Essential fatty acids are structural components of all tissues and are indispensable for cell membrane synthesis; the brain, retina and other neural tissues are particularly rich in long-chain polyunsaturated fatty acids (LC-PUFA). These fatty acids serve as specific precursors for eicosanoids, which regulate numerous cell and organ functions. Recent human studies support the essential nature of n-3 fatty acids in addition to the well-established role of n-6 essential fatty acids in humans, particularly in early life. The main findings are that light sensitivity of retinal rod photoreceptors is significantly reduced in newborns with n-3 fatty acid deficiency, and that docosahexaenoic acid (DHA) significantly enhances visual acuity maturation and cognitive functions. DHA is a conditionally essential nutrient for adequate neurodevelopment in humans. Comprehensive clinical studies have shown that dietary supplementation with marine oil or single-cell oil sources of LC-PUFA results in increased blood levels of DHA and arachidonic acid, as well as an associated improvement in visual function in formula-fed infants matching that of human breast-fed infants. The effect is mediated not only by the known effects on membrane biophysical properties, neurotransmitter content, and the corresponding electrophysiological correlates but also by a modulating gene expression of the developing retina and brain. Intracellular fatty acids or their metabolites regulate transcriptional activation of gene expression during adipocyte differentiation and retinal and nervous system development. Regulation of gene expression by LC-PUFA occurs at the transcriptional level and may be mediated by nuclear transcription factors activated by fatty acids. These nuclear receptors are part of the family of steroid hormone receptors. DHA also has significant effects on photoreceptor membranes and neurotransmitters involved in the signal transduction process; rhodopsin activation, rod and cone development, neuronal dendritic connectivity, and functional maturation of the central nervous system.

Iron deficiency anemia has long been thought to have effects on the central nervous system (CNS). Finding direct evidence of this in human infants, however, has been challenging. Auditory brainstem responses (ABRs) provide a noninvasive means of examining an aspect of the CNS that is rapidly maturing during the age period when iron deficiency is most common. ABRs represent the progressive activation of the auditory pathway from the acoustic nerve (wave I) to the lateral lemniscus (wave V). The central conduction time (CCT, or wave I-V interpeak latency) is considered an index of CNS development because myelination of nerve fibers and maturation of synaptic relays lead to an exponential reduction in the CCT from birth to 24 mo. In 55 otherwise healthy, 6-mo-old Chilean infants (29 with iron deficiency anemia and 26 nonanemic control infants), the CCT was longer in those who had been anemic at 6 mo, with differences becoming more pronounced at 12- and 18-mo follow-ups despite effective iron therapy. The pattern of results--differences in latencies but not amplitudes, more effects on the late ABR components (waves III and V), and longer CCTs (as an overall measure of nerve conduction velocity)--suggested altered myelination as a promising explanation, consistent with recent laboratory work documenting iron's essential role in myelin formation and maintenance. This study shows that iron deficiency anemia in 6-mo-old infants is associated with adverse effects on at least one aspect of CNS development and suggests the fruitfulness of studying other processes that are rapidly myelinating during the first 2 y of life.

Evoked potentials provide noninvasive measures of nerve transmission and CNS functioning. Auditory brainstem responses (ABR) and visual evoked potentials (VEP) show dramatic changes in infancy, largely as a result of progressive myelination. Because iron is required for normal myelination, pathway transmission in these sensory systems might be affected by early iron deficiency. We previously reported evidence to that effect: infants with iron-deficiency anemia (IDA) had slower transmission through the auditory brainstem pathway, uncorrected by iron therapy. To determine long-term effects, ABR and/or VEP of healthy Chilean children who were treated for IDA or were nonanemic in infancy were compared at approximately 4 y of age. Absolute latencies for all ABR waves and interpeak latencies (except I-III interval) were significantly longer in former IDA children. Longer latency was also observed for the P100 wave on VEP. The magnitude of differences was large-about 1 SD. These findings, with differences in latencies but not amplitudes, further support the hypothesis that IDA in infancy alters myelination and provide evidence that effects on transmission through the auditory and visual systems can be long lasting. Subtle changes in sensory pathway transmission might be an underlying mechanism for the derailment of other developmental aspects in early IDA. Neurophysiologic methodologies are noninvasive approaches that can provide information about the functional integration of the CNS. For example, dramatic decreases in latencies in auditory and visual evoked potentials in infancy are often used to index the overall intactness and maturation of the CNS. Progressively shorter latencies until adult levels are achieved are thought to reflect the increasing speed of transmission through sensory pathways, resulting in large part from increased myelination of the auditory and optic nerves and at the intracerebral level (1-5).ABR represent the progressive activation of different levels of the auditory pathway: wave I is generated peripherally in the auditory nerve, wave III reflects the firing of axons exiting the cochlear nuclear complex, and wave V reflects an action potential generated by axons from the lateral lemniscus (6, 7). We recently reported the use of ABR to determine the effects of early IDA on the functional development of the auditory system (8). Six-month-old Chilean infants with IDA tended to show longer latencies than controls, indicating slower transmission through the brainstem portion of the auditory pathway. Differences became pronounced at 12 and 18 mo, despite iron therapy. Because iron is required for the functioning of several neurotransmission systems, myelination, and neuronal metabolic activity, different processes may relate to these lasting ABR abnormalities. However, the findings of differences in latency but not amplitude and more effects on the central (versus peripheral) portion of the auditory pathway appeared to be strong support for the hypothesis that impaired myelination was the explana...

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Objective To determine the long-term effects of iron deficiency on the neural correlates of recognition memory. Study design Non-anemic control participants (n=93) and 116 otherwise healthy formerly iron-deficient anemic (FIDA) Chilean children were selected from a larger longitudinal study. Participants were identified at 6, 12, or 18 months as iron-deficient anemic or non-anemic and subsequently received oral iron treatment. This follow-up was conducted when participants were 10 years old. Behavioral measures and event-related potentials from 28 scalp electrodes were measured during an old/new word recognition memory task. Results The new/old effect of the FN400 amplitude, where new words are associated with greater amplitude than old words, was present within the control group only. The control group also showed faster FN400 latency than the FIDA group and larger mean amplitude for the P300 component. Conclusions Although overall behavioral performance is comparable between groups, the results show that group differences in cognitive function have not been resolved ten years after iron treatment. Long-lasting changes in myelination and energy metabolism, perhaps especially in the hippocampus, may account for these long-term effects on an important aspect of human cognitive development.