Matthew J. Burden

Iron deficiency in infancy and neurocognitive functioning at 19 years: evidence of long-term deficits in executive function and recognition memory

Abstract Iron deficiency in infancy negatively impacts a variety of neurodevelopmental processes at the time of nutrient insufficiency, with persistent central nervous system alterations and deficits in behavioral functioning, despite iron therapy. In rodent models, early iron deficiency impairs the hippocampus and the dopamine system. We examined the possibility that young adults who had experienced chronic, severe, iron deficiency as infants would exhibit deficits on neurocognitive tests with documented frontostriatal (Trail Making Test, Intra-/Extra-dimensional Shift, Stockings of Cambridge, Spatial Working Memory, Rapid Visual Information Processing) and hippocampal specificity (Pattern Recognition Memory, Spatial Recognition Memory). Participants with chronic, severe iron deficiency in infancy performed less well on frontostriatal-mediated executive functions, including inhibitory control, set-shifting, and planning. Participants also exhibited impairment on a hippocampus-based recognition memory task. We suggest that these deficits may result from the long-term effects of early iron deficiency on the dopamine system, the hippocampus, and their interaction.

Effects of Prenatal Alcohol Exposure on Attention and Working Memory at 7.5 Years of Age.

BACKGROUND A broad range of attentional and neuropsychological impairments have been demonstrated in children with fetal alcohol exposure. This study was designed to investigate which specific aspects of attentional function are most directly affected by moderate to heavy doses of prenatal alcohol exposure. METHODS A total of 337 black children who were aged 7.5 years and recruited prospectively to overrepresent prenatal alcohol exposure at moderate to heavy levels were assessed on a diverse battery of neuropsychological tests. Principal components analyses were used to replicate and extend Mirsky et al.s (1991) four-component model of attention. The relation of prenatal alcohol exposure to empirically derived attentional constructs was examined. RESULTS Both the replicated and the extended attentional models produced solutions similar to the original Mirsky et al. model, reflecting elements of encode (working memory), shift, and focused and sustained attention, as well as a distinct component reflecting impulsivity. Adverse effects of maternal drinking across pregnancy were found primarily for working memory, and these effects were exacerbated when mothers were aged 30 or older at the time of the childs birth. CONCLUSIONS These data confirm previous studies using diverse methods that suggest that working memory may be the most important aspect of attention that is adversely affected by prenatal alcohol exposure.

Iron deficiency anemia and cognitive function in infancy.

OBJECTIVES: This study examined effects of iron deficiency anemia (IDA) on specific domains of infant cognitive function and the role of IDA-related socioemotional deficits in mediating and/or moderating these effects. METHODS: Infants were recruited during routine 9-month visits to an inner-city clinic. IDA was defined as hemoglobin level <110 g/L with ≥2 abnormal iron deficiency indicators (mean corpuscular volume, red cell distribution width, zinc protoporphyrin, transferrin saturation, and ferritin). At 9 and 12 months, the Fagan Test of Infant Intelligence (FTII); A-not-B task; Emotionality, Activity, and Sociability Temperament Survey; and Behavior Rating Scale were administered. Analyses were adjusted for potential confounders, including age and sociodemographic variables. RESULTS: Twenty-eight infants met criteria for IDA, 28 had nonanemic iron deficiency (NA ID) and 21 had iron sufficiency (IS). There was a linear effect for object permanence at 9 months: infants with IDA were least likely to exhibit object permanence, IS most likely, and NA ID intermediate. Infants with IDA and those with hemoglobin level ≤105 g/L showed poorer recognition memory on the FTII than infants without IDA. The Behavior Rating Scale orientation/engagement measure partially mediated these effects. Stronger effects of IDA on these outcomes were seen in infants who scored more poorly on the socioemotional measures. CONCLUSIONS: These data indicate poorer object permanence and short-term memory encoding and/or retrieval in infants with IDA at 9 months. These cognitive effects were attributable, in part, to IDA-related deficits in socioemotional function. Children with poor socioemotional performance seem to be more vulnerable to the effects of IDA on cognitive function.

Neurophysiologic and neurobehavioral evidence of beneficial effects of prenatal omega-3 fatty acid intake on memory function at school age

BACKGROUND The beneficial effects of prenatal and early postnatal intakes of omega-3 (n-3) polyunsaturated fatty acids (PUFAs) on cognitive development during infancy are well recognized. However, few studies have examined the extent to which these benefits continue to be evident in childhood. OBJECTIVE The aim of this study was to examine the relation of n-3 PUFAs and seafood-contaminant intake with memory function in school-age children from a fish-eating community. DESIGN In a prospective, longitudinal study in Arctic Quebec, we assessed Inuit children (n = 154; mean age: 11.3 y) by using a continuous visual recognition task to measure 2 event-related potential components related to recognition memory processing: the FN400 and the late positive component (LPC). Children were also examined by using 2 well-established neurobehavioral assessments of memory: the Digit span forward from Wechsler Intelligence Scales for Children, 4th edition, and the California Verbal Learning Test-Childrens Version. RESULTS Repeated-measures analyses of variance revealed that children with higher cord plasma concentrations of docosahexaenoic acid (DHA), which is an important n-3 PUFA, had a shorter FN400 latency and a larger LPC amplitude; and higher plasma DHA concentrations at the time of testing were associated with increased FN400 amplitude. Cord DHA-related effects were observed regardless of seafood-contaminant amounts. Multiple regression analyses also showed positive associations between cord DHA concentrations and performance on neurobehavioral assessments of memory. CONCLUSION To our knowledge, this study provides the first neurophysiologic and neurobehavioral evidence of long-term beneficial effects of n-3 PUFA intake in utero on memory function in school-age children.

An Event-Related Potential Study of Attention and Recognition Memory in Infants With Iron-Deficiency Anemia

OBJECTIVES. The purpose of this work was to determine whether iron-deficiency anemia in infancy represents a risk factor for deficits in attention and memory development using event-related potentials. METHODS. Artifact-free event-related potential data were obtained at 9 and/or 12 months from 15 infants with iron-deficiency anemia and 19 who were iron sufficient during a test of the infants ability to discriminate a highly familiar stimulus, the mothers face, from a strangers face. RESULTS. A midlatency negative component associated with attention and a late-occurring positive slow wave associated with memory updating were identified at both ages in the iron-deficiency anemia and iron-sufficient groups. Consistent with the age-appropriate pattern of development at 9 months, the iron-sufficient group showed a greater attentional response (negative component) to the mother and a greater updating of memory for the stranger (positive slow wave). This pattern of responses was not evident in the iron-deficiency anemia group until 12 months, suggesting a delay in cognitive development. CONCLUSIONS. These data suggest that iron-deficiency anemia adversely affects the allocation of neurophysiologic resources to attention and recognition memory during the processing of information about familiar and unfamiliar stimuli. This delay in cognitive development may reflect alterations in efficiency of central nervous system functions that seem related to early iron deficiency.

Response inhibition and error monitoring during a visual go/no-go task in inuit children exposed to lead, polychlorinated biphenyls, and methylmercury.

Background: Lead (Pb) and polychlorinated biphenyls (PCBs) are neurotoxic contaminants that have been related to impairment in response inhibition. Objectives: In this study we examined the neurophysiological correlates of the response inhibition deficits associated with these exposures, using event-related potentials (ERPs) in a sample of school-age Inuit children from Arctic Québec exposed through their traditional diet. Methods: In a prospective longitudinal study, we assessed 196 children (mean age, 11.3 years) on a visual go/no-go response inhibition paradigm. Pb, PCB, and mercury (Hg) concentrations were analyzed in cord and current blood samples. Hierarchical multiple regression analyses were conducted to examine the associations of contaminant levels to go/no-go performance (mean reaction time, percent correct go, percent correct no-go) and five ERPs [N2, P3, error-related negativity, error positivity (Pe), and correct response positivity (Pc)] after control for confounding variables. Results: Current blood Pb concentrations were associated with higher rates of false alarms and with decreased P3 amplitudes to go and no-go trials. Current plasma PCB-153 concentrations were associated with slower reaction times and with reduced amplitudes of the Pe and Pc response-related potentials. Hg concentrations were not related to any outcome on this task but showed significant interactions with other contaminants on certain outcomes. Conclusions: These results suggest that Pb exposure during childhood impairs the child’s ability to allocate the cognitive resources needed to correctly inhibit a prepotent response, resulting in increased impulsivity. By contrast, postnatal PCB exposure appears to affect processes associated with error monitoring, an aspect of behavioral regulation required to adequately adapt to the changing demands of the environment, which results in reduced task efficiency.

Number Processing in Adolescents With Prenatal Alcohol Exposure and ADHD: Differences in the Neurobehavioral Phenotype

BACKGROUND Poor arithmetic performance is among the most sensitive outcomes associated with prenatal alcohol exposure and is also common in individuals with attention-deficit hyperactivity disorder (ADHD). We hypothesized that prenatal alcohol exposure would be associated with deficits in the most fundamental aspects of number processing, representation of quantity and distance, whereas ADHD would be associated with deficits in calculation, the form of number processing most dependent on attention and memory. METHODS Two hundred and sixty-two inner-city, African American adolescents, who had been evaluated prospectively for prenatal alcohol exposure and ADHD, were assessed on a number-processing test comprised of 7 subtests. RESULTS More heavily alcohol-exposed adolescents were 4 times more likely to meet diagnostic criteria for ADHD than those whose mothers abstained from alcohol use during pregnancy. Two dimensions of number processing were identified in a factor analysis-magnitude comparison and calculation. As hypothesized, prenatal alcohol exposure was more strongly related to the former and ADHD to the latter. Moreover, the relation of prenatal alcohol to calculation was fully mediated by magnitude comparison, whereas the relation of ADHD to calculation was mediated by IQ but not by magnitude comparison. CONCLUSION These data confirm findings from previous studies identifying arithmetic as a particularly sensitive developmental endpoint for prenatal alcohol exposure. Whereas difficulties with arithmetic in ADHD are mediated by domain-general deficits in overall cognitive ability, fetal alcohol-related arithmetic difficulties are mediated primarily by a specific deficit in the core quantity system involving the ability to mentally represent and manipulate number. These data suggest that different interventions are likely to be effective for remediating arithmetic problems in children with prenatal alcohol exposure than in non-exposed children with ADHD.

An event-related potential study of response inhibition in ADHD with and without prenatal alcohol exposure.

BACKGROUND The attention and cognitive problems seen in individuals with a history of prenatal alcohol exposure often resemble those associated with attention deficit hyperactivity disorder (ADHD), but few studies have directly assessed the unique influence of each on neurobehavioral outcomes. METHODS We recorded event-related potentials (ERPs) during a Go/No-go response inhibition task in young adults with prospectively obtained histories of prenatal alcohol exposure and childhood ADHD. RESULTS Regardless of prenatal alcohol exposure, participants with childhood ADHD were less accurate at inhibiting responses. However, only the ADHD group without prenatal alcohol exposure showed a markedly diminished P3 difference between No-go and Go, which may reflect a more effortful strategy related to inhibitory control at the neural processing level. CONCLUSION This finding supports a growing body of evidence suggesting that the manifestation of idiopathic ADHD symptoms may stem from a neurophysiologic process that is different from the ADHD symptomatology associated with prenatal alcohol exposure. Individuals who have been prenatally exposed to alcohol and present with ADHD symptomatology may represent a unique endophenotype of the disorder, which may require different treatment approaches from those found to be effective with idiopathic ADHD.

The Effects of Maternal Binge Drinking During Pregnancy on Neural Correlates of Response Inhibition and Memory in Childhood

BACKGROUND Although an extensive literature has documented a broad range of cognitive performance deficits in children with prenatal alcohol exposure, little is known about how the neurophysiological processes underlying these deficits may be affected. Event-related potentials (ERPs), which reflect task-specific changes in brain electrical activity, provide a method for examining multiple constituents of cognitive processing at the neural level. METHODS We recorded ERPs in 217 children from Inuit communities in Arctic Quebec (M age = 11.3 years) during 2 different tasks-Go/No-go response inhibition and continuous recognition memory. Children were classified as either alcohol-exposed (ALC) or controls (CON) depending on whether the mother reported binge drinking during pregnancy. RESULTS Both groups performed comparably in terms of accuracy and reaction time on the tasks, and both tasks elicited the expected effects on ERPs when responses were compared across conditions. However, the ALC group showed slower P2 latencies on Go/No-go, suggesting an altered neurophysiological response associated with initial visual processing of the stimuli. On the memory task, the ALC group showed reduced FN400 amplitude to New items, known as the familiarity effect, and reduced amplitude for the late positive component, possibly reflecting impairment in memory retrieval. CONCLUSIONS These findings show that, even in tasks in which alcohol-exposed children exhibit behavioral performance that is comparable to controls, fetal alcohol exposure is associated with altered neurophysiological processing of response inhibition and recognition memory. The data suggest that fetal alcohol exposure is associated with reduced efficiency in the initial extracting of the meaning of a stimulus, reduced allocation of attention to the task, and poorer conscious, explicit recognition memory processing.

Prenatal tobacco exposure and response inhibition in school-aged children: An event-related potential study

Prenatal cigarette smoke exposure (PCSE) has been linked to problems in behavioral inhibition and attention deficit hyperactivity disorder in children in several epidemiological studies. We used event-related potentials (ERPs) to examine the effects of PCSE on neural correlates of inhibitory control of behavior. In a prospective longitudinal study on child development in the Canadian Arctic, we assessed 186 Inuit children (mean age=11.3years) on a visual Go/No-go response inhibition paradigm. PCSE was assessed through maternal recall. Potential confounders were documented from a maternal interview, and exposure to neurotoxic environmental contaminants was assessed from umbilical cord and child blood samples. PCSE was not related to behavioral performance on this simple response inhibition task. Nevertheless, this exposure was associated with smaller amplitudes of the N2 and P3 components elicited by No-go stimuli, suggesting an impairment in the neural processes underlying response inhibition. Amplitude of the No-go P3 component was also inversely associated with behavioral measures of externalizing problems and hyperactivity/impulsivity in the classroom. This study is the first to report neurophysiological evidence of impaired response inhibition in school-aged children exposed to tobacco smoke in utero. Effects were found on ERP components associated with conflict processing and inhibition of a prepotent response, indicating neurophysiological deficits that may play a critical role in the attention and behavior problems observed in children with PCSE.