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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Attention helps us to manage conflicting perceptual inputs

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


Attention helps us to manage conflicting perceptual inputs

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


Attention allows us to persist in task performance

ATTENTION ALLOWS US TO PERSIST IN TASK PERFORMANCE


Attention helps us focus on the task at hand

ATTENTION HELPS US FOCUS ON THE TASK AT HAND


Attention enables us to perform tasks that require planning and working memory

ATTENTION ENABLES US TO PERFORM TASKS THAT REQUIRE PLANNING AND WORKING MEMORY


Attention enables us to maintain vigilance when monitoring signals

ATTENTION ENABLES US TO MAINTAIN VIGILANCE WHEN MONITORING SIGNALS


Attention enables us to avoid costly errors

ATTENTION ENABLES US TO AVOID COSTLY ERRORS


Attention helps us to manage conflicting perceptual inputs

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

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

  • PSYCHOPHARMACOLOGY

  • MOLECULAR BIOLOGY

  • BRAIN IMAGING

  • ELECTROPHYSIOLOGY

  • NEUROPSYCHOLOGY


I psychopharmacology

I. PSYCHOPHARMACOLOGY

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

  • 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)


Attention helps us to manage conflicting perceptual inputs

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


Attention helps us to manage conflicting perceptual inputs

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


Biological basis of adhd iii structural imaging

BIOLOGICAL BASIS OF ADHD III: STRUCTURAL IMAGING

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

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

  • 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

  • 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 SerumChildren 8-12 Years Old (n = 167)Oahu vs. Neighbor Islands

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


Attention helps us to manage conflicting perceptual inputs

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


Attention helps us to manage conflicting perceptual inputs

STUDIES ASSOCIATING HAIR MANGANESE [Mn] LEVELS WITH ADHD

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


Attention helps us to manage conflicting perceptual inputs

IS MN EXPOSURE AN ETIOLOGIC AGENT IN ADHD?

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

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


Hypotheses

HYPOTHESES

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


Attention helps us to manage conflicting perceptual inputs

an

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


Concentrations of mn in brain of rats killed at day 14 21 and 35

Concentrations of Mn in brain of rats killed at day 14, 21 and 35


Striatal dopamine in animals killed at d35

Striatal Dopamine in Animals Killed at d35

*

*

*Significant difference between control and low Mn exposure


Attention helps us to manage conflicting perceptual inputs

PASSIVE AVOIDANCE TEST


Results of passive avoidance test at d32

Results of Passive Avoidance Test at d32


Results of burrowing detour test d55

Results of Burrowing Detour Test d55


Attention helps us to manage conflicting perceptual inputs

STRIATAL DOPAMINE LEVELS AT d65


Nonhuman primate models

NONHUMAN PRIMATE MODELS

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

  • 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

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


Attention helps us to manage conflicting perceptual inputs

Gross Motor Maturation

Control

Soy

Soy + Mn


Amount of activity

Cow’s milk

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


Attention helps us to manage conflicting perceptual inputs

WGTA

One-way mirror

Door on pulley

Sliding test board


Delayed nonmatch to sample

Cow’s milk

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

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


Attention helps us to manage conflicting perceptual inputs

Food reward

Test board

Sliding opaque cover

MOTOR

IMPULSIVITY

TEST


Impulsivity response inhibition

Cow’s milk

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

CANTABFixed interval;dopamine challengeContinuous performance test


Dopamine drug challenge

Cow’s milk

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

  • 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


Attention helps us to manage conflicting perceptual inputs

dyadic interactions during round robin

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 onCSF 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

  • 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


Attention helps us to manage conflicting perceptual inputs

Tooth Enamel Biomarker

  • 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


Attention helps us to manage conflicting perceptual inputs

Human Tooth Enamel

  • 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


Attention helps us to manage conflicting perceptual inputs

Analytical Measurements

  • 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

  • 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

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)


Attention helps us to manage conflicting perceptual inputs

MULTIPLE REGRESSION ANALYSIS

(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

  • 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

  • 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)

  • 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

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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