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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]
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
CAN’T ATTEND TO DETAILS
CAN’T SUSTAIN ATTENTION
FAILS TO FINISH
CAN’T ORGANIZE TASKS
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 INTRUDESDSM-IV SYMPTOMS OF ADHD
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).
From Grady, Moyzis & Swanson, (2005), Clinical Neuroscience Research, 5, 265-272
From Grady, Moyzis & Swanson (2005), Clinical Neuroscience Research, 5, 265-272.
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.
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.
From Baker, Yang & Crinella, 2004, Neurotoxicology, 25, 700-701
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.
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
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)
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
Tissue Mn Assays
d1 d6 d10 d14 d20 d35 d58 d60
50 µg Mn/d
250 µg Mn/d
500 µg Mn/d
running time (d58)
Hb and Wt
*Significant difference between control and low Mn exposure
ADVANTAGES OVER RODENT MODEL
NON-MATCH TO SAMPLE
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Soy + Mn
Door on pulley
Sliding test board
Sliding opaque cover
Soy + MnDopamine drug challenge
Fixed interval responding
Change in response rate from vehicle injection
apomorphine, dopamine agonist,response rate
haloperidol, dopamine antagonist, response rate
socialization (16 sessions)
number of occurrences
3 10 12
3 10 12
Months of age
5HIAA- 10 months of age
HVA- 10 months of age
R2 = 0.19
R2 = 0.156
Mn LEVELS WERE POSITIVELY CORRELATED WITH:
(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
(F of change = .13, p = .97)
Barkley, Smith, Fischer & Bradford, (2006), American Journal of Medical Genetics. 141B, 487-498.
Kern, Stanwood & Smith, (2010), Synapse, 64, 363-378.
Jonathon E. Ericson
K. Alison Clarke-Stewart
Virginia D. Allhusen
Richard T. Robertson
University of California, Davis
University of California, San Francisco
City University of New York