1. Scientific Update of ADHD
Russell Schachar
The Hospital for Sick Children
Department of Psychiatry
Brain and Behaviour Programme
University of Toronto

2. Affiliations CIHR NINDS Lilly Purdue Frederick Shire
Barr, Kennedy, Ickowicz, Crosbie, Pakulak, Ornstein
Noseworthy, Chevrier
Robaey, Perusse
NINDS
Levin, Dennis, Barnes
Lilly
Purdue Frederick
Shire

3. Outline Summary and overview current understanding Neuroscience 101
Genes
Proteins
Brain structure
Cognitive function
Behavior
Caveats
Caveats
not an overview of ADHD
not focused on treatment (RT)

4. ADHD g 1 g 2 g 3 hyp-imp inattention function environment
Cell membranes, transmitters, assemblies…
Refer to this schematic several times. It is important to know how genes influence complex behaviours as a context for what is currently known about the etiology of ADHD.
Implications
Genes with a weak effect on behavioural manifestations of ADHD, may have stronger effects on fundamental processes
Proteins
g 1
g 2
g 3

5. Genetics

6. What are genes?
DNA is specific sequence of nucleotide bases that encode instructions for proteins
Genome is complete set of DNA

7. How do genes function? Many changes evident and passed on
Most changes cannot be seen by microscope
Most base pairs are not involved in genes and are not functional
Can be used to track functional changes
May regulate gene expression or function
Epigenetic factors affect gene function
Many hereditary effects may be outside of genes

8. Neurotransmitter systems
Serotonin
Noradrenalin
Glutamate
GABA
Transporters and receptors variably distributed
Dopamine transporter
DAT not expressed in some parts of brain

9. Dopamine D4 48bp Repeat Variants: Pharmacologic differences not linearly correlated with number of repeats
EC50
Asghari et al, 1995 Jovanovic et al, 1999
2R 4R 7R 10R
Implication: the 7R allele has a blunted response to dopamine

10. Critical for controlled release of neurotransmitters into the synaptic cleft
Loss of expression of a single copy of the gene results in dysregulation in the controlled release of glutamate, dopamine, and serotonin in select brain regions
SNAP-25
SNAP-25

11. Genes, proteins and neural development

12. Neural development Stem cells differentiate Half survive
Growth factors (sonic hedgehog, notch, BDNF)
Half survive
Development depends of where they end up, activity there (use it or lose it!)
Rate of division/survival depends on experience, formation of synapses, integration into networks
Loss of neurons normal (exaggerated in some diseases)
Neurons likely regenerate and affected by experience (can teach old dog new tricks)
Environment can affect gene expression

13. Brain tour

14. Phineas Gage

15. Prefrontal cortex Not involved in specific tasks
Executive control of behaviour, thought and affect
Organization and planning for future action and social goals
Balances perceptual, instinctual and motivational input
Reflective: guided by internal states and intentions
Control subordinate attention and motor processes

16. Prefrontal subcortical circuits
Begin and end in frontal cortex
Pass through subcortical structures
Reciprocal and interacting connections
Excitatory and inhibitory neurotransmitters
Separate yet overlapping and interacting
Specific and intermingled mixture of deficits
Evident in individuals with massive lesions

17. Dorsolateral circuit Organization, planning, attention
Lesions generate concrete thinking, inability to stop, shift set, filter and ignore distractions, plan and organize

18. Orbitofrontal circuit
Mediates socially appropriate behaviour
Lesions lead to marked personality change, social disinhibition, explosiveness, tactlessness, lability, lack of interpersonal sensitivity

19. Anterior cingulate circuit
Motivation, balancing competing demands, performance monitoring
Lesions result in akinetic mutism, apathy, lack of motivation, insensitive to errors

20. Frontal/ executive processes “wave of attention”
Encoding, maintaining, retrieving in working memory
Preparing and anticipating
Interference management
Withholding of response tendency
Maintain set
Retract or inhibition
Error detection
Error correction
Advances in conceptualization and measurement of EF
problems of EF theories
implies localization
tightly relates symptoms and functions
invokes homunculus
mixes levels of analysis
not all PFC functions are executive
not all EF are PFC

21. Summary Considerable understanding of brain development and function
Differentiation in structure and function
Cognitive deficits
Genetic risks
Structural and functional anomalies

22. ADHD genetics Highly genetic Not simple Mendelian inheritance
Multigenic
Non-genetic factors contribute separately and through various combinations
Disorder occurs when combination of genetic and non-genetic factors exceeds some threshold
Nature of risk and mode of inheritance unknown

23. Genetics of ADHD % risk to family % concordance
Genetic risk high but not complete
Incomplete penetrance
Non genetic risks
Variable expression

24. Genome Scan
D19S229
D19S247
D19S204
D19S221
D19S179
D19S248
D19S178
D19S246
D19S180
D19S254
Systematically screen all of the chromosomes for linkage using DNA markers spaced at regular intervals

25. Genome scans for ADHD Fisher et al., 2002 Ogdie et al., 2003
UCLA 126 affected sib pairs
no regions met genome-wide significance levels
suggestive 5p12, 10q26, 12q23, 16p13 (Smalley, 2002)
Ogdie et al., 2003
expansion of Fisher et al., sample sib pairs
17p11 (LOD 2.98), 16p13
Bakker et al., 2003
164 Dutch affected sib pairs
regions with LOD scores > 3, 15q15.1, 7p13
LOD score > 2, 9q33.3

26. Candidate gene study Case-control Ethnicity
Compare samples
Ethnicity
Associated characteristic or disorder
Family-based
Compare children and their parents or siblings

27. Dopamine, cognition and behaviour
Neurotoxin reduces DA in rats
hyperlocomotion, learning problems
DA depletion impairs working memory
Impulsiveness associated with low extracellular DA
Blocking DA reuptake makes DA more available and improves executive control
DA particularly important
uptake [18F]F-DOPA labels CAT terminals
uptake significantly less in left and medial PFC of ADHD adults compared to controls

28. Drugs and ADHD

29. Psychostimulants and ADHD
54 – 75 % adults and children with ADHD responds to methylphenidate (0.6 mg/kg)
(Spencer et al 2001)
The behavioural modifications induced by stimulants occurs with the reaching of peak plasma level

30. Dopamine Transporter
Some individuals with ADHD, have higher expression of the dopamine transporter.
Possible mechanism of genetic susceptibility is over expression of the DAT protein
Stimulants blockade dopamine transporter and temporarily correct the levels of dopamine.
DAT Knock Out mouse
difficulty shifting - perseverative errors
novelty-driven hyperactivity
spatial learning deficit

31. Synaptosomal-Associated Protein of 25 kDa (SNAP-25)
Rationale: mouse irradiation mutant strain Coloboma has a single copy of the SNAP-25 gene. The other copy has been deleted.
1) hyperactive
2) responsive to dextroamphetamine
3) not responsive to methylphenidate
4) delayed in some developmental milestones

32. A number of Genes Identified as linked to ADHD What now?
Confirm linkage in larger samples
Determine how these genes contribute to ADHD
Additional candidates e.g., neurotrophic factors

33. Neuroimaging Computed tomography (CT)
Series of x rays from different angles
Positron emission tomography (PET)
Inject radioisotope that emits positrons
Water labelled with oxygen-15 measure changes in blood flow
Deoxyglucose labelled with florine-18 which accumulates in active cells
Magnetic resonance imaging (MRI)
Magnets detect magnetic molecules
fMRI detects changes in magnetic properties of hemoglobin as it carries O2 to active brain cells

35. Brain structure and ADHD

36. Inhibitory control
Withholding and withdrawing of responses if intention or circumstances change or error is made
Failure of inhibition results in errors & impulsiveness

37. Inhibition and ADHD Activates orbital, DLPF and basal ganglia
Rich in DA
Disruption of DA by knock out or neurotoxins affects executive control
DA tone associated with executive control
Impulsiveness associated with low extracellular DA
Blocking DA (mostly in basal ganglia) reuptake makes DA more available and improves executive control

38. Stop Signal Task * X/O fixation point
go stimulus: choice reaction time task
500 ms
motor response
1000 ms
Inter-trial interval = 3000 ms

39. Stop Signal Task * X/O stop signal delay (variable) stop signal 500 ms
RED
SCREEN or
TONE
stop signal
1000 ms
500 ms

40. Latency of inhibition (SSRT) in ADHD and controls
SSRT (ms)
Schachar et al., 2001

41. Inhibition & psychopathology
IQ, age, aggression, speed, reading
Osterlaans et al., 1999

42. Impulsive Personality

43. Inhibition and Methylphenidate Response
T-score (Mean = 50, SD = 10)
Tannock, Schachar & Logan, 1995

45. Inhibition in concordant and discordant siblings
SSRT ms
Concordant
Disconcordant
Controls

46. Evidence of performance monitoring
Introspection
Slowing following errors
Slowing following correct responses
Self-detected action slips or errors due to faulty knowledge (external feedback)
Pattern seen in range of tasks
Speeded choice response tasks
Memory tasks
Inhibition tasks

47. Relevance of performance monitoring to ADHD
Poorly regulated behaviour
“often fails to give close attention to details or makes careless mistakes in schoolwork, work, or other activities”
Inaccurate and variable task performance

48. Slowing after non-stopped responses in ADHD and controlsms

49. Executive control summary
New breed of measures of specific processes
Cognitively and neurally distinct, multiple deficits characteristic of ADHD
Functional assessment warranted

50. What do you mean “Cognitive tests are not diagnostic”?
Clinic sample (N = 100)
ADHD controls
50/25 50/5
Of 30 cases with “diagnostic marker”, 25/30 =83% will be ADHD
General population (N = 100)
5/ /19
Therefore, of every 21.5 cases with the “diagnostic marker”, 19/21.5 = 88% will be controls!

51. “Environmental” causes of ADHD/cognitive deficit
Traumatic
closed head injury
prematurity
radiation
Toxic
alcohol (FAS)
smoking
Social / stress (alteration in DA, NA, S release in PFC)
in animals & humans disrupts complex cognitive function
maternal stress during pregnancy
disrupted early care–giving

52. School policy dilemma
ADHD is a learning problem associated with cognitive deficits and academic underachievement

53. Approach differs from RD
But is handled differently than learning disability
Accommodation in classroom

54. Summary Heritable Genetic risks Structure Function Non-genetic factors
Educational system

55. Opportunities for participation
Children years
Presumptive diagnosis of ADHD
Two affected children and both parents
Willing to give blood
No exclusions
Teju Pathare (416)
One affect, sibling unaffected
Tracee Francis (416)