular teachers in regular classrooms without expensive, highly technical equipment, without 1:1 attention, without highly trained specialists.