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Iron-Deficiency Anemia is Associated with Altered Characteristics of Sleep Spindles in NREM Sleep in Infancy

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Abstract

Objective

To determine the effects of iron-deficiency anemia on the development of non-rapid-eye-movement (NREM) sleep stages, as indexed by sleep spindles.

Study design

Patterns of sleep spindles during NREM sleep stages 2 and 3–4 (slow-wave-sleep, SWS) were compared in 26 otherwise healthy 6-month-old Chilean infants with iron-deficiency anemia and 18 non-anemic control infants. From polygraphic recordings, EEG activity was analyzed for sleep spindles to assess their number (density), duration, frequency, and inter-spindle interval.

Results

Iron-deficient anemic infants differed from the control group by having sleep spindles with reduced density, lower frequency, and longer inter-spindle intervals in NREM sleep stage 2 and SWS.

Conclusions

These results provide evidence of delayed sleep spindle patterns in iron-deficient anemic infants, suggesting that iron is an essential micronutrient for the normal progression of NREM sleep pattern development in the human.

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References

  1. Youdim MBH, Yehuda S, Ben-Uriah Y (1981) Iron deficiency-induced circadian rhythm reversal of dopaminergic-mediated behaviours and thermoregulation in rats. Eur J Pharmacol 74:295–301

    Article  PubMed  CAS  Google Scholar 

  2. Glover J, Jacobs A (1972) Activity pattern of iron-deficient rats. BMJ 2:627–628

    PubMed  CAS  Google Scholar 

  3. Youdim MBH, Yehuda S (1985) Iron deficiency induces reversal of dopamine dependent circadian cycles: differential response to d-Amphetamine and TRH. Peptides 6:851–855

    Article  PubMed  CAS  Google Scholar 

  4. Youdim MBH (1988) Brain iron: neurochemical and behavioural aspects. Taylor & Francis, London

    Google Scholar 

  5. Beard J, Stoltzfus R (2001) Iron-deficiency anemia: reexamining the nature and magnitude of the public health problem. J Nutr 131:563S–703S

    CAS  Google Scholar 

  6. Mannar V, Bellamy C (2004) Vitamin and mineral deficiency – a global progress report. UNICEF, New York

    Google Scholar 

  7. WHO (1998) Global Database on Child Growth and Malnutrition. WHO, Geneva

    Google Scholar 

  8. Administrative Committee on Coordination Sub-Committee on Nutrition (ACC/SCN) (2000) Fourth Report on the World Nutrition Situation. ACC/SCN in collaboration with IFPRI, Geneva

    Google Scholar 

  9. Stoltzfus RJ, Mullany L, Black RE (2004) Iron deficiency anaemia. In: Ezzati M, Lopez AD, Rodgers A, Murray CJL (eds) Comparative quantification of health risks: global and regional burden of disease attributable to selected major risk factors. World Health Organization, Geneva, pp 163–209

    Google Scholar 

  10. Brotanek JM, Halterman J, Auinger P et al (2005) Iron deficiency, prolonged bottle-feeding, and racial/ethnic disparities in young children. Arch Pediatr Adolesc Med 159:1038–1042

    Article  PubMed  Google Scholar 

  11. Smith LB, Thelen E, Titzer R et al (1999) Knowing in the context of acting: the task dynamics of the A-not-B error. Psychol Bul 106:235–260

    CAS  Google Scholar 

  12. Beard JL, Connor JR (2003) Iron status and neural functioning. Ann Rev Nutr 23:41–58

    Article  CAS  Google Scholar 

  13. Lozoff B, Georgieff MK (2006) Iron deficiency and brain development. Semen Pediatr Neurol 13:158–165

    Article  Google Scholar 

  14. Roncagliolo M, Garrido M, Walter T et al (1998) Evidence of altered central nervous system development in infants with iron deficiency anemia at 6 mo: delayed maturation of auditory brain stem responses. Am J Clin Nutr 68:683–690

    PubMed  CAS  Google Scholar 

  15. Angulo-Kinzler RM, Peirano P et al (2002) Spontaneous motor activity in human infants with iron-deficiency anemia. Early Hum Dev 66:67–79

    Article  PubMed  CAS  Google Scholar 

  16. Angulo-Kinzler RM, Peirano P, Lin E et al (2002) Twenty-four-hour motor activity in human infants with and without iron deficiency anemia. Early Hum Dev 70:85–101

    Article  PubMed  CAS  Google Scholar 

  17. Fagioli I, Salzarulo P (1982) Sleep states development in the first year of life assessed through 24-h recordings. Early Hum Dev 6:215–228

    Article  PubMed  CAS  Google Scholar 

  18. Coons S, Guilleminault C (1982) The development of sleep-wake patterns and non-rapid eye movement stages during the first six months of life in normal infants. Pediatrics 69:793–798

    PubMed  CAS  Google Scholar 

  19. Louis J, Cannard C, Bastuji H et al (1997) Sleep ontogenesis revisited: a longitudinal 24-h home polygraphic study on 15 normal infants during the first two years of life. Sleep 20:323–333

    PubMed  CAS  Google Scholar 

  20. Steriade M, Deschenes M, Domich L et al (1985) Abolition of spindle oscillations in thalamic neurons disconnected from nucleus reticularis thalami. J Neurophysiol 54:1473–1497

    PubMed  CAS  Google Scholar 

  21. Metcalf DR (1970) EEG sleep spindle ontogenesis. Neuropadiatrie 1:428–433

    PubMed  CAS  Google Scholar 

  22. Curzi-Dascalova L (1977) Waking and sleeping E.E.G. in normal babies before 6 months of age. Revue d’Electroencephalographie et de Neurophysiologie Clinique 7:316–326

    Article  PubMed  CAS  Google Scholar 

  23. Ellingson RJ (1982) Development of sleep spindle bursts during the first year of life. Sleep 5:39–46

    PubMed  CAS  Google Scholar 

  24. Louis J, Zhang JX, Revol M et al (1992) Ontogenesis of nocturnal organization of sleep spindles: a longitudinal study during the first 6 months of life. Electroencephalogr Clin Neurophysiol 83:289–296

    Article  PubMed  CAS  Google Scholar 

  25. Hughes JR (1996) Development of sleep spindles in the first year of life. Clin Electroencephalogr 27:107–115

    PubMed  CAS  Google Scholar 

  26. Monod N, Eliet-Flesher J, Dreyfus-Brisac C (1977) Le sommeil du nouveau-ne et du premature. III. Les troubles de l’organization du sommeil chez le nouveau-ne pathologique: analyse des etudes polygraphiques. Biol Neonatorum 11:216–247

    Article  Google Scholar 

  27. Dreyfus-Brisac C, Curzi-Dascalova L (1975) The EEG during the first year of life. In: Remond A (ed) The evolution of the EEG. Handbook of electroencephalography. Elsevier, Amsterdam, pp 24–30

    Google Scholar 

  28. Shibagaki M, Kiyono S, Watanabe K (1982) Spindle evolution in normal and mentally retarded children: a review. Sleep 5:47–57

    PubMed  CAS  Google Scholar 

  29. Lozoff B, De Andraca I, Castillo M et al (2003) Behavioral and developmental effects of preventing iron-deficiency anemia in healthy full-term infants. Pediatrics 112:846–854

    PubMed  Google Scholar 

  30. Rechtschaffen A, Kales A (1968) A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. UCLA Brain Research Institute/Brain Information Services, Los Angeles

    Google Scholar 

  31. Guilleminault C, Souquet M (1979) Sleep states and related pathology. In: Korobkin R, Guilleminault C (eds) Advances in perinatal neurology. Spectrum, New York, pp 415–426

    Google Scholar 

  32. McCullagh P, Nelder JA (1989) Generalized linear models. Chapman and Hall, New York

    Google Scholar 

  33. Lozoff B, Brittenham GM, Viteri FE, Wolf AW, Urrutia JJ (1982) The effects of short-term oral iron therapy on developmental deficits in iron deficient anemic infants. J Pediatr 100:351–357

    Article  PubMed  CAS  Google Scholar 

  34. Lozoff B, Brittenham GM, Wolf AW et al (1987) Iron deficiency anemia and iron therapy: effects on infant developmental test performance. Pediatrics 79:981–995

    PubMed  CAS  Google Scholar 

  35. Lozoff B, Walter T, Kaciroti N (2006) Predicting iron deficiency in infancy: application of a physiologic framework. Am J Clin Nutr 84:1412–1421

    PubMed  CAS  Google Scholar 

  36. Lozoff B (1998) Considering environmental factors in research on nutrient deficiencies and infant development. In: Perman JA, Rey J (eds) Clinical trials in infant nutrition. Lippincott-Raven Publishers, Philadelphia, pp 203–218

    Google Scholar 

  37. Pollitt E (2000) Developmental sequel from early nutritional deficiencies: conclusive and probability judgments. J Nutr 130:350S–353S

    PubMed  CAS  Google Scholar 

  38. Salzarulo P, Fagioli I, Salomon F et al (1982) Developmental trend of quiet sleep is altered by early human malnutrition and recovered by nutritional rehabilitation. Early Hum Dev 7:257–264

    Article  PubMed  CAS  Google Scholar 

  39. Peirano P, Fagioli I, Singh BB et al (1989) Effect of early human malnutrition on waking and sleep organization. Early Hum Dev 20:67–76

    Article  PubMed  CAS  Google Scholar 

  40. Fagioli I, Peirano P, Bes F et al (1989) Sleep in early human malnutrition. In: Horne J (ed) Sleep 88. Gustav Fischer Verlag, Stuttgart, pp 59–62

    Google Scholar 

  41. Peirano P, Fagioli I, Singh BB et al (1990) Quiet sleep and slow wave sleep in malnourished infants. Brain Dysfunct 3:80–83

    Google Scholar 

  42. Fagioli I, Salzarulo P, Salomon F et al (1983) Sinus pauses in early human malnutrition during waking and sleeping. Neuropediatrics 14:43–46

    Article  PubMed  CAS  Google Scholar 

  43. Lenard HG, Schulte FJ (1974) Sleep spindles in hormonal and metabolic diseases of infancy and childhood. In: Petre-Quadens O, Schlag JD (eds) Basic sleep mechanisms. Academic Press, New York, pp 380–403

    Google Scholar 

  44. Gurses D, Kilic I, Sahiner T (2005) The effects of hyperbilirubinemia on sleep-spindle characteristics in infants. Sleep 28:644–648

    PubMed  Google Scholar 

  45. De Giorgis GF, Nonnis E, Crocioni F et al (1996) Evolution of daytime quiet sleep components in early treated phenylketonuric infants. Brain Dev 18:201–206

    Article  PubMed  Google Scholar 

  46. De Giorgis GF, Nonnis E, Crocioni F et al (1972) Development of sleep patterns in autistic children. In: Clement C, Purpura DP, Mayer FE (eds) Sleep and the maturing mervous system. Academic Press, New York, pp 321–363

    Google Scholar 

  47. Contreras D, Destexhe A, Sejnowski TJ et al (1996) Control of spatiotemporal coherence of a thalamic oscillation by corticothalamic feedback. Science 274:771–774

    Article  PubMed  CAS  Google Scholar 

  48. Steriade M (1999) Coherent oscillations and short-term plasticity in corticothalamic networks. Trends Neurosci 22:337–345

    Article  PubMed  CAS  Google Scholar 

  49. Beard JL, Wiesinger JA, Connor JR (2003) Pre- and postweaning iron deficiency alters myelination in Sprague-Dawley rats. Dev Neurosci 25:308–315

    Article  PubMed  CAS  Google Scholar 

  50. Larkin EC, Rao GA (1990) Importance of fetal and neonatal iron: Adequacy for normal development of central nervous system. In: Dobbing J (ed) Brain, behaviour, and iron in the infant diet. Springer-Verlag, London, pp 43–62

    Google Scholar 

  51. Kwik-Uribe CL, Gietzen D, German JB et al (2000) Chronic marginal iron intakes during early development in mice result in persistent changes in dopamine metabolism and myelin composition. J Nutr 130:2821–2830

    PubMed  CAS  Google Scholar 

  52. Ortiz E, Pasquini JM, Thompson K et al (2004) Effect of manipulation of iron storage, transport, or availability on myelin composition and brain iron content in three different animal models. J Neurosci Res 77:681–689

    Article  PubMed  CAS  Google Scholar 

  53. Hill JM (1988) The distribution of iron in the brain. In: Youdim MBH (ed) Brain iron: neurochemical and behavioural aspects. Taylor and Francis, London

    Google Scholar 

  54. Carmody DP, Dunn SM, Boddie-Willis AS et al (2004) A quantitative measure of myelination development in infants, using MR images. Neuroradiology 46:781–786

    Article  PubMed  Google Scholar 

  55. Jorgenson LA, Wobken JD, Georgieff MK (2003) Perinatal iron deficiency alters apical dendritic growth in hippocampal CA1 pyramidal neurons. Dev Neurosci 25:412–420

    Article  PubMed  CAS  Google Scholar 

  56. Schade JP, Meeter K (1963) Neuronal and dendritic patterns in the uncinate area of human hippocampus. Prog Brain Res 3:89–110

    Article  Google Scholar 

  57. Lozoff B, Beard J, Connor J et al (2006) Long-lasting neural and behavioral effects of iron deficiency in infancy. Nutr Rev 64:S34–S43

    Article  PubMed  Google Scholar 

  58. Beard JL, Felt B, Schallert T et al (2006) Moderate iron deficiency in infancy: biology and behavior in young rats. Beba Brain Res 170:224–232

    Article  CAS  Google Scholar 

  59. Felt BT, Beard JL, Schallert T et al (2006) Persistent neurochemical and behavioral abnormalities in adulthood despite early iron supplementation for perinatal iron deficiency anemia in rats. Behav Brain Res 171:261–270

    Article  PubMed  CAS  Google Scholar 

  60. Lanoir J, Ternaux JP, Pons C et al (1981) Long-term effects of a tryptophan-free diet on serotonin metabolism and sleep-waking balance in rats. Exp Brain Res 41:346–357

    Article  PubMed  CAS  Google Scholar 

  61. Hommes FA (1993) The effect of hyperphenylalaninaemia on the muscarinic acetylcholine receptor in the HPH-5 mouse brain. J Inherit Metab Dis 16:962–974

    Article  PubMed  CAS  Google Scholar 

  62. Jenni OG, Borbely AA, Achermann P (2004) Development of the nocturnal sleep electroencephalogram in human infants. Am J Physiol Regul Integr Comp Physiol 286:R528–R538

    PubMed  CAS  Google Scholar 

  63. Rosanova M, Ulrich D (2005) Pattern-specific associative long-term potentiation induced by a sleep spindle-related spike train. J Neurosci 25:9398–9405

    Article  PubMed  CAS  Google Scholar 

  64. Walker MP, Stickgold R (2006) Sleep, memory, and plasticity. Ann Rev Psychol 57:139–166

    Article  Google Scholar 

  65. Schabus M, Gruber G, Parapatics S et al (2004) Sleep spindles and their significance for declarative memory consolidation. Sleep 27:1479–1485

    PubMed  Google Scholar 

  66. Fogel SM, Smith CT (2006) Learning-dependent changes in sleep spindles and Stage 2 sleep. Sleep 15:250–255

    Article  Google Scholar 

  67. Schabus M, Hodlmoser K, Gruber G et al (2006) Sleep spindle-related activity in the human EEG and its relation to general cognitive and learning abilities. Eur J Neurosci 23:1738–1746

    Article  PubMed  CAS  Google Scholar 

  68. Schmidt C, Peigneux P, Muto V et al (2006) Encoding difficulty promotes postlearning changes in sleep spindle activity during napping. J Neurosci 26:8976–8982

    Article  PubMed  CAS  Google Scholar 

  69. Peirano P, Algarin C, Uauy R (2003) Sleep-wake states and their regulatory mechanisms throughout early human development. J Pediatr 143:S70–S79

    Article  PubMed  Google Scholar 

  70. Parmelee AH, Sigman M, Garbanati J et al (1994) Neonatal electroencephalographic organization and attention in early adolescence. In: Dawson G, Fischer KW (eds) Human behavior and the developing brain. Guilford, New York, pp 537–554

    Google Scholar 

  71. Grantham-McGregor S, Ani C (2001) A review of studies on the effect of iron deficiency on cognitive development in children. J Nutr 131:649S–668S

    PubMed  CAS  Google Scholar 

  72. Chase MH, Harper RM (1971) Somatomotor and visceromotor correlates of operantly conditioned 12–14 c/sec sensorimotor cortical activity. Electroencephalogr Clin Neurophysiol 31:85–92

    Article  PubMed  CAS  Google Scholar 

  73. Trenkwalder C, Paulus W, Walters AS (2005) The restless legs syndrome. Lancet Neurol 4:465–474

    Article  PubMed  CAS  Google Scholar 

  74. Earley CJ, Heckler D, Allen RP (2004) The treatment of restless legs syndrome with intravenous iron dextran. Sleep Med 5:231–235

    Article  PubMed  Google Scholar 

  75. Simakajornboon N, Gozal D, Vlasic V et al (2003) Periodic limb movements in sleep and iron status in children. Sleep 26:735–738

    PubMed  Google Scholar 

  76. Simakajornboon N (2006) Periodic limb movement disorder in children. Paediatr Respir Rev 7:S55–S57

    Article  PubMed  Google Scholar 

  77. Shinomiya S, Nagata K, Takahashi K et al (1999) Development of sleep spindles in young children and adolescents. Clin Electroencephalogr 30:39–43

    PubMed  CAS  Google Scholar 

  78. De Gennaro L, Ferrara M (2003) Sleep spindles: an overview. Sleep Med Rev 7:423–440

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors thank the infants and parents whose participation made this study possible. We also thank Miriam Dinamarca for valuable assistance, technicians for performing the polysomnographic recordings during the course of this study, drivers for providing careful transportation services to infants and parents, and Yuezhou Jing for statistical support. The work was supported by grants from the U.S. National Institutes of Health (R01 HD14122 and R01 HD33487, Betsy Lozoff, P.I.) and FONDECYT in Chile (1040945, Patricio Peirano, P.I.).

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Authors and Affiliations

  1. Sleep and Functional Neurobiology Laboratory, Institute of Nutrition and Food Technology (INTA), University of Chile, Av. JP Alessandri 5540, Santiago, 11, Chile

    Patricio Peirano, Cecilia Algarín, Marcelo Garrido & Diógenes Algarín

  2. Center for Human Growth and Development and the Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA

    Betsy Lozoff

Authors
  1. Patricio Peirano
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  2. Cecilia Algarín
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  3. Marcelo Garrido
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  4. Diógenes Algarín
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  5. Betsy Lozoff
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Correspondence to Patricio Peirano.

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Special issue dedicated to Dr. Moussa Youdim.

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Peirano, P., Algarín, C., Garrido, M. et al. Iron-Deficiency Anemia is Associated with Altered Characteristics of Sleep Spindles in NREM Sleep in Infancy. Neurochem Res 32, 1665–1672 (2007). https://doi.org/10.1007/s11064-007-9396-8

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  • DOI: https://doi.org/10.1007/s11064-007-9396-8

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