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

Speaker’s Bureau

Research Contract

Cephalon X X

Lilly X

McNeil X X

Shire X

UCB X X

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

Categorical Diagnosis of ADHD

Based on “symptom count” by domain

6 or more of 9 Inattention

6 or more of 9 Hyperactive/Impulsive

Dimensional Adjunct for DSM V

Use ratings of symptom severity along with “symptom count” criteria

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

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

Continuum of Behavior

Use ratings of full range of ADHD-like behavior from positive to negative

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

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

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)

Dopamine Deficit Hypothesis of ADHDDopamine Deficit Hypothesis of ADHD

SNVTA

DRD2DAT

Dopamine Receptor D4 (DRD4)

Dopamine Receptor D2 (DRD2)

Wender, (1971); Levy (1990)

Positron Emission Tomography (PET) image showing the striatum of the

human brain

PET studies of ADHD

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

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

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

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

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

[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

Biological Bases of ADHD:The Dopamine Hypothesis

RECEPTOR

TRANSPORTER

Caudate nucleus (Attention Network)

Nucleus accumbens (Motivation Network)

Substantia nigraVentral tegmental area

Hypothalamus

Dopamine Pathways

Frontal Cortex

RECEPTOR TRANSPORTER

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”.

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

(Attention)

(Motivation)

(Attention)

(Motivation)

(Attention)

(Motivation)

(Attention)

(Motivation)

(Attention)

(Motivation)

Transporter PET Image

(Attention)

(Motivation)

Receptor PET Image

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

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

DAT images in the first visit

ControlSubjects(n = 5)

Striatum Cerebellum

ADHDSubjects(n = 9)

High

Low

[C-11]cocaine

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

ROI measures of DAT availability

23±25%p < 0.04

18±19%p < 0.03

41±31%p < 0.005

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).

MPH-related Decrease in Task-related Increase in Glucose Metabolism from PET

ADHD-off Control-off

ADHD-onControl-on

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

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

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

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*

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

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

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

Attention Training: Training of Alerting Function

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

(Attention)

(Motivation)

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)