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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
Source Consultant Advisory Board
Stock Equity >$10,000
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Research Contract
Cephalon X X
Lilly X
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UCB X X
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Table 1: The SNAP Rating Scale
For each item, check the column that best describes this child: Not At Just A Quite Very All Little A Bit Much
1. Often fails to give close attention to details or makes careless mistakes in schoolwork or tasks ______ ______ ______ ______ 2. Often has difficulty sustaining attention in tasks or play activities ______ ______ ______ ______ 3. Often does not seem to listen when spoken to directly ______ ______ ______ ______ 4. Often does not follow through on instructions and fails to finish schoolwork, chores, or duties ______ ______ ______ ______ 5. Often has difficulty organizing tasks and activities ______ ______ ______ ______ 6. Often avoids, dislikes, or reluctantly engages in tasks requiring sustained mental effort ______ ______ ______ ______ 7. Often loses things necessary for activities (e.g., toys, school assignments, pencils, or books) ______ ______ ______ ______ 8. Often is distracted by extraneous stimuli ______ ______ ______ ______ 9. Often is forgetful in daily activities ______ ______ ______ ______10. Often fidgets with hands or feet or squirms in seat ______ ______ ______ ______11. Often leaves seat in classroom or in other situations in which remaining seated is expected ______ ______ ______ ______12. Often runs about or climbs excessively in situations in which it is inappropriate ______ ______ ______ ______13. Often has difficulty playing or engaging in leisure activities quietly ______ ______ ______ ______14. Often is "on the go" or often acts as if "driven by a motor" ______ ______ ______ ______15. Often talks excessively ______ ______ ______ ______16. Often blurts out answers before questions have been completed ______ ______ ______ ______17. Often has difficulty awaiting turn ______ ______ ______ ______18. Often interrupts or intrudes on others (e.g., butts into conversations/games) ______ ______ ______ ______
DSM IV Symptoms of ADHD
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Categorical Diagnosis of ADHD
Based on “symptom count” by domain
6 or more of 9 Inattention
6 or more of 9 Hyperactive/Impulsive
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Dimensional Adjunct for DSM V
Use ratings of symptom severity along with “symptom count” criteria
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Table 1: The SNAP Rating Scale
For each item, check the column that best describes this child: Not At Just A Quite Very All Little A Bit Much
1. Often fails to give close attention to details or makes careless mistakes in schoolwork or tasks ______ ______ ______ ______ 2. Often has difficulty sustaining attention in tasks or play activities ______ ______ ______ ______ 3. Often does not seem to listen when spoken to directly ______ ______ ______ ______ 4. Often does not follow through on instructions and fails to finish schoolwork, chores, or duties ______ ______ ______ ______ 5. Often has difficulty organizing tasks and activities ______ ______ ______ ______ 6. Often avoids, dislikes, or reluctantly engages in tasks requiring sustained mental effort ______ ______ ______ ______ 7. Often loses things necessary for activities (e.g., toys, school assignments, pencils, or books) ______ ______ ______ ______ 8. Often is distracted by extraneous stimuli ______ ______ ______ ______ 9. Often is forgetful in daily activities ______ ______ ______ ______10. Often fidgets with hands or feet or squirms in seat ______ ______ ______ ______11. Often leaves seat in classroom or in other situations in which remaining seated is expected ______ ______ ______ ______12. Often runs about or climbs excessively in situations in which it is inappropriate ______ ______ ______ ______13. Often has difficulty playing or engaging in leisure activities quietly ______ ______ ______ ______14. Often is "on the go" or often acts as if "driven by a motor" ______ ______ ______ ______15. Often talks excessively ______ ______ ______ ______16. Often blurts out answers before questions have been completed ______ ______ ______ ______17. Often has difficulty awaiting turn ______ ______ ______ ______18. Often interrupts or intrudes on others (e.g., butts into conversations/games) ______ ______ ______ ______
Often fails to give close attention to detail
0 +1 +2 +3
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Definition of ADHD as Psychopathology
Increasing Symptom SeverityIncreasing Symptom Severity
00 332211Not PresentNot Present
Not at All Just 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
ExampleExample:: SNAP-IV-18 score = 45 SNAP-IV-18 score = 45Divide 45 by the number of items (18) Divide 45 by the number of items (18)
45 45 18 = 2.5 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”Often fails to give close attention to detail”
Degree PresentDegree Present
Example:Example: SNAP-IV-18 score = 16 Divide SNAP-IV-18 score = 16 Divide 17 by the number of items (18) 17 by the number of items (18)
16 16 18 = 0.9 18 = 0.9
54543636181800
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Continuum of Behavior
Use ratings of full range of ADHD-like behavior from positive to negative
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Table 2: The SWAN Rating Scale
Compared to other children, how does this child do the following: far slightly slightly farbelow Below below avg. above above above avg. avg. avg. avg.
1. Give close attention to detail and avoid careless mistakes _____ _____ _____ _____ _____ _____ _____
2. Sustain attention on tasks or play activities _____ _____ _____ _____ _____ _____ _____
3. Listen when spoken to directly _____ _____ _____ _____ _____ _____ _____
4. Follow through on instructions and finish school work or chores _____ _____ _____ _____ _____ _____ _____
5. Organize tasks and activities _____ _____ _____ _____ _____ _____ _____
6. Engage in tasks that require sustained mental effort _____ _____ _____ _____ _____ _____ _____
7. Keep track of things necessary for activities _____ _____ _____ _____ _____ _____ _____
8. Ignore extraneous stimuli _____ _____ _____ _____ _____ _____ _____
9. Remember daily activities _____ _____ _____ _____ _____ _____ _____
10. Sit still (control movement of hands or feet or control squirming) _____ _____ _____ _____ _____ _____ _____
11. Stay seated (when required by class rules or social conventions) _____ _____ _____ _____ _____ _____ _____
12. Modulate motor activity (inhibit inappropriate running or climbing) _____ _____ _____ _____ _____ _____ _____
13. Play quietly (keep noise level reasonable) _____ _____ _____ _____ _____ _____ _____
14. Settle down and rest (control constant activity) _____ _____ _____ _____ _____ _____ _____
15. Modulate verbal activity (control excess talking) _____ _____ _____ _____ _____ _____ _____
16. Reflect on questions (control blurting out answers) _____ _____ _____ _____ _____ _____ _____
17. Await turn (stand in line and take turns) _____ _____ _____ _____ _____ _____ _____
18. Enter into conversations & games without interrupting or intruding _____ _____ _____ _____ _____ _____ _____
How does this child give close attention to detail? +3 +2 +1 0 -1 -2 -3
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ADHD - Combined
0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
-3 -2.5 -2 -1.5 -1 -0.5 0 0.5 1 1.5 2 2.5 3
SCORE
Pe
rce
nt
SWAN SCORE
SNAP SCORE
N = 656mean = 2.13, sd = 1.46, skew = .01
N = 847mean = .54, sd = .67, skew = 1.47
Below AverageAbove Average Average
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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)
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Dopamine Deficit Hypothesis of ADHDDopamine Deficit Hypothesis of ADHD
SNVTA
DRD2DAT
Dopamine Receptor D4 (DRD4)
Dopamine Receptor D2 (DRD2)
Wender, (1971); Levy (1990)
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Positron Emission Tomography (PET) image showing the striatum of the
human brain
PET studies of ADHD
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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
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DA
N
CH3
H311C
D
D
*
CONHCH2
ClCl
O11CH3HO
N C2H5
H
H O
HOHO OH
OH
18F
O N
Cl
Cl
11CH3HN
H
H311CO2C C6H5
H
signal
DA
DA
DA DA
MAO A
MAO A
MAO B
DA transporters
DA receptors
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Nora D. Volkow, M.D., DirectorNational Institute on Drug AbuseBrookhaven National Laboratory
Effects of Methylphenidate on the Brain
Nora D. Volkow, M.D., DirectorNational Institute on Drug AbuseBrookhaven National Laboratory
Effects of Methylphenidate on the Brain
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NHCH3
H H
H3C H
NHCH3
H H
H3C H
O
O
NH2
H H
H3C H
NH3C
CO2CH3
O
O
HN CO2CH3 S
NH2
OO
*
cocaine d-methamphetamine MDMA
methylphenidate modafinil amphetamine
Psychostimulant Drugs
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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
11C
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[11C]Cocaine
[11C]Methylphenidate
0
20
40
60
80
100
0 10 20 30 40 50 60 70 80
% P
eak
"High"
Time (min)
0
20
40
60
80
100
0 10 20 30 40 50 60 70 80
"High"% P
eak
NH3C
CO2CH3
O
O
HN CO2CH3
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Biological Bases of ADHD:The Dopamine Hypothesis
RECEPTOR
TRANSPORTER
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Caudate nucleus (Attention Network)
Nucleus accumbens (Motivation Network)
Substantia nigraVentral tegmental area
Hypothalamus
Dopamine Pathways
Frontal Cortex
RECEPTOR TRANSPORTER
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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”.
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Images Obtained with [11C]Cocaine to Assess Dopamine Transporters
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(Attention)
(Motivation)
(Attention)
(Motivation)
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(Attention)
(Motivation)
(Attention)
(Motivation)
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(Attention)
(Motivation)
Transporter PET Image
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(Attention)
(Motivation)
Receptor PET Image
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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, CADuke University, Durham, NC
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SubjectsADHD First vs FU Control ADHD vs NC
First visit Follow up p value First visit
5 F, 4 M 5 F, 4 M 1F, 4 M
Age range (yrs) 18-42 18-42 29-43
Age mean (yrs) 29.7±10 29.7±10 34.9±6.0 NS
Education (yrs) 15.7±1.9 15.7±1.9 16±2.2 NS
CARRS-A Inattention/Memory Problems
73±12 50±15 p < 0.0003 39±10 p < 0.00006
CARRS-BHyperactive/restless
58±13 43±8 p < 0.0003 40±6 p < 0.003
CARRS-EDSM-IV Inattentive symptoms
80±10 51±15 p < 0.0005 42±8 p < 0.003
SNAP Inattentive 2.1±0.9 0.6±0.5 p < 0.0007 0.7±0.5 p < 0.00002
SNAP Hyperactive 0.6±0.7 0 NS 0.5±0.8 NS
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DAT images in the first visit
ControlSubjects(n = 5)
Striatum Cerebellum
ADHDSubjects(n = 9)
High
Low
[C-11]cocaine
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Effect of chronic treatment (12 months) with oral methylphenidate in ADHD subjects
Baseline After methylphenidate
ADHDSubjects(n = 9)
Baseline
ControlSubject(n = 5)
12 months retest(no medication)
High
Low
[C-11]cocaine
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ROI measures of DAT availability
23±25%p < 0.04
18±19%p < 0.03
41±31%p < 0.005
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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).
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MPH-related Decrease in Task-related Increase in Glucose Metabolism from PET
ADHD-off Control-off
ADHD-onControl-on
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National Children’s Study SampleAll 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
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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
1st Trimester 5 years
2nd Trimester 7 years
3rd Trimester 9 years
Delivery 12 years
6 months 16 years
12 months 20 years
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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
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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*
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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
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Different techniques and their relative ease of implementation
0.00
1.00
2.00
3.00
4.00
5.00
6.00
Rating
Praise/PositiveAttention
Rewarding
TransitionalStatements
When ThenStatements
Planned Ignoring
Planning Ahead
PointSystems/StarChart
Time Out
Time out frompriviledges
ProblemSolving/Paste
Praise/Positive Attention 5.14
Rewarding 4.67
Transitional Statements 5.19
When Then Statements 5.00
Planned Ignoring 3.95
Planning Ahead 4.48
Point Systems/Star Chart 4.10
Time Out 4.10
Time out from priviledges 3.85
Problem Solving/Paste 3.90
Technique taught in COPE
Different techniques and their relative ease of implementation
0.00
1.00
2.00
3.00
4.00
5.00
6.00
Rating
Praise/PositiveAttention
Rewarding
TransitionalStatements
When ThenStatements
Planned Ignoring
Planning Ahead
PointSystems/StarChart
Time Out
Time out frompriviledges
ProblemSolving/Paste
Praise/Positive Attention 5.14
Rewarding 4.67
Transitional Statements 5.19
When Then Statements 5.00
Planned Ignoring 3.95
Planning Ahead 4.48
Point Systems/Star Chart 4.10
Time Out 4.10
Time out from priviledges 3.85
Problem Solving/Paste 3.90
Technique taught in COPE
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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 jar2) 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
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Attention Training: Training of Alerting Function
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Images Obtained with [11C]Cocaine to Assess Dopamine Transporters
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(Attention)
(Motivation)
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DA
signal
DA
DADA DA
MAO A
DA transporters [11C] MPH or Cocaine
DA D2 receptors[11C] Raclopride
PET Measures1. DA Transporters2. DA D2 Receptors
DRD2DAT
Dopamine- Deficit Hypothesis of ADHD/HKD(based on stimulant drug site-of- action hypothesis)