adhd dopamine and dat

7/27/2019 ADHD Dopamine and DAT

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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.


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In ADHD there is a primary

problem in the striatum

I hypothesize thatin ADD there is a primary

problem in PFC (inthe PFC-parietal network)


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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.


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The dopamine receptorsubtype, DRD4, is present in

prefrontal cortex in humans,but not in the striatum

(Meador-Woodruffet al., 1996)


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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


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ADHD ADD

Striatum Prefrontal Cortex

DAT1 DRD4


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ADD (ADHD without hyperactivity), aneurobiologically and behaviorally distinct disorder

from ADHD (with hyperactivity)

Adele Diamond (2005)

Development and Psychopathology, 17, 807-825


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Levels of hyperactive-

impulsivesymptoms are

correlated withthe number

of DAT1 high-risk alleles

but levels of inattentive

symptoms are not

(Waldman et al., 1998)


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DAT binding specifically in

the striatum has been found

to be related to motor

hyperactivity but no t to

inattentive symptoms

(Jucaite et al., 2005)


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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 innormal infants (those with the 7-

repeat-allele performing worse)


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A role for polymorphisms of the

DAT1 gene in ADHD is consistentwith the efficacy of

methylphenidate in treating

ADHD, as methylphenidate acts

directly on DAT function

(Dresel et al., 2000; Seeman &Madras, 1998; Shenker, 1992;

Volkowet al.

, 1998)


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The dopamine transporter

normally moves dopamine

from the synapse back into the

sending neuron.

Methylphenidate blocks thedopamine transporter, causing

an increase in dopamine

concentration at the synapse.

Synapse

Dopamine

Dopamine receptor

Methylphenidates mechanism of action


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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.


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On the other hand, a significant

percentage of children with ADDare 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)


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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)


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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 arecombining 2 different disorders into one group

Attention deficit disorder is a misnomer

problems with motivation and with working

memory


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By focusing on early stages in the

development of executive functions ratherthan trying to remediate deficits at laterages, it might be possible to reduce the

incidence or severity of mental healthdisorders of executive function, such asADHD, addictions, or conduct disorder.


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How can young children behelped to develop these

critical EF abilities?


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The Tools of theMind program is

based on theories

of Vygotsky andLuria

Elena Bodrova & Deborah Leong


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Vygotsky: Engagement in mature make-believe play ithe major mechanism for developing self-regulation inyoung children.


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flexibly adjust to twists and

turns in the evolving plot(cognitive flexibility)

-- all three of the coreexecutive functions thusget exercise.

During social pretend play, children must holdtheir own role and those of others in mind

(working memory)

inhibit acting out of character (employinhibitory control), and


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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, butthe benefits did not transfer to other

contexts or other EF skills.


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They found that for benefits to

generalize to other contexts andother EF skills, supports for,

training in, and challenges to EFneeded to be embedded in all

aspects of the school day.


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Buddy Reading


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vs. what teachers usually do:

- avoid problem situations

- provide external control- scold for lack of control


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In evaluatingToolswe specifically

chose EF measures completelydifferent 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 newsituations.


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Congruent

Push Left

Push Right Push Left

Push Right

Incongruent

HEARTS & FLOWERS


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Flanker Task


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Reverse Flanker

attend to the flankers


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Flanker Effect for Single-Task Block vs. Mixed Block

Non-Switching Trials Only

0

50

100

150

200

250

300

Block 1 Block 3 (Mixed)

LargeInside

SmallInside

LargeOutside

SmallOutside

msec

LargeInside

SmallInside

LargeOutside

SmallOutside

Regardless of stimulus size, or whether a trial has an Inside or Outside target,The Mixed block always shows a significantly greater Flanker Effect.


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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).


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The conditions differed in some

approaches to instruction but

primarily in that the Tools

condition included EF-

promoting activities interwoven in

all school activities throughoutthe day.


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All children came from thesame neighborhood and

were randomly assigned toTools or district-curriculum

classrooms.


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1 or2 Yrs of 1 Yr of 2Yrs of

District Curr. Tools Tools

Mean age in years 5.14 5.15 5.12

Percent Hispanic 93 91 91

Percent Male 55 41 51

% w/ family income


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Congruent

Push Left

Push Right Push Left

Push Right

Incongruent

HEARTS & FLOWERS


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Percentage of Correct Responses onthe Incongruent Block of Hearts & Flowers Task

30

35

40

45

50

55

60

65

70

75

80

85

90

PercentC

orrect

No Tools 1 Year Tools 2 Year Tools

Dots Task Mixed Block

Mi d Bl k (H t & Fl T i l I t i d)


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25

30

35

40

45

Percent

Correct

50

55

60

Dots Task - Mixed Block

Percent of Children Who Passed Criteria for Testing

No Tools Tools

Over 2x

as many

in Tools

passedpractice

sarah please

check

accuracy

Mixed Block (Hearts & Flower Trials Intermixed)Percent of Children who Passed Criterion for Testing

Almost 2x

as many in

Tools

passed

practice

P

ercentPass

ing


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Reverse Flanker

attend to the flankers


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Percentage of Correct Responses onReverse Flanker

30

35

40

45

50

55

60

65

70

75

80

85

90

PercentC

orrect

No Tools 1 Year Tools 2 Year Tools


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Whether children were inTools of the Mind or not

accounted for more variance inEF than did age or gender.


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Our finding of better performance

on these objective, behavioralmeasures is consistent with

findings that on questionnaire

measures, parents and teachersrate children in Tools as higher on

EF (Bartnett et al. 2007).


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The more EF-demanding the

task, the more highly the task

correlated with academic

performance.

C l ti f P t f C t R th H t & Fl T k ith


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Congruent:No EF

required

Incongruent:An IntermediateLevel of EF

Needed

MIxed:Most EFrequired

SRSS (Social Skills Rating Scale) Externalizing subscale 0.178 0.456** 0.177

SSRS Internalizing subscale 0.161 0.149 0.023

PPVT (Peabody Picture Vocabulary) raw score 0.036 .290* .464**

IDEA Oral Language proficiency raw score 0.165 0.183 .390*

Expressive (EOWPVT) raw score -0.037 .272* .383**

WIPPSI raw score 0.012 0.125 0.03

WCJ (Woodcock Johnson) letter word raw score 0.091 0.166 0.068

WCJ applied problems raw score -0.027 .264* .392**

Get Ready To Read raw score 0.05 .315* .423**

PPVT standard score 0.034 .275* .444**

Expressive (EOWPVT) standard score -0.117 0.207 .289*

Expressive standard score new (accts for floor effect) -0.086 0.242 .329**

WCJ (Woodcock Johnson) letter word standard score 0.08 0.167 0.12

WCJ applied problems standard score -0.071 0.218 .359**

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.


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November 30, 2007


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Superior academic performance in

children who have been through Toolshas 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.


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EF skills can be improvedeven in children as young as 4-5 years

by regular teachersin regular classrooms

without expensive, highly technical

equipment,

without 1:1 attention,

without highly trained specialists.

Take-home Message #1:

adhd dopamine and dat

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