the neurotoxicology of attention deficits francis m. crinella, trinh tran & joey trampush...
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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