In this study of the effects of ID in infancy on motor development over time, children who had chronic ID in infancy had lower motor scores than children with good iron status, statistically significant at all ages. Mean scores of the chronic ID group were at the lower end of the range considered ‘normal’ (mean ±1 SD), and more of them had scores more than 1 SD below the US norm at each age. In longitudinal analysis, boys in the chronic ID group continued to have scores at the low end of the normal range at 5 years and in adolescence, showing a parallel but lower motor development trajectory compared to boys with good iron status in infancy. The motor trajectory for the chronic ID girls was also parallel and lower than that of the good iron status girls; girls in general scored much lower than the boys in adolescence. Thus, there was no evidence that children with chronic ID during infancy caught up over time in their motor test scores. Furthermore, chronic ID children were over-represented in a ‘stable-low’ cluster and under represented in the ‘stable-high’ cluster. Both fine and gross motor skills appeared to be equally affected. This finding suggests that ID in infancy contributed to broad early effects on a variety of brain processes and/or structures that are involved in motor production and control.
Recent research points to several central nervous system (CNS) effects of early ID that could help explain our results. Iron is involved in myelin production, and disruption in the availability of iron has been shown to impede myelination (Beard, Wiesinger, & Connor, 2003
; Connor & Menzies, 1996
; Ortiz et al., 2004
). Specifically, ID during gestation and lactation in the rat is associated with changes in myelin components (protein, cholesterol, phospholipids and galactolipids) and compaction at adulthood despite an iron-sufficient diet since weaning (Ortiz et al., 2004
It is possible that ID during infancy delayed and/or altered the myelination process of the corticospinal tract, which in turn contributed to delay and/or alteration in the normal acquisition and refinement of motor skills. The corticospinal tract, which encompasses the vast majority of the pyramidal tract fibers, connects motor and sensory regions of the cerebral cortex with the spinal cord and as such, constitutes the main path through which motor commands travel from the brain to the limbs. Myelination of the pyramidal tract is partial at birth and is not completed for several years (Rothwell, 1994
). The process of myelination during the initial years of life increases conduction velocity along this tract. Over time, this process enables the refinement of motor performance and improvement in motor skills to adult-like level (Lemon, Olivier, & Edgley, 1997
). Indeed, Heinen et al. (1998)
have attributed poorer motor performance of children relative to adults to differences in maturation of the corticospinal system, as expressed in differences in central conduction time during application of transcranial magnetic stimulation. More direct support for the idea that ID in infancy has long-lasting effects on myelination in humans comes from a recent study that examined auditory brainstem responses and visual evoked potentials. In 4-year-old children who were treated for IDA during infancy, transmission was slower in both the visual and auditory systems, suggesting that long-lasting effects of early IDA on myelination could be widespread (Algarin, Peirano, Garrido, Pizarro, & Lozoff, 2003
Another possible explanation for long-term effects of ID on motor function relates to reduced dopamine function, especially in the striatum. In rodent models, reduced brain iron concentration due to severe dietary iron restriction results in changes in the density of D1
dopamine receptors and dopamine transporter in the striatum (part of the basal ganglia) that persist to adulthood despite iron repletion (Beard & Connor, 2003
; Lozoff et al., 2006
; Youdim, 2000
). Even in a more moderate ID rodent model, there are short-and long-term effects on motor behaviors that depend on intact striatal dopamine neurons (Beard et al., 2006
; Felt et al., 2006
). Long-term potentiation (LTP) and long-term depression (LDP) in the striatum, with the cooperative action of D1
R and D2
R, are thought to play a role in the regulation of motor learning (Nakano, Kayahara, Tsutsumi, & Ushiro, 2000
). Thus, persisting changes in striatal D1
R and D2
R densities could alter the process and/or regulation of motor learning in IDA children, despite iron therapy.
Dopaminergic neurotransmission is also important in the motor cortico-basal ganglia–thalamo-cortical loop, which consists of two pathways within the basal ganglia – direct and indirect. The direct pathway, which acts to increase excitatory output from the thalamus to the cortex, contains mainly D1
dopamine receptors. In contrast, the indirect pathway, which acts to decrease excitatory output from the thalamus to the cortex, contains mainly D2
dopamine receptors (Obeso, Rodriguez-Oroz, Rodriguez, Arbizu, & Gimenez-Amaya, 2002
). Normal motor behavior appears to depend on a balance between the output of the direct and indirect pathways, a balance that both facilitates desired movements and inhibits potentially competing movements. Imbalances between the direct and indirect pathways are hypothesized to lead to hypokinetic syndromes such as Parkinson's disease – with increased output of the indirect pathway relative to the direct pathway – or hyperkinetic syndromes such as Huntington disease with increased output of the direct pathway relative to the indirect one (Nakano et al., 2000
). Thus, persisting changes in D1
R and D2
R due to ID in infancy may affect this delicate balance and consequently motor performance.
Dopamine neurons of the substantia nigra also code positive reward expectation errors by increasing their dopamine release to the striatum, to facilitate adaptive changes of synaptic transmission related to reward (Satoh, Nakai, Sato, & Kimura, 2003
). Thus, reduced dopamine transporter and receptors in the striatum with early ID may reduce motivation, exploration and learning due to reduced input signaling positive internal reward. A related mechanism through which ID during infancy could have long-term effects is known as ‘the functional isolation hypothesis’ (Levitsky & Barnes, 1972
; Lozoff et al., 1998
; Strupp & Levitsky, 1995
). According to this hypothesis, reduced activity and exploration and/or changes in affect and attention may lead ID infants to seek and receive less stimulation from the physical and social environment. Over time these alterations in child and caregiver behavior affect the child's mental, motor, and social-emotional development. Long-lasting alterations in social-emotional and mental development have been observed in the same sample (Lozoff et al., 2000
; Lozoff, Jimenez, & Smith, 2006
), which could interact with motor development over time to contribute to the long-term effects.
An encompassing framework may incorporate the specific hypotheses mentioned above. This is derived from Johnson's ‘neuroconstructivism’ or ‘interactive specialization’ view (Johnson, 2003
). According to this framework, brain development is determined by interaction between typical maturation of innate developmental processes and environment. Neurochemical, physiological, and behavioral deviations from ‘normal’ development may affect the process of brain development and cause the brain to develop somewhat differently. Thus, it is possible that chronic ID during infancy caused some delay or alteration in the infants' motor development while it lasted. The brain of these infants may well have compensated for, and/or adapted to, this deficiency by taking a different course of development. It is possible that, once iron status returned to normal, this adaptation enabled the ID infants to develop motorically at a similar rate as the good iron status infants. However, without an accelerated rate, there was no catch up in motor performance.
Gender issues were not the focus of this study, but the difference in motor performance between boys and girls in adolescence was striking. Poorer motor proficiency in girls, especially in adolescence, has been reported in the past and attributed to both biological and environmental (cultural and social) factors (Thomas & French, 1985
). Although biological factors may contribute to this gender difference from a very early age (Piek, Gasson, Barrett, & Case, 2002
), their effect is increased substantially during puberty, when boys develop larger muscle mass, larger hearts and consequently larger stroke volume, greater lung capacity, higher pulmonary ventilation and higher oxygen uptake than girls (Bale, Mayhew, Piper, Ball, & Willman, 1992
). These structural and physiological changes result in greater increase in speed, strength, power and physical work capacity, resulting in increased gender differences in the performance of many motor tasks, including items on the Bruininks-Oseretsky (Hattie & Edwards, 1987
). However, the scores of adolescent girls in Costa Rica were much lower than typically observed. The marked decrease in the girls' motor scores in adolescence in our sample may be due to social and cultural factors that limit girls' motor opportunities, activities, and performance more in Costa Rica than in the US. The extremely low scores of the chronic ID girls should be viewed cautiously, given their small number.
The question of continuity between test scores in infancy and those later on has received little attention with respect to motor proficiency, compared to cognitive functioning. One study addressed this question with the same measures used in our study. That study (with a considerably small sample size than ours) found no correlation between Bayley motor scores in infancy and Bruininks-Oseretsky at 9 years (MacCobb et al., 2005
). In contrast, we found continuity with both correlational analyses and the more powerful analytical approach of hierarchical linear modeling. The reason for such differing findings is unknown and warrants further study.
Our relatively small sample consisted of children born healthy at term, who were free of growth faltering or other chronic or acute health problems. Most ID children in the world have more health problems than our sample. Thus, it is not clear to what extent our results generalize to them. More longitudinal research is needed in larger, more varied samples. The limited number of ID girls in our sample limits generalization to females. The use of different tests of motor development in infancy and later ages also presented some challenges in analysis and interpretation. In addition, the age and duration of onset ID cannot be known with certainty in our study or most previous studies. It is possible that longer duration of ID during early motor development contributed to the observed long-term effects, since our participants were identified at 12–23 months and were therefore likely to have been ID for some time. If their ID started in the 1st year of life, timing may also have played a role, and earlier iron treatment might have reversed or prevented those effects. Furthermore, observational studies such as ours cannot prove that ID caused the effects, even though we controlled for a comprehensive set of background factors. Future research should consider causality and onset age and duration of ID. Such studies would require a different design, such as randomized control trials of preventing ID in infancy.
Longitudinal effects of changes in family and environment were not examined in this study. This question was not our focus and would be better studies in a larger sample with less stability in such important influences as socio-economic status, father absence, etc. Since culture, family, home environment, and socio-economic status (and changes in them) can affect motor development over time, they should be considered in more depth in future research.
In sum, this study shows that lower motor scores of chronic ID infants did not improve over time despite iron therapy in infancy that corrected IDA. ID children who started with relatively low motor scores were more likely to score lower through early adolescence. There was no evidence of catch-up in motor scores. Thus, iron treatment at the age of 12–23 months did not prevent long-term effects of ID in infancy on motor development. These results emphasize the importance of preventing ID, the most common nutrient deficiency in the world.