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We also know that (a) in adult monkeys these cognitive abilities depend critically on the dopaminergic projection to prefrontal cortex and (b) the distribution of dopamine axons within dorsolateral prefrontal cortex changes, and the level of dopamine increases, during the period that infant monkeys are improving on tasks that require the cognitive abilities dependent on prefrontal cortex. To begin to look at whether these cognitive abilities depend critically on the prefrontal dopamine projection in humans even during infancy and early childhood we have been studying children who we hypothesized might have a selective reduction in the dopaminergic innervation of prefrontal cortex and a selective impairment in the cognitive functions subserved by dorsolateral prefrontal cortex. These are children treated early and continuously for the genetic disorder, phenylketonuria (PKU). In PKU the ability to convert the amino acid, phenylalanine (Phe), into another amino acid, tyrosine (Tyr), is impaired. This causes Phe to accumulate in the bloodstream to dangerously high levels and the plasma level of Tyr to fall. Widespread brain damage and severe mental retardation result. When PKU is moderately well controlled by a diet low in Phe (thus keeping the imbalance between Phe and Tyr in plasma within moderate limits) severe mental retardation is averted, but deficits remain in higher cognitive functions. In a four-year longitudinal study we have found these deficits to be in the working memory and inhibitory control functions dependent upon dorsolateral prefrontal cortex in PKU children with plasma Phe levels 3-5 times normal. The fact that even infants showed these impairments suggests that dopaminergic innervation to prefrontal cortex is critical for the proper expression of these abilities even during the first year of life. To test the hypothesis about the underlying biological mechanism we have created the first animal model of early and continuously treated PKU. As predicted, the experimental animals had reduced levels of dopamine and the dopamine metabolite, homovanillic acid (HVA), in prefrontal cortex and showed impaired performance on delayed alternation, a task dependent on prefrontal cortex function. Noradrenaline levels were unaffected; however some reduction in serotonin levels and in dopamine levels outside the prefrontal cortex was found. If prefrontal cortex functions are vulnerable in children with a moderate plasma Phe:Tyr imbalance because of the special properties of the dopamine neurons that project to prefrontal cortex, then other dopamine neurons that share those same properties should also be vulnerable in these children. The dopamine neurons in the retina share these properties (i.e. unusually high firing and dopamine turnover rates), and we have found that PKU children with plasma Phe levels 3-5 times normal are impaired in their contrast sensitivity, a behavioural measure sensitive to retinal dopamine levels.<\/jats:p>","DOI":"10.1098\/rstb.1996.0134","type":"journal-article","created":{"date-parts":[[2006,12,15]],"date-time":"2006-12-15T15:32:03Z","timestamp":1166196723000},"page":"1483-1494","source":"Crossref","is-referenced-by-count":101,"title":["Evidence for the importance of dopamine for prefrontal cortex functions early in life"],"prefix":"10.1098","volume":"351","author":[{"given":"Adele","family":"Diamond","sequence":"first","affiliation":[{"name":"Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Building E10-044, Cambridge, MA 02139, U. S. 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Bad deley ( . Departmentof Psychology University of Bristol information in mind + inhibitory control. The inter"},{"key":"p_113","unstructured":"Woodland Road Bristol BS8 1TN U.K.). Inter-correlations"},{"key":"p_114","unstructured":"between tests of frontal lobe or executive function have"},{"key":"p_115","unstructured":"typically not been very high. What is your experience with"},{"key":"p_116","unstructured":"the battery of cognitive tests you have used to study PKU in"},{"key":"p_117","unstructured":"children ?"},{"key":"p_118","unstructured":"A. D iam ond. The intercorrelation between performance on"},{"key":"p_119","unstructured":"the frontal tasks for infants AB and object retrieval was 0.35"},{"key":"p_120","unstructured":"(P < 0.001); both of these tasks require holding information"},{"key":"p_121","unstructured":"in mind + inhibitory control. There were no significant correlation between performance on the tapping and three pegs tasks was 0.53 (P < 0.0001) on tapping and the daynight Stroop-like tasks it was 0.35 (P < 0.0001) and on the day-night Stroop-like task and the tapping task it was 0.20 (P = 0.01); all three of these tasks require holding information in mind + inhibitory control. Performance on the other frontal tests (the six boxes task and the Corsi-Malner test of temporal order memory) which did not require holding information in mind + inhibitory control did not correlate significantly with performance on any other test."}],"container-title":["Philosophical Transactions of the Royal Society of London. 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