The Neurotoxicology of attention deficits: Dietary Manganese Exposure as a Particular Case
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The Neurotoxicology of attention deficits: Dietary Manganese Exposure as a Particular Case Sabrina E.B. Schuck, Ph.D., Melody Yi, Ph.D. & Francis M. Crinella, Ph.D. The Child Development Center University of California, Irvine.

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The Neurotoxicology of attention deficits: Dietary Manganese Exposure as a Particular Case Sabrina E.B. Schuck, Ph.D., Melody Yi, Ph.D. & Francis M. Crinella, Ph.D.The Child Development CenterUniversity of California, Irvine


Everyone knows what attention is. It is the taking possession in the mind, in clear and vivid form, of one out of what seem several simultaneous object or trains of thought.

William James [The Principles of Psychology, 1890]


Attention helps us to manage conflicting perceptual inputs
ATTENTION HELPS US TO MANAGE CONFLICTING PERCEPTUAL INPUTS possession in the mind, in clear and vivid form, of one out of what seem several simultaneous object or trains of thought.


Attention allows us to persist in task performance
ATTENTION ALLOWS US TO PERSIST IN TASK PERFORMANCE possession in the mind, in clear and vivid form, of one out of what seem several simultaneous object or trains of thought.


Attention helps us focus on the task at hand
ATTENTION HELPS US FOCUS ON THE TASK AT HAND possession in the mind, in clear and vivid form, of one out of what seem several simultaneous object or trains of thought.





HOWEVER: ATTENTION IS THE MOST FRAGILE OF ALL MENTAL FUNCTIONS

1. ATTENTION CAN BE ADVERSELY AFFECTED BY ANY NUMBER OF INTERNAL AND EXTERNAL INFLUENCES2. ALL NEURODEVELOPMENTAL AND NEUROPSYCHIATRIC DISORDERS ARE ACCOMPANIED BY ATTENTION DEFICITS3. ADHD IS BUT ONE OF MANY DIAGNOSABLE CONDITIONS IN WHICH ATTENTION IS AFFECTED


Dsm iv symptoms of adhd

INATTENTION FUNCTIONS

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

DSM-IV SYMPTOMS OF ADHD


Biological basis of adhd
BIOLOGICAL BASIS OF ADHD FUNCTIONS

  • PSYCHOPHARMACOLOGY

  • MOLECULAR BIOLOGY

  • BRAIN IMAGING

  • ELECTROPHYSIOLOGY

  • NEUROPSYCHOLOGY


I psychopharmacology
I. PSYCHOPHARMACOLOGY FUNCTIONS

TREATMENT WITH CNS STIMULANTS

BENZEDRINE (Bradley, 1937)

DEXTROAMPHETAMINES (e.g., Dexedrine, Adderall)

METHYLPHENIDATES (e.g., Ritalin, Concerta)

THE DOPAMINE HYPOTHESIS

Wender P. Minimal brain dysfunction in children. Wiley-Liss, New York (1971).

Levy F. The dopamine theory of attention deficit hyperactivity disorder (ADHD). Aust. N. Z. J. Psychiatry 25, 277-83 (1991).

Grady D, Moyzis R, Swanson JM. Molecular genetics and attention in ADHD. Clin. Neurosci. Res. 5, 265-272 (2005).


Biological basis of adhd ii molecular biology
BIOLOGICAL BASIS OF ADHD II: MOLECULAR BIOLOGY FUNCTIONS

  • DOPAMINE D4 RECEPTOR GENE POLYMORPHISM ASSOCIATED WITH ADHD (Lahoste, Swanson et al., 1996, Molecular Psychiatry)

  • ASSOCIATION OF THE DOPAMINE RECEPTOR D4 (DRD4) GENE WITH A REFINED PHENOTYPE OF ADHD (Swanson, Sunohara, Kennedy et al., 1998, Molecular Psychiatry)

  • MOLECULAR GENETICS AND ATTENTION IN ADHD (Grady, Moyzis & Swanson, 2005, Clinical Neuroscience Research)


From Grady, Moyzis & Swanson, (2005), FUNCTIONSClinical Neuroscience Research, 5, 265-272


From Grady, Moyzis & Swanson (2005), FUNCTIONSClinical Neuroscience Research, 5, 265-272.


Biological basis of adhd iii structural imaging
BIOLOGICAL BASIS OF ADHD III: STRUCTURAL IMAGING FUNCTIONS

LONGITUDINAL MAPPING OF CORTICAL THICKNESS AND CLINICAL OUTCOME IN CHILDREN AND ADOLESCENTS WITH ATTENTION-DEFICIT/HYPERACTIVITY DISORDER. Shaw, Lerch, Greenstein et al. (2006), Archives of Genetic Psychiatry, 63, 540-549.


Iv electrophysiology
IV. ELECTROPHYSIOLOGY FUNCTIONS

Early studies of analog EEG:

Satterfield, J.H., & Schell, A.M. (1984). Childhood brain function differences in delinquent and non-delinquent hyperactive boys. Electroencephalography and Clinical Neurophysiology, 57, 199-207.

Finding: Abnormal maturational effects of auditory event- related potential differentiated ADHD from non-ADHD subjects

Recent brain mapping studies:

Pliszka, S.R., Liotti, M., & Woldorff, M.G. (2000). Inhibitory control in children with attention-deficit/hyperactivity disorder. Biological Psychiatry, 48,238-46.

Finding: Event related potentials identify the processing component and timing of an impaired right-frontal response- inhibition mechanism.


V neuropsychological evidence
V: NEUROPSYCHOLOGICAL EVIDENCE FUNCTIONS

  • ADHD conceptualized as “frontal lobe” disorder (e.g., Douglas, 1980; Chelune et al., 1986)

  • ADHD conceptualized as disorder of “executive function” (Pennington et al., 1990; Barkley 1997; Schuck & Crinella, 2000)


Brief definitions of executive function
Brief Definitions of Executive Function FUNCTIONS

  • Appropriate set maintenance to achieve a future goal (Pennington, Welsh & Grossier, 1990)

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

  • 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)


Executive functions can be adversely affected by any number of neurotoxins
EXECUTIVE FUNCTIONS CAN BE ADVERSELY AFFECTED BY ANY NUMBER OF NEUROTOXINS

FOR EXAMPLE:

  • PESTICIDES

  • LEAD (Pb)

  • CNS STIMULANTS


Odds ratio of detectable pesticide in serum children 8 12 years old n 167 oahu vs neighbor islands
Odds Ratio of Detectable Pesticide in Serum OF NEUROTOXINSChildren 8-12 Years Old (n = 167)Oahu vs. Neighbor Islands

From Baker, Yang & Crinella, 2004, Neurotoxicology, 25, 700-701


STANDARD SCORES ON NEUROBEHAVIORAL TESTS FOR SUBJECTS BORN ON OAHU (n = 332) vs. SUBJECTS BORN ELSEWHERE (n = 112)


STUDIES ASSOCIATING HAIR MANGANESE [Mn] LEVELS WITH ADHD ON OAHU (n = 332) vs. SUBJECTS BORN ELSEWHERE (n = 112)

Pihl, R.O. & Parks, M. (1977). Hair element content in learning disabled children. Science, 198, 204-206.

Collip, P.J., Chen, S.Y. & Maitinsky, S. (1983). Manganese in infant formulas and learning disability. Annals of Nutrition and Metabolism, 27, 488-494.

Marlowe, M. & Bliss, L. (1993). Hair element concentrations and young children's behavior at school and home. Journal of Orthomolecular Medicine, 9, 1-12.

Cordova, E.J., Ericson, J., Swanson, J.M., & Crinella, F.M. (1997). Head hair manganese as a biomarker for ADHD. Proceedings of the 15th Annual Conference on Neurotoxicology.


Head hair mn level
HEAD HAIR Mn LEVEL ON OAHU (n = 332) vs. SUBJECTS BORN ELSEWHERE (n = 112)


IS MN EXPOSURE AN ETIOLOGIC AGENT IN ADHD? ON OAHU (n = 332) vs. SUBJECTS BORN ELSEWHERE (n = 112)

1. CHILDREN WITH ADHD HAVE HIGH LEVELS OF HEAD HAIR MN

2. MN IS A KNOWN NEUROTOXIN

3. MN TOXICITY AFFECTS BRAIN DOPAMINE SYSTEMS

4. ADHD IS A PRIMARILY DOPAMINERGIC DISORDER


Critical observations regarding mn in infants and children
Critical Observations Regarding Mn in infants and children ON OAHU (n = 332) vs. SUBJECTS BORN ELSEWHERE (n = 112)

Manganese in head hair of children with ADHD may be the result of soy-based infant formulas (Collip et al., 1983)

Term infants fed soy formula have significantly higher blood Mn than breast-fed infants (Kirchgessner et al., 1981)

High, positive retention of Mn from formula, but not breast milk in preterm infants (Lonnerdal, 1994)


Infant dietary mn intake
INFANT DIETARY MN INTAKE ON OAHU (n = 332) vs. SUBJECTS BORN ELSEWHERE (n = 112)


Hypotheses
HYPOTHESES ON OAHU (n = 332) vs. SUBJECTS BORN ELSEWHERE (n = 112)

Since Mn is well absorbed from infant diets, and absorbed Mn is retained by the body, it will accumulate in brain, resulting in:

1. Depleted striatal DA

2. Neuromotor delay

3. Executive function deficits


an ON OAHU (n = 332) vs. SUBJECTS BORN ELSEWHERE (n = 112)

Tissue Mn Assays

d1 d6 d10 d14 d20 d35 d58 d60

Control (0)

50 µg Mn/d

250 µg Mn/d

500 µg Mn/d

Passive Avoidance

(d35)

Righting

(d6)

Digging latency

running time (d58)

Homing

(d10)

Passive Avoidance

(60-64)

Other measurements

Hb and Wt



Striatal dopamine in animals killed at d35
Striatal Dopamine in Animals Killed at d35 and 35

*

*

*Significant difference between control and low Mn exposure






Nonhuman primate models
NONHUMAN PRIMATE MODELS and 35

ADVANTAGES OVER RODENT MODEL

  • Maturity of brain development at birth

  • Prolonged period of postnatal brain development

  • Complexity of behavioral repertoire

  • Assessments similar to humans


Study design
Study Design and 35

  • Subjects: Male newborn rhesus monkeys

  • Treatment: Exclusively formula fed freom 0-4 months of age

  • Groups (n = 8):

    • Cow’s milk based infant formula, 0.03 µg Mn /ml

    • Soy based infant formula, 0.3 µg Mn/ml

    • Soy + Mn; soy based infant formula with added manganese, 1 µg Mn/ml


Behavior testing schedule
Behavior testing schedule and 35

APOMORPHINE

DRUG

CHALLENGE

FORMULA FEEDING

IMPULSIVITY TESTS:

NON-MATCH TO SAMPLE

POSITION REVERSAL

CPT

DIURNAL ACTIVITY

MOTOR MATURATION

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18


Gross Motor Maturation and 35

Control

Soy

Soy + Mn


Amount of activity

Cow’s milk and 35

Soy

Soy + Mn

Amount of activity

WAKE

120

100

80

Number of counts/ 2 min

60

40

20

0

SLEEP

14

12

10

*.01

8

6

4

2

0

4 months

8 months


WGTA and 35

One-way mirror

Door on pulley

Sliding test board


Delayed nonmatch to sample

Cow’s milk and 35

Soy

Soy + Mn

Delayed nonmatch to sample

Test board 1

Test board 2

.12

.

.1

.

.08

.

Percent

.06

.

.04

.

.02

0

Balks-no sample choice made


Position reversals

8 and 35

7

6

5

Sessions

4

3

Cow’s milk

Soy

2

Soy + Mn

1

0

Position reversals

Test board

sessions to criterion for learning

*.05

6


Food reward and 35

Test board

Sliding opaque cover

MOTOR

IMPULSIVITY

TEST


Impulsivity response inhibition

Cow’s milk and 35

Soy

Soy + Mn

Impulsivity-response inhibition

average number of trials (of 40) on which the monkey responded at each interval

25

22.5

20

17.5

15

*.04

12.5

10

7.5

*.03

number of trials

5

2.5

0

0 1-6 7 balk

interval


Cantab fixed interval dopamine challenge continuous performance test
CANTAB and 35Fixed interval;dopamine challengeContinuous performance test


Dopamine drug challenge

Cow’s milk and 35

Soy

Soy + Mn

Dopamine drug challenge

Fixed interval responding

100

75

50

25

*.01

0

0.1 mg/kg

0.2 mg/kg

Change in response rate from vehicle injection

amphetamine

-25

.0.3 mg/kg

-------apomorphine-----

-50

-75

*.02

-100

haloperidol

haloperidol+

apomorphine

-125

-150

apomorphine, dopamine agonist,response rate

haloperidol, dopamine antagonist,  response rate


Social interaction study
Social Interaction Study and 35

  • Method-videotape of dyadic interaction

  • Familiar same group, unfamiliar same group, unfamiliar opposite group

  • Social buffering

  • Used previously to compare field cage with nursery reared males


dyadic interactions during round robin and 35

socialization (16 sessions)

40

*.01

35

30

*.03

25

control

number of occurrences

Soy

20

.06

*.003

Soy+Mn

*.003

15

*.003

10

5

0

Chase play

Rough play

cling


Age and formula effects on csf catecholamine metabolites
Age and formula effects on and 35CSF catecholamine metabolites

5HIAA

HVA

500

160

450

control

140

400

low mn

120

350

hi mn

100

300

Cell Mean

250

Cell Mean

80

200

60

150

40

100

20

50

0

0

3 10 12

3 10 12

Months of age


Relationship between csf catecholamine metabolites and impulsivity
Relationship between CSF catecholamine metabolites and impulsivity

5HIAA- 10 months of age

HVA- 10 months of age

45

45

40

40

35

35

30

30

25

25

Earlyresponses

20

20

15

15

10

10

5

5

10

20

30

40

50

60

70

80

90

100

150

200

250

300

350

400

450

500

550

R2 = 0.19

R2 = 0.156


The tooth fairy study
THE “TOOTH FAIRY” STUDY impulsivity

  • Participants: 27 children (11 boys) from the NICHD Study of Early Child Care and Youth Development

  • Procedures:

    • Shed molars collected from 400 children (ages 11-13); 27 teeth randomly selected

    • Measures of children’s behavioral disinhibition collected from ages 3 to 9 years.

    • IMS analyses of teeth performed by CAMECA IMS 1270

    • Concentration of manganese in the molar cusp tip (formed at approximately the 20th gestational week) used as an indication of prenatal Mn absorption


Tooth Enamel Biomarker impulsivity

  • Tooth enamel layers, like tree rings, provide a temporal record of mineral absorption

  • Absorbed minerals, as reflected in the tooth enamel record, may be associated with embryogenetic variations

  • Depending on corresponding embryological developments in CNS, Mn absorption, as reflected in tooth enamel record, may be associated with specific variation in behavioral outcomes


Human Tooth Enamel impulsivity

  • As tooth develops over rime, incremental growth rings of enamel are deposited

  • Oldest enamel is found at the incisal tip

  • Mature enamel is a metabolic isolate

  • Mn is stable in calcium hydroxyapatite


Analytical Measurements impulsivity

  • ion microprobe mass spectrometer (ims)

  • 10 - 35 um spot resolution

  • auger & sputter sample

  • measurement of Mn concentration

  • detection <30 ppb

  • 90% accuracy


Behavior battery
Behavior Battery impulsivity

  • Data base of NICHD Early Childhood Study

  • Administered Age 3, Grade 1 and Grade 3

  • Teachers, mothers, and standardize tests of subjects

  • 21 behavior measures (disinhibition, intelligence and depression) over 5 years

  • Same subjects maintain position


Results
RESULTS impulsivity

Mn LEVELS WERE POSITIVELY CORRELATED WITH:

  • Increased play with “Forbidden Toy” (36 mo.)

  • More impulsive errors on CPT (54 mo.)

  • More impulsive errors on Stroop Test (54 mo.)

  • Higher ratings on externalizing behavior and attentional problems (teachers and mothers; 1st and 3rd grades)

  • Higher incidence of disruptive disorders (ADHD, hyperactivity/impulsivity, and inattention (teachers, 1st and 3rd grades)


MULTIPLE REGRESSION ANALYSIS impulsivity

(Predicting Mn Level With Behavioral Measures)

CPT (54 months)

Stroop (54 months)

CBCL Inattention (1st grade)

DBD3 HYPERACTIVITY (3RD GRADE)

R2 = 0.62; df = 4, 26; P < .001

Adjustment for socioeconomic confounds did not increase significance

  • Mother’s education

  • Income

  • Ethnicity

    (F of change = .13, p = .97)


Discussion
DISCUSSION impulsivity

  • A link was demonstrated between prenatal Mn absorption and measures of behavioral disinhibition in later childhood

  • The source of Mn was unknown, but may have been due to maternal gestational anemia, a common occurrence during pregnancy that results in overabsorption of Mn.


Conclusions
CONCLUSIONS impulsivity

  • Attention deficits are observed in almost all neuropsychiatric disorders, including ADHD

  • ADHD symptoms may are associated with a number of genetic, epigenetic and environmental influences, including toxic exposures

  • Mn serves as an example of a toxic exposure that can produce ADHD-like symptoms in rodents, non-human primates, and humans

  • The Mn-ADHD link is likely to be mediated by toxic effects on DRD4 and DAT genes.


Conclusions cont d
CONCLUSIONS (CONT’D) impulsivity

  • The Mn-ADHD link is likely to be mediated by toxic effects on DRD4 and DAT genes.

  • A DAT1 40bp VNTR 9/10 polymorphism was reliably associated with greater symptoms of ADHD.

    Barkley, Smith, Fischer & Bradford, (2006), American Journal of Medical Genetics. 141B, 487-498.

  • And, there is persistent evidence that DAT can be adversely impacted by Mn.

    Kern, Stanwood & Smith, (2010), Synapse, 64, 363-378.


Contributors

University of California, Irvine impulsivity

Aleksandra Chicz-DeMet

Louis Le

Mike Parker

Jonathon E. Ericson

K. Alison Clarke-Stewart

Virginia D. Allhusen

Tony Chan

Richard T. Robertson

University of California, Davis

Bo Lonnerdal

Mari Golub

Winyoo Chowanadisai

Stacey Germann

Casey Hogrefe

University of California, San Francisco

Trinh Tran

City University of New York

Joey Trampush

CONTRIBUTORS


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