THE NEUROTOXICOLOGY OF ATTENTION DEFICITS

Francis M. Crinella, Trinh Tran & Joey Trampush

University of California, Irvine

University of California, Davis

• REVIEW OF ADHD

• CURRENT STATUS

• BIOLOGICAL THEORIES OF ADHD– NEUROIMAGING EVIDENCE– MOLECULAR BIOLOGICAL EVIDENCE– COGNITIVE NEUROPSYCHOLOGY

• ADHD AS DISORDER OF EXECUTIVE FUNCTION

• FEATURES OF EXECUTIVE FUNCTION

• CNS EF NETWORK

• ADHD SYMPTOMS AND TOXIC EXPOSURES– Pb– PSE– Mn

• SHARED MECHANISMS

• EXPERIMENTAL MODEL OF Mn-INDUCED ATTENTION DEFICITS– EF DEFICITS

Historic Overview of Attention Deficit Hyperactivity Disorder (ADHD)

Year Name DiagnosticSystem

1937 Minimal Brain damage -----

1960s Minimal Brain dysfunction -----

1968 Hyperkinetic reaction of Childhood DSM-II

1980 Attention Deficit Disorder DSM-III + or – Hyperactivity

1987 Attention Deficit DSM-III-R Hyperactivity Disorder

1994 Attention Deficit DSM-IV Hyperactivity Disorder

DSM-IV SYMPTOMS OF ADHD

INATTENTION

• CAN’T ATTEND TO DETAILS

• CAN’T SUSTAIN ATTENTION

• DOESN’T LISTEN

• FAILS TO FINISH

• CAN’T ORGANIZE TASKS

• AVOIDS SCHOOLWORK

• LOSES THINGS

• EASILY DISTRACTED

• FORGETFUL

HYPERACTIVITY/IMPULSIVITY

• FIDGETS

• CAN’T STAY SEATED

• RUN ABOUT AND CLIMBS

• CAN’T PLAY QUIETLY

• IS OFTEN ON THE GO

• TALKS TOO MUCH

• BLURTS OUT ANSWERS

• CAN’T WAIT TURN

• INTERRUPTS OR INTRUDES

PSYCHOPHARMACOLOGY OF ADHD

• CNS STIMULANTS

– DEXTROAMPHETAMINES

– METHYLPHENIDATES

– EFFECTS:

• Improved classroom behavior

• Improved academic productivity

• Improved peer/adult interactions

• Less frequent oppositional conduct

• Reduced aggression

BIOLOGICAL BASES OF ADHD

• MOLECULAR BIOLOGY– CATECHOLAMINE HYPOTHESIS --GENETIC VARIATION IN

NEUROTRANSMITTER FUNCTION (WENDER, 1971)

– SUBSENSITIVE DOPAMINE HYPOTHESIS; DRD4 GENE (LaHOSTE, SWANSON, WIGAL, et al, 1996)

• BRAIN IMAGING

– MBD (Clements, 1963)

– VARIATIONS IN SIZE AND SYMMETRY (Filipek et al, 1997) • FRONTO-STRIATAL

• CAUDATE

• BASAL GANGLIA

RECENT BRAIN IMAGING STUDIES IN ADHD

0

1

2

3

4

5

6

7

8

9 CaudateDL FrontalPutamen-gpOccipitalTemporalInsulaA. CingulatePremotorThalamusHippocampusInsulaCC (genu)CC (splenium)PeriventricularPremotorbasal gangial

Attention operates by changing the relative activity within

specified anatomical areas that perform computations

DISTINCT ANATOMICAL NETWORKS CARRY OUT SPECIFIC ASPECTS OF ATTENTION

• ALERTING NETWORK– LOCATION: ARAS, ETC.

– FUNCTION: ACHIEVE AND MAINTAIN STATE OF READINESS

• ORIENTING NETWORK– LOCATIONS: PARIETAL LOBE, SUPERIOR COLLICULUS & PULVINAR

– FUNCTION: REACT TO SENSORY STIMULI

• EXECUTIVE NETWORK– LOCATION: ANTERIOR CINGULATE; DORSOLATERAL FRONTAL

CORTEX & BASAL GANGLIA

– FUNCTIONS: • CONTROL NEURAL RESPONSES TO STIMULI

• GENERATE NEW INFORMATION FROM LONG TERM MEMORY

• PRIORITIZE OPERATION OF OTHER BRAIN AREAS

ADHD and EF

• ADHD is a disorder of Executive Function (Barkley)

SOME FEATURES OF EXECUTIVE FUNCTION

• Decision as to just what the problem is that needs to be solved• Selection of lower-order components• Selection of one or more representations of organizations for

information• Selection of a strategy for combining lower order components• Decision regarding tradeoffs in the speed and accuracies with

which various components are executed• Solution monitoring

STERNBERG, 1985

BRIEF DEFINITIONS OF EXECUTIVE FUNCTION

• Processes used to plan, monitor and revise strategies of information processing (STERNBERG. 1985)

• Appropriate set maintenance to achieve a future goal (PENNINGTON, WELSH & GROSSIER, 1990)

• A process which enables the brain to function as many machines in one, setting and resetting itself dozens of times in the course of a day, now for one type of operation, now for another (SPERRY, 1955)

• A process that alters the probability of subsequent responses to an event, thereby altering the probability of later consequences (Barkley, 1997).

BRAIN STRUCTURES COMPRISING THE RODENT

EF SYSTEM

• SUPERIOR COLLICULUS

• MEDIAN RAPHE NUCLEI

• VENTRAL MESENCEPHALIC AREA

• SUBSTANTIA NIGRA

• PONTINE RETICULAR FORMATION

• CAUDATOPUTAMEN

• VENTREAL LATERAL THALAMUS

• GLOBUS PALLIDUS

EXECUTIVE FUNCTION DEFICITS ASSOCIATED WITH LESIONS IN THE

RODENT EF SYSTEM

• Shifting cognitive sets

• Selective attention

• Procedural knowledge

• Planning behavioral sequences

• State control

• Inhibition of motor reactivity

• Response flexibility

• Transfer strategies

• Working memory

Attention deficits associated with prenatal

stimulant exposure

Eghbalieh, B., Crinella, F. M., & Hunt, L., & Swanson, J. M.

Journal of Attention Disorders, 2000, 4, 5-13.

PRENATAL STIMULANT EXPOSURE: TOXIC MECHANISM (COCAINE)

• cocaine crosses placenta,affecting fetal dopaminergic and serotonergic systems, which play key roles in regulating attention and arousal.

• Cocaine permanently alters development of DA-innervated cortical areas, predominantly the anterior cingulate cortex (ACC) – Long lasting structural and functional changes in

the ACC– ADHD imaging studies shown ACC

dysmorphology (Filipek et al., 1997)

PRENATAL STIMULANT EXPOSURE: TOXIC MECHANISM (AMPHETAMINE)

• Amphetamine crosses placenta, affecting fetal dopaminergic and serotonergic systems, which play key roles in regulating attention and arousal.

• Target areas for toxic effects are catecholaminergic

• The precise mechanism of toxicity is somewhat different from cocaine

• More evidence of permanent damage to neurons (Seiden and Kleven, 1988).

A

X

HIT REACTION TIME

300

325

350

375

400

425

450

475

500

525

550

575

600

625

650

675

700

MIL

LIS

EC

ON

DS

CONTROLSADHD

PSI 1 SEC

2 SEC

4 SEC

STANDARD ERROR OF HIT REACTION TIME

0

10

20

30

40

50

60

70

80

90

100

MIL

LIS

EC

ON

DS

CONTROLSADHDPSI

1 SEC

2 SEC

4 SEC

COMMISSION ERRORS

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

MIL

LIS

EC

ON

DS

CONTROLSADHDPSI

1 SEC2 SEC 4 SEC

DEVELOPMENTAL NEUROTOXICOLOGY OF Pb

MECHANISMS OF PB-INDUCED NEUROTOXICITY

• NEURAL CELL ADHESION MOLECULE (N-CAM) IMPAIRED

• METABOLIC UNCOUPLING IN IMMATURE BRAIN GLIAL DIFFERENTIATION SYNAPTOGENESIS NEURAL PRUNING PATHWAYS WITH NO SYSTEMATIC RELATIONSHIP TO PROJECTING

CELLS

• DOPAMINE RECEPTOR DOWNRETULATION IN MESOLIMBIC SYSTEM

– PREFRONTAL CORTEX

– HIPPOCAMPUS RESPONSE DISINHIBITION– NUCLEUS ACCUMBENS

SOIL LEAD CONCENTRATIONS AND PREVALENCE OF HYHPERACTIVE

BEHVIOR AMONG SCHOOL CHILDREN IN OTTAWA, CANADA

Jonathan E. Ericson & Shiraz I. Mishra

Environmental International, 1990, 1, 247-256

ATTENTIONAL CORRELATES OF DENTIN AND BONE LEAD LEVELS

IN ADOLESCENTS

David Bellinger, Howard Hu, Libby Titlebaum & Herbert Needleman

Archives of Environmental Health, 1994, 49, 98-105

IMPERSISTENCE

0

5

10

15

20

25

30

<5.1 5.1-8.1

8.2-11.8

11.9-17.1

17.2-27.0

>27.0

% REPORTED

DISTRACTIBILITY

0

5

10

15

20

25

30

35

40

45

<5.1 5.1-8.1

8.2-11.8

11.9-17.1

17.2-27.0

>27.0

% REPORTED

OVERDEPENDENCE

0

5

10

15

20

25

30

<5.1 5.1-8.1

8.2-11.8

11.9-17.1

17.2-27.0

>27.0

% REPORTED

DISORGANIZED

0

5

10

15

20

25

30

<5.1 5.1-8.1

8.2-11.8

11.9-17.1

17.2-27.0

>27.0

% REPORTED

HYPERACTIVE

0123456789

10

<5.1 5.1-8.1

8.2-11.8

11.9-17.1

17.2-27.0

>27.0

% REPORTED

IMPULSIVE

02468

101214161820

<5.1 5.1-8.1

8.2-11.8

11.9-17.1

17.2-27.0

>27.0

% REPORTED

LOW FRUSTRATION TOLERANCE

0

5

10

15

20

25

30

<5.1 5.1-8.1

8.2-11.8

11.9-17.1

17.2-27.0

>27.0

% REPORTED

UNABLE TO FOLLOW DIRECTIONS

0

2

4

6

8

10

12

14

16

18

<5.1 5.1-8.1

8.2-11.8

11.9-17.1

17.2-27.0

>27.0

% REPORTED

POOR SEQUENCING ABILITY

0

5

10

15

20

25

30

35

<5.1 5.1-8.1

8.2-11.8

11.9-17.1

17.2-27.0

>27.0

% REPORTED

LOW OVERALL FUNCTIONING

0

5

10

15

20

25

30

<5.1 5.1-8.1

8.2-11.8

11.9-17.1

17.2-27.0

>27.0

% REPORTED

SOCIAL PROBLEMS-AGE 7

0

0.2

0.4

0.6

0.8

1

1.2

LOW Pb HIGH Pb

1.0-3.0 RATING

DELINQUENT BEHAVIOR-AGE 7

0

0.2

0.4

0.6

0.8

1

1.2

LOW Pb HIGH Pb

1.0-3.0 RATING

AGGRESSIVE BEHAVIOR-AGE 7

0

0.5

1

1.5

2

2.5

3

LOW Pb HIGH Pb

1.0-3.0 RATING

AGGRESSIVE BEHAVIOR-AGE 11

2.1

2.2

2.3

2.4

2.5

2.6

2.7

2.8

2.9

LOW Pb HIGH Pb

1.0-3.0 RATING

SOMATIC COMPLAINTSAGE 11

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

LOW Pb HIGH Pb

1.0-3.0 RATING

ANXIOUS/DEPRESSEDAGE 11

0

0.2

0.4

0.6

0.8

1

1.2

1.4

LOW Pb HIGH Pb

1.0-3.0 RATING

DELINQUENT BEHAVIOR AGE 11

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

LOW Pb HIGH Pb

1.0-3.0 RATING

TEACHERS RATINGS-AGE 11

CBCL Low Pb High Pb PSomatic .24 .55 <.001Anxious 1.35 1.95 <.001Social 1.18 1.71 .001Attention 3.07 3.51 .05Delinquent 1.04 1.63 <.001Aggressive 2.56 3.71 <.001

DIGIT SPAN--AGES 19 & 20

9.5

10

10.5

11

11.5

12

<6 6--9 10--19

>19

SS

ARITHMETIC--AGES 19 & 20

10.7

10.8

10.9

11

11.1

11.2

11.3

11.4

11.5

<6 6--9 10--19

>19

SS

DIGIT SYMBOLAGES 19 & 20

8.5

9

9.5

10

10.5

11

11.5

<6 6--9 10--19

>19

SS

CANCELLATIONAGES 19 & 20

0

50

100

150

200

250

300

350

<6 6--9 10--19

>19

#

TRAILMAKING (B)AGES 19 & 20

0

10

20

30

40

50

60

70

80

<6 6--9 10--19

>19

SECS

STROOP COLOR/WORDAGES 19 & 20

0

20

40

60

80

100

120

140

<6 6--9 10--19

>19

SECS

REACTION TIME ERRORSAGES 19 & 20

345

350

355

360

365

370

375

380

385

<6 6--9 10--19

>19

Errors

WISCONSIN CARD SORTING ERRORS--AGES 19 & 20

0

5

10

15

20

25

30

35

<6 6--9 10--19

>19

Errors

WISCONSIN CARD SORTING CATEGORIES--AGES 19 & 20

0

1

2

3

4

5

6

7

<6 6--9 10--19

>19

CATS

WISCONSIN CARD SORTING PERSEVERATION (19 & 20)

0

2

4

6

8

10

12

14

16

18

<6 6--9 10--19

>19

Rawscore

COVARIATES ADJUSTED FOR

• PARENT IQ

• DRUG/ALCOHOL USE

• MATERNAL EDUCATION

• MATERNAL AGE

• SES

• BIRTH ORDER

EFFECTS OF NEONATAL DIETARY MANGANESE EXPOSURE ON BRAIN DOPAMINE

LEVELS AND NEUROCOGNITIVE FUNCTIONS

Francis M. Crinella, Aleksandra Chicz-DeMet, Trinh TranBo Lönnerdal, Louis Le and Michael Parker

Neurotoxicology, 2002 (in press)

HEAD HAIR Mn LEVEL

0

0.02

0.04

0.06

0.08

0.1

0.12

0.14

ADHD CONTROL

PPM

MECHANISMS OF Mn-INDUCED NEUROTOXICITY

Autoxidation of dopamine Catalysis of toxic catecholamines, e.g., 6-

hydroxydopamine Free radicals, e.g., O2

. and OH*

• Mn2+ oxidation Mn3+ Lipid peroxidation of membranes NMDA excitotoxic process Aberrant neuronal sprouting Compensatory imbalances among basal ganglia nuclei

– caudate– putamen– globus pallidus.

Calcium metabolism synaptic transmission O-methyl transferase activity homovanillic acid

RESULTS OF Mn-INDUCED NEUROTOXICITY

• Major feature of Mn is its ready transformation into several oxidative states

• 2H+ + O2. + Mn2+ H2O2 + Mn3+

• Neurotoxic effect of Mn stems from aberrations of regulatory role

• Chemical constituents of particular brain regions favor formation of higher valency Mn--lesions tend to occur in these areas– substantia nigra– globus pallidus– putamen

HOW COULD MN NEUROTOXICITY OCCUR?

MN HOMEOSTASIS IS ABSENT IN INFANTS

MATERNAL BREAST MILK HAS RELATIVELY SMALL LEVELS OF MN

INFANT FORMULA, ESPECIALLY SOY-BASED FORMULA, IS VERY HIGH IN MN

MANGANESE CONCENTRATIONS

Humanbreastmilk

Cowmilkformula

Soy-basedformula

IS NEONATAL MN EXPOSURE AN ETIOLOGIC AGENT IN ADHD?

•CHILDREN WITH ADHD HAVE HIGH LEVELS OF HEAD HAIR MN

•MN IS A KNOWN NEUROTOXIN

•MN TOXICITY AFFECTS BRAIN DOPAMINE SYSTEMS

•ADHD IS A PRIMARILY DOPAMINERGIC DISORDER

•BRAIN AREAS AFFECTED BY MN TOXICITY HAVE EXTENSIVE ANATOMICAL AND NEUROCHEMICAL OVERLAP WITH SYSTEMS SHOWN TO BE DYSFUNCTIONAL IN ADHD

PATTERNS OF NEONATAL NUTRITION

Prolonged bottle feeding is directly correlated with iron-deficiency anemia.

Anemic animals will absorb more excessive amounts of Mn.

Furthermore, infants are slow to develop Mn homeostasis.

Thus there is a combination of low Fe-High Mn absorption in formula fed infants, especially fed soy formula.

Breast-feeding has declined significantly since 1900

BEHAVIORAL DEFICITS ASSOCIATED WITH Fe DEFICIENCY

Capacity for sustaining attention (Vega et al, 1994),

Psychometric tests of executive function (Vega et al., 1994),

Conduct disorder (Tu et al, 1994),

Hyperactivity (Kozielec et al, 1994),

Dysthymia (Lozoff et al, 1998),

Language development (Walter, 1992; 1994).

Psychomotor development (Walter, 1992; 1994).

CAN AN ANIMAL MODEL OF ADHD BE INDUCED BY NEONATAL MN EXPOSURE?

ADHD IS A DISORDER OF EXECUTIVE FUNCTION Selective attention Shifting mental sets Response inhibition Preparatory set Working memory

EXECUTIVE FUNCTION DEFICITS ARE CAUSED BY LESIONS TO EF SYSTEM

Substantia nigra Caudate nucleus Putamen Globus pallidus

SAME STRUCTURES ARE DAMAGED BY MN NEUROTOXICITY

SAME STRUCTURES ARE IDENTIFIED IN IMAGING STUDIES OF ADHD

SUBJECTS;: male Sprague-Dawley rats

TREATMENTS

POST NATAL DAYS 1- 21ALL ANIMALS BREAST FEDAND GAVAGED DAILY:

Control--0 g/L Low group--50 g/L Medium group--250 g/L High group--500 g/L

POST NATAL DAYS 22-50 AND 55-65(Animals fed commercial chow ad lib)

•POSTNATAL DAYS 50 - 64 Behavioral testing

•POSTNATAL DAY 65Neurochemical assays

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

0 50 250 500

TREATMENT LEVEL (ug/l)

DA

LE

VE

L (

ng

/mg

)

0

0.5

1

1.5

2

2.5

3

0 50 250 500

TREATMENT LEVEL (ug/l)

DA

LE

VE

L (

ng

/mg

)

050

100150200

250300350400450

0 50 250 500

TREATMENT LEVEL (ug/L)

Tim

e (s

econ

ds)

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

0 50 250 500

TREATMENT LEVEL (ug/l)

FO

OT

SH

OC

KS

RUNWAY EXTINCTIONMn only

0

5

10

15

20

25

30

35

40

8TH 9TH 10TH

0 ug/dl

250ug/dl500ug/dl

RUNWAY EXTINCTIONMn & Low Fe

0

5

10

15

20

25

30

35

40

45

8TH 9TH 10TH

0 ug/dl

250ug/dl

500ug/dl

PASSIVE AVOIDANCE

0

0.5

1

1.5

2

2.5

3

3.5

FOOTSHOCKS

Fe

Fe+250

Fe+500

N-Fe

N-Fe+250N-Fe+500

Straight runway (low Fe)

05

101520253035404550

trial1

trial2

trial3

trial4

trial5

trial6

trial7

trial8

trial9

trial10

trials

time

control

medium

high

Straight runway (control)

05

1015202530354045

trial1

trial2

trial3

trial4

trial5

trial6

trial7

trial8

trial9

trial10

trials

time

control

medium

high

0

10

20

30

40

50

60

MULT-LOW MULT-HIGH DRUG-LOW

DRUG-HIGH

NON-ADHD

GROUPS

PE

RC

EN

T C

ON

VIC

TO

N

0

10

20

30

40

50

60

MULT-LOW MULT-HIGH DRUG-LOW DRUG-HIGH NON-ADHD

GROUPS

PE

RC

EN

T C

ON

VIC

TO

N