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 MnINDUCED ATTENTION DEFICITS
– EF DEFICITS
Historic Overview of Attention Deficit
Hyperactivity Disorder (ADHD)
Y ea r
N am e
D ia gn osticS y stem
1937
M in im al B rain d am age
-----
1960s
M in im al B rain d ysfu n ction
-----
1968
H yp erk in etic reaction of C h ild h ood
D S M -II
1980
A tten tion D eficit D isord er
+ or – H yp eractivity
D S M -III
1987
A tten tion D eficit
H yp eractivity D isord er
D S M -III-R
1994
A tten tion D eficit
H yp eractivity D isord er
D S M -IV
DSM-IV SYMPTOMS OF
ADHD
•
•
•
•
•
•
•
•
•
INATTENTION
HYPERACTIVITY/IMPULSIVITY
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
•
•
•
•
•
•
•
•
•
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
9
8
7
6
5
4
3
2
1
0
Caudate
DL Frontal
Putamen-gp
Occipital
Temporal
Insula
A. Cingulate
Premotor
Thalamus
Hippocampus
Insula
CC (genu)
CC (splenium)
Periventricular
Premotor
basal 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 DAinnervated 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
700
675
650
4 SEC
MILLISECONDS
625
600
2 SEC
575
550
525
500
475
450
425
400
375
350
325
300
1 SEC
CONTROLS
ADHD
PSI
STANDARD ERROR OF HIT REACTION TIME
100
4 SEC
90
MILLISECONDS
80
2 SEC
70
1 SEC
60
50
40
30
20
10
0
CONTROLS
ADHD
PSI
COMMISSION ERRORS
1.8
1.6
MILLISECONDS
1.4
1.2
1
CONTROLS
ADHD
PSI
0.8
0.6
1 SEC
0.4
0.2
0
2 SEC
4 SEC
DEVELOPMENTAL
NEUROTOXICOLOGY OF Pb
MECHANISMS OF PBINDUCED 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
– NUCLEUS ACCUMBENS
RESPONSE DISINHIBITION
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
30
25
20
15
% REPORTED
10
5
0
<5.1
5.18.1
8.211.8
11.9- 17.2- >27.0
17.1 27.0
DISTRACTIBILITY
45
40
35
30
25
20
15
10
5
0
% REPORTED
<5.1
5.18.1
8.211.8
11.9- 17.2- >27.0
17.1 27.0
OVERDEPENDENCE
30
25
20
15
% REPORTED
10
5
0
<5.1
5.18.1
8.211.8
11.9- 17.2- >27.0
17.1 27.0
DISORGANIZED
30
25
20
15
% REPORTED
10
5
0
<5.1
5.18.1
8.211.8
11.9- 17.2- >27.0
17.1 27.0
HYPERACTIVE
10
9
8
7
6
5
4
3
2
1
0
% REPORTED
<5.1
5.18.1
8.211.8
11.9- 17.2- >27.0
17.1 27.0
IMPULSIVE
20
18
16
14
12
10
8
6
4
2
0
% REPORTED
<5.1
5.18.1
8.211.8
11.9- 17.2- >27.0
17.1 27.0
LOW FRUSTRATION
TOLERANCE
30
25
20
15
% REPORTED
10
5
0
<5.1
5.18.1
8.211.8
11.9- 17.2- >27.0
17.1 27.0
UNABLE TO FOLLOW
DIRECTIONS
18
16
14
12
10
8
6
4
2
0
% REPORTED
<5.1
5.18.1
8.211.8
11.9- 17.2- >27.0
17.1 27.0
POOR SEQUENCING ABILITY
35
30
25
20
15
% REPORTED
10
5
0
<5.1
5.18.1
8.211.8
11.9- 17.2- >27.0
17.1 27.0
LOW OVERALL
FUNCTIONING
30
25
20
15
% REPORTED
10
5
0
<5.1
5.18.1
8.211.8
11.9- 17.2- >27.0
17.1 27.0
SOCIAL PROBLEMS-AGE 7
1.2
1
0.8
0.6
1.0-3.0 RATING
0.4
0.2
0
LOW Pb
HIGH Pb
DELINQUENT BEHAVIORAGE 7
1.2
1
0.8
0.6
1.0-3.0 RATING
0.4
0.2
0
LOW Pb
HIGH Pb
AGGRESSIVE BEHAVIORAGE 7
3
2.5
2
1.5
1.0-3.0 RATING
1
0.5
0
LOW Pb
HIGH Pb
AGGRESSIVE BEHAVIORAGE 11
2.9
2.8
2.7
2.6
2.5
1.0-3.0 RATING
2.4
2.3
2.2
2.1
LOW Pb
HIGH Pb
SOMATIC COMPLAINTS
AGE 11
0.9
0.8
0.7
0.6
0.5
1.0-3.0 RATING
0.4
0.3
0.2
0.1
0
LOW Pb
HIGH Pb
ANXIOUS/DEPRESSED
AGE 11
1.4
1.2
1
0.8
1.0-3.0 RATING
0.6
0.4
0.2
0
LOW Pb
HIGH Pb
DELINQUENT BEHAVIOR
AGE 11
1.6
1.4
1.2
1
0.8
1.0-3.0 RATING
0.6
0.4
0.2
0
LOW Pb
HIGH Pb
TEACHERS RATINGS-AGE 11
CBCL
Low Pb
H ig h P b
P
S om atic
.24
.55
< .001
A nxious
1.35
1.95
< .001
S ocial
1.18
1.71
.001
A ttention
3.07
3.51
.05
D elinquent
1.04
1.63
< .001
A ggressive
2.56
3.71
< .001
DIGIT SPAN--AGES 19 & 20
12
11.5
11
SS
10.5
10
9.5
<6
6--9 10-- >19
19
ARITHMETIC--AGES 19 & 20
11.5
11.4
11.3
11.2
11.1
SS
11
10.9
10.8
10.7
<6
6--9 10-- >19
19
DIGIT SYMBOL
AGES 19 & 20
11.5
11
10.5
10
SS
9.5
9
8.5
<6
6--9 10-- >19
19
CANCELLATION
AGES 19 & 20
350
300
250
200
150
#
100
50
0
<6
6--9
10-19
>19
TRAILMAKING (B)
AGES 19 & 20
80
70
60
50
40
SECS
30
20
10
0
<6 6--9 10-- >19
19
STROOP COLOR/WORD
AGES 19 & 20
140
120
100
80
60
SECS
40
20
0
<6 6--9 10-- >19
19
REACTION TIME ERRORS
AGES 19 & 20
385
380
375
370
365
Errors
360
355
350
345
<6 6--9 10-- >19
19
WISCONSIN CARD SORTING
ERRORS--AGES 19 & 20
35
30
25
20
15
Errors
10
5
0
<6 6--9 10-- >19
19
WISCONSIN CARD SORTING
CATEGORIES--AGES 19 & 20
7
6
5
4
3
CATS
2
1
0
<6 6--9 10-- >19
19
WISCONSIN CARD SORTING
PERSEVERATION (19 & 20)
18
16
14
12
10
8
6
4
2
0
Raw
score
<6 6--9 10-- >19
19
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 Tran
Bo Lönnerdal, Louis Le and Michael Parker
Neurotoxicology, 2002 (in press)
HEAD HAIR Mn LEVEL
0.14
0.12
0.1
0.08
PPM
0.06
0.04
0.02
0
ADHD
CONTROL
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
Human
breast
milk
Cow
milk
formula
Soybased
formula
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- 21
ALL ANIMALS BREAST FED
AND 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 65
Neurochemical assays
2
1.8
DA LEVEL (ng/mg)
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
0
50
250
TREATMENT LEVEL (ug/l)
500
3
DA LEVEL (ng/mg)
2.5
2
1.5
1
0.5
0
0
50
250
TREATMENT LEVEL (ug/l)
500
Time (seconds)
450
400
350
300
250
200
150
100
50
0
0
50
250
TREATMENT LEVEL (ug/L)
500
5
4.5
FOOTSHOCKS
4
3.5
3
2.5
2
1.5
1
0.5
0
0
50
250
TREATMENT LEVEL (ug/l)
500
RUNWAY EXTINCTION
Mn only
40
35
30
0 ug/dl
25
250
ug/dl
500
ug/dl
20
15
10
5
0
8TH
9TH
10TH
RUNWAY EXTINCTION
Mn & Low Fe
45
40
35
0 ug/dl
30
25
250
ug/dl
500
ug/dl
20
15
10
5
0
8TH
9TH
10TH
PASSIVE AVOIDANCE
3.5
Fe
3
Fe+250
2.5
Fe+500
2
1.5
N-Fe
1
0.5
0
FOOTSHOCKS
NFe+250
NFe+500
time
Straight runway (low Fe)
50
45
40
35
30
25
20
15
10
5
0
control
medium
high
trial trial trial trial trial trial trial trial trial trial
1
2
3
4
5
6
7
8
9 10
trials
time
Straight runway (control)
45
40
35
30
25
20
15
10
5
0
control
medium
high
trial trial trial trial trial trial trial trial trial trial
1
2
3
4
5
6
7
8
9 10
trials
PERCENT CONVICTON
60
50
40
30
20
10
0
MULT-LOW MULT-HIGH
DRUGLOW
GROUPS
DRUGHIGH
NON-ADHD
PERCENT CONVICTON
60
50
40
30
20
10
0
MULT-LOW
MULT-HIGH DRUG-LOW DRUG-HIGH NON-ADHD
GROUPS
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THE NEUROTOXICOLOGY OF ATTENTION DEFICITS