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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 Center University of California, Irvine.

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ATTENTION HELPS US TO MANAGE CONFLICTING PERCEPTUAL INPUTS

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  1. 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

  2. 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]

  3. ATTENTION HELPS US TO MANAGE CONFLICTING PERCEPTUAL INPUTS

  4. ATTENTION ALLOWS US TO PERSIST IN TASK PERFORMANCE

  5. ATTENTION HELPS US FOCUS ON THE TASK AT HAND

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

  7. ATTENTION ENABLES US TO MAINTAIN VIGILANCE WHEN MONITORING SIGNALS

  8. ATTENTION ENABLES US TO AVOID COSTLY ERRORS

  9. 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

  10. 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

  11. BIOLOGICAL BASIS OF ADHD • PSYCHOPHARMACOLOGY • MOLECULAR BIOLOGY • BRAIN IMAGING • ELECTROPHYSIOLOGY • NEUROPSYCHOLOGY

  12. 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).

  13. 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)

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

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

  16. 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.

  17. 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.

  18. 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)

  19. 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)

  20. EXECUTIVE FUNCTIONS CAN BE ADVERSELY AFFECTED BY ANY NUMBER OF NEUROTOXINS FOR EXAMPLE: • PESTICIDES • LEAD (Pb) • CNS STIMULANTS

  21. 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

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

  23. 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.

  24. HEAD HAIR Mn LEVEL

  25. 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

  26. 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)

  27. INFANT DIETARY MN INTAKE

  28. 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

  29. 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

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

  31. Striatal Dopamine in Animals Killed at d35 * * *Significant difference between control and low Mn exposure

  32. PASSIVE AVOIDANCE TEST

  33. Results of Passive Avoidance Test at d32

  34. Results of Burrowing Detour Test d55

  35. STRIATAL DOPAMINE LEVELS AT d65

  36. 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

  37. 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

  38. 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

  39. Gross Motor Maturation Control Soy Soy + Mn

  40. 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

  41. WGTA One-way mirror Door on pulley Sliding test board

  42. 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

  43. 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

  44. Food reward Test board Sliding opaque cover MOTOR IMPULSIVITY TEST

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