This fMRI study investigated the development of language lateralization in left- and right-handed children between 5 and 18 years of age. Twenty-seven left-handed children (17 boys, 10 girls) and 54 age- and gender-matched right-handed children were included. We used functional MRI at 3T and a verb generation task to measure hemispheric language dominance based on either frontal or temporo-parietal regions of interest (ROIs) defined for the entire group and applied on an individual basis. Based on the frontal ROI, in the left-handed group, 23 participants (85%) demonstrated left-hemispheric language lateralization, 3 (11%) demonstrated symmetric activation, and 1 (4%) demonstrated right-hemispheric lateralization. In contrast, 50 (93%) of the right-handed children showed left-hemisphere lateralization and 3 (6%) demonstrated a symmetric activation pattern, while one (2%) demonstrated a right- hemisphere lateralization. The corresponding values for the temporo-parietal ROI for the left-handed children were 18 (67%) left-dominant, 6 (22%) symmetric, 3 (11%) right-dominant and for the right-handed children 49 (91%), 4 (7%), 1 (2%). Left-hemispheric language lateralization increased with age in both groups but somewhat different lateralization trajectories were observed in girls when compared to boys. The incidence of atypical language lateralization in left-handed children in this study was similar to that reported in adults. We also found similar rates of increase in left-hemispheric language lateralization with age between groups (i.e., independent of handedness) indicating the presence of similar mechanisms for language lateralization in left- and right-handed children.

Objectives:

The pathophysiology of sports-related concussion (SRC) is incompletely understood. Human adult and experimental animal investigations have revealed structural axonal injuries, decreases in the neuronal metabolite N-acetyl aspartate, and reduced cerebral blood flow (CBF) after SRC and minor traumatic brain injury. The authors of this investigation explore these possibilities after pediatric SRC.

Patients And Methods:

Twelve children, ages 11 to 15 years, who experienced SRC were evaluated by ImPACT neurocognitive testing, T1 and susceptibility weighted MRI, diffusion tensor imaging, proton magnetic resonance spectroscopy, and phase contrast angiography at <72 hours, 14 days, and 30 days or greater after concussion. A similar number of age- and gender-matched controls were evaluated at a single time point.

Results:

ImPACT results confirmed statistically significant differences in initial total symptom score and reaction time between the SRC and control groups, resolving by 14 days for total symptom score and 30 days for reaction time. No evidence of structural injury was found on qualitative review of MRI. No decreases in neuronal metabolite N-acetyl aspartate or elevation of lactic acid were detected by proton magnetic resonance spectroscopy. Statistically significant alterations in CBF were documented in the SRC group, with reduction in CBF predominating (38 vs 48 mL/100 g per minute; P = .027). Improvement toward control values occurred in only 27% of the participants at 14 days and 64% at >30 days after SRC.

Conclusions:

Pediatric SRC is primarily a physiologic injury, affecting CBF significantly without evidence of measurable structural, metabolic neuronal or axonal injury. Further study of CBF mechanisms is needed to explain patterns of recovery.

Objective

The purpose of the research study was to examine the manifestation of variability in reaction times (RT) in children with Attention Deficit Hyperactivity Disorder (ADHD) and to examine whether RT variability presented differently across a variety of neuropsychological tasks, was present across the two most common ADHD subtypes, and whether it was affected by reward and event rate (ER) manipulations.

Method

Children with ADHD-Combined Type (n=51), ADHD-Predominantly Inattentive Type (n=53) and 47 controls completed five neuropsychological tasks (Choice Discrimination Task, Child Attentional Network Task, Go/No-Go task, Stop Signal Task, and N-back task), each allowing trial-by-trial assessment of reaction times. Multiple indicators of RT variability including RT standard deviation, coefficient of variation and ex-Gaussian tau were used.

Results

Children with ADHD demonstrated greater RT variability than controls across all five tasks as measured by the ex-Gaussian indicator tau. There were minimal differences in RT variability across the ADHD subtypes. Children with ADHD also had poorer task accuracy than controls across all tasks except the Choice Discrimination task. Although ER and reward manipulations did affect children’s RT variability and task accuracy, these manipulations largely did not differentially affect children with ADHD compared to controls. RT variability and task accuracy were highly correlated across tasks. Removing variance attributable to RT variability from task accuracy did not appreciably affect between-group differences in task accuracy.

Conclusions

High RT variability is a ubiquitous and robust phenomenon in children with ADHD.

OBJECTIVE:

To determine the effectiveness of a quality improvement program to improve pediatricians' adherence to existing, evidence-based, attention-deficit/hyperactivity disorder (ADHD) practice guidelines.

METHODS:

Forty-nine community-based pediatricians at 8 practices participated in a cluster-randomized trial. Practices were matched according to the numbers of pediatricians and the proportions of patients receiving Medicaid. The medical charts for a random sample of patients with ADHD for each of the participating pediatricians were examined at baseline and 6 months. All practices participated in 4 sessions of training, including didactic lectures and office flow modification workshops. Practices were then given access to an ADHD Internet portal that allowed parents, teachers, and pediatricians to input information (eg, rating scales) about patients, after which information was scored, interpreted, and formatted in a report style that was helpful for assessment and treatment of patients with ADHD. Physicians evaluated their practice behaviors quarterly and addressed underperforming areas.

RESULTS:

Pediatricians in the intervention group, compared with those in the control group, demonstrated significantly higher rates of many American Academy of Pediatrics–recommended ADHD care practices, including collection of parent (Cohen's d = 0.69) and teacher (d = 0.68) rating scales for assessment of children with ADHD, use of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria (d = 0.85), and use of teacher rating scales to monitor treatment responses (d = 1.01).

CONCLUSION:

A quality improvement intervention that can be widely disseminated by using Internet-based information technology significantly improved the quality of ADHD care in community-based pediatric settings.

Objective

To examine the association of prenatal exposure to bisphenol A and select common phthalates with infant neurobehavior measured at 5 weeks.

Methods

We compared the concentration of maternal urinary metabolites of bisphenol A and phthalates at two distinct time points in pregnancy (16w, 26w) with scores on the NICU Network Neurobehavioral Scale (NNNS) at 5 weeks of age in a cohort of 350 mother/infant pairs.

Results

Prenatal exposure to BPA was not significantly associated with neurobehavioral outcomes at 5 weeks. Significant associations between prenatal exposure to measured phthalates and infant neurobehavioral outcomes differed by type of phthalate and were only seen with exposure measured at 26 weeks. Higher total di-butyl phthalate (DBP) metabolites at 26w was associated with improved behavioral organization evidenced by decreased arousal (p=.04), increased self-regulation (p=.052), and decreased handling (p=.02). In males, higher total di-2-ethylhexyl phthalate (DEHP) metabolites at 26w was associated with more nonoptimal reflexes (p=.02).

Conclusion

The association between prenatal phthalate exposure and infant neurobehavior differed by type of phthalate and was evident only with exposure measured at 26w. Prenatal exposure to DBP was associated with improved behavioral organization in 5-week-old infants. Prenatal exposure to DEHP was associated with nonoptimal reflexes in male infants. There was no evidence of an association between prenatal BPA exposure and infant neurobehavior.

This study investigates the morphometry of Heschl's gyrus and its included primary auditory cortex (PAC) in hearing impaired (HI) and normal hearing (NH) infants. Fourty-two infants, age 8–19 months, with NH (n = 26) or hearing impairment (n = 16) were studied using high-resolution 3D magnetic resonance imaging. Gray matter (GM) and white matter (WM) volumes were obtained using software for automatic brain imaging segmentation to estimate the volume of each tissue within manually defined regions for the anterior portion of Heschl's gyrus (aHG) in each individual subject, transformed to an infant brain template space. Interactions among group (HI, NH), tissue type (GM, WM), and hemisphere (left, right) were examined using analysis of variance. Whole-brain voxel-based morphometry was utilized to explore volume differences between groups across the entire brain. The HI group showed increased GM and decreased WM in aHG compared with the NH group; likely effects of auditory deprivation. The HI group did not exhibit their typical L > R asymmetry pattern that the NH group showed. Increased GM in aHG in HI infants may represent abnormal cortical development in PAC as seen in animal models of sensory deprivation. Lower WM volume is consistent with studies with deaf adults.

This study examined the effects of methylphenidate (MPH) on reaction time (RT) variability in children with attention deficit hyperactivity disorder (ADHD). Using a broad battery of computerized tasks, and both conventional and ex-Gaussian indicators of RT variability, in addition to within-task manipulations of incentive and event rate (ER), this study comprehensively examined the breadth, specificity, and possible moderators of effects of MPH on RT variability. A total of 93 children with ADHD completed a 4-week within-subject, randomized, double-blind, placebo-controlled crossover trial of MPH to identify an optimal dosage. Children were then randomly assigned to receive either their optimal MPH dose or placebo after which they completed five neuropsychological tasks, each allowing trial-by-trial assessment of RTs. Stimulant effects on RT variability were observed on both measures of the total RT distribution (ie, coefficient of variation) as well as on an ex-Gaussian measure examining the exponential portion of the RT distribution (ie, τ). There was minimal, if any, effect of MPH on performance accuracy or RT speed. Within-task incentive and ER manipulations did not appreciably affect stimulant effects across the tasks. The pattern of significant and pervasive effects of MPH on RT variability, and few effects of MPH on accuracy and RT speed suggest that MPH primarily affects RT variability. Given the magnitude and breadth of effects of MPH on RT variability as well as the apparent specificity of these effects of MPH on RT variability indicators, future research should focus on neurophysiological correlates of effects of MPH on RT variability in an effort to better define MPH pharmacodynamics.

Examined predictors of academic achievement, measured by standardized test scores, and performance, measured by school grades, in adolescents (Mage=16.8 yr) who met diagnostic criteria for ADHD-Combined type in early childhood (Mage = 8.5; N = 579). Several mediation models were also tested to determine whether ADHD medication use, receipt of special education, classroom performance, homework completion, or homework management mediated the relationship between symptoms of ADHD and academic outcomes. Childhood predictors of adolescent achievement differed from those for performance. Classroom performance and homework management mediated the relationship between symptoms of inattention and academic outcomes. Implications for understanding the relationship between symptoms of ADHD and academic functioning are discussed.

This study examined the effects of methylphenidate (MPH) on reaction time (RT) variability in children with Attention Deficit Hyperactivity Disorder (ADHD). Using a broad battery of computerized tasks and both conventional and ex-Gaussian indicators of RT variability, in addition to within-task manipulations of Incentive and Event Rate (ER), this study comprehensively examined the breadth, specificity, and possible moderators of MPH effects on RT variability. Ninety-three children with ADHD completed a four-week within subject, randomized, double-blind, placebo-controlled crossover trial of MPH to identify an optimal dosage. Children were then randomly assigned to receive either their optimal MPH dose or placebo after which they completed five neuropsychological tasks, each allowing trial-by-trial assessment of reaction times (RT). Stimulant effects on RT variability were observed on both measures of the total RT distribution (i.e., coefficient of variation) as well as on an ex-Gaussian measure examining the exponential portion of the RT distribution (i.e., tau). There was minimal, if any, effect of MPH on performance accuracy or RT speed. Within-task Incentive and ER manipulations did not appreciably affect stimulant effects across the tasks. The pattern of significant and pervasive MPH effects on RT variability and few MPH effects on accuracy and RT speed suggest that MPH primarily affects RT variability. Given the magnitude and breadth of MPH effects on RT variability as well as the apparent specificity of these MPH effects to RT variability indicators, future research should focus on neurophysiological correlates of MPH effects on RT variability in an effort to better define MPH pharmacodynamics.

The Attention Deficit Hyperactivity Disorder (ADHD) symptom presentation of young adolescents with ADHD was examined in association with the transition to middle school. The current study used data collected in the Multimodal Treatment Study of ADHD which included children between 7–9 years of age with a diagnosis of ADHD (n=258) and grade and sex matched controls (n=112). The trajectory of ADHD symptoms before, during and after the transition to middle school was modeled using hierarchical linear modeling. A clear developmental reduction in ADHD symptomatology was observed for all three ADHD symptom domains. For young adolescents with ADHD, the transition to middle school was associated with a disruption in the developmental decline of inattention, hyperactivity and impulsivity symptoms as measured by parent ratings. This effect was also observed for teacher ratings of inattention and hyperactivity. These results support the assertion that the environmental changes associated with transitioning to middle school coincide with a transient reversal in ADHD symptom decline among children with ADHD.

Parent-report of child homework problems was examined as a treatment outcome variable in the MTA - Multimodal Treatment Study of Children with Attention-Deficit/Hyperactivity Disorder (ADHD). Five hundred seventy-nine children ages 7.0–9.9 were randomly assigned to either medication management, behavioral treatment, combination treatment, or routine community care. Results showed that only participants who received behavioral treatment (behavioral and combined treatment) demonstrated sustained improvements in homework problems in comparison to routine community care. The magnitude of the sustained effect at the 24-month assessment was small to moderate for combined and behavioral treatment over routine community care (d = .37; .40, respectively). Parent ratings of initial ADHD symptom severity was the only variable found to moderate these effects.

The factor structure of a parent-report measure of child homework problems, the Homework Problems Checklist, was examined in a geographically and ethnically diverse sample of children with Attention-Deficit/Hyperactivity Disorder (ADHD). This measure was completed by the parents of 579 children ages 7.0-9.9 diagnosed with ADHD Combined Type as part of the Multimodal Treatment Study of Children with ADHD (MTA). Results replicated previous work showing two salient factors that measure homework completion behaviors (Factor I) and homework management behaviors (Factor II). This two-factor solution remained consistent when examined across child sex and ethnicity subgroups. Analysis of patterns revealed that homework problems are greater for children in higher grades and that children with ADHD and comorbid Learning Disabilities experience significantly more homework problems than children with ADHD alone. This study also replicated previous work showing that homework problems and ADHD inattentive symptoms are highly correlated whereas correlations between homework problems and hyperactivity and impulsivity are low to moderate. Implications of the findings for the assessment of homework problems in children with ADHD and for intervention are discussed.

A microanalysis of task events in a common go/no-go task was completed to examine how task events impact individual reaction times. Predictors of long reaction times were analyzed in order to better understand increased intra-individual variability (IIV) among children with ADHD compared to normal controls. 65 children with ADHD and 65 normal controls matched on gender, ethnicity, age completed a go/no-go task. Children across both groups were slower before and after omission errors than all other trials. They were also slower on the trial before successfully inhibiting their response to no-go trials. Children with ADHD exhibited a pronounced slowing on trials prior to omission errors and trials prior to successful inhibitions compared to the normal control group. Pre-error slowing in children with ADHD may represent the beginning stages of attentional disengagement that subsequently results in the absence of responding (i.e., errors of omission or successful inhibition). While these event-related increases in RT explain some of the increased IIV observed in children with ADHD, the removal of these trials did not remove the pronounced between-group differences in IIV suggesting that additional unmeasured processes are contributing to IIV in children with ADHD.

Background

Childhood lead exposure adversely affects neurodevelopment. However, few studies have examined changes in human brain metabolism that may underlie known adverse cognitive and behavioral outcomes.

Objective

We examined the association between mean childhood blood lead levels and in vivo brain metabolite concentrations as adults, determined by proton magnetic resonance spectroscopy (MRS) in a birth cohort with documented low-to-moderate lead exposure.

Methods

Adult participants from the Cincinnati Lead Study [n = 159; mean age (± SD), 20.8 ± 0.9 years] completed a quantitative, short-echo proton MRS protocol evaluating seven regions to determine brain concentrations of N-acetyl aspartate (NAA), creatine and phosphocreatine (Cr), cholines (Cho), myo-inositol, and a composite of glutamate and glutamine (GLX). Correlation and multiple linear regression analyses were conducted.

Results

Mean childhood blood lead levels were associated with regionally specific brain metabolite concentrations adjusted for age at imaging and Full-Scale intelligence quotient. Adjusted analyses estimated for a unit (micrograms per deciliter) increase in mean childhood blood lead concentrations, a decrease of NAA and Cr concentration levels in the basal ganglia, a decrease of NAA and a decrease of Cho concentration levels in the cerebellar hemisphere, a decrease of GLX concentration levels in vermis, a decrease of Cho and a decrease of GLX concentration levels in parietal white matter, and a decrease of Cho concentration levels in frontal white matter.

Conclusions

Gray-matter NAA reductions associated with increasing childhood blood lead levels suggest that sustained childhood lead exposure produces an irreversible pattern of neuronal dysfunction, whereas associated white-matter choline declines indicate a permanent alteration to myelin architecture.

Background

Diffusion tensor imaging (DTI) is a non-invasive MRI technique that has been used to quantify CNS abnormalities in various pathologic conditions. This study was designed to quantify the anisotropic diffusion properties in the brain of neonatal rats with hydrocephalus (HCP) and to investigate association between DTI measurements and cytopathology.

Methods

DTI data were acquired between postnatal day 7 (P7) and P12 in 12 rats with HCP induced at P2 and in 15 age-matched controls. Animals were euthanized at P11 or P22/P23 and brains were processed with immunohistochemistry for glial fibrillary acidic protein (GFAP), ionized calcium-binding adaptor molecule (Iba-1), and luxol fast blue (LFB) to assess astrocytosis, microglial reactivity and degree of myelination, respectively.

Results

Hydrocephalic rats were consistently found to have an abnormally low (at corrected p-level of <0.05) fractional anisotropy (FA) value and an abnormally high mean diffusivity (MD) value in the cerebral cortex (CX), the corpus callosum (CC), and the internal capsule (IC). Immunohistochemical analysis demonstrated trends of increasing astrocyte and microglial reactivity in HCP rats at P11 that reached statistical significance at P22/P23. A trend toward reduced myelination in the HCP rats was also found at P22/P23. Correlation analysis at P11 for the CC demonstrated statistically significant correlations (or trends) between the DTI measurement (the decreased FA and increased MD values) and the GFAP or Iba-1 rankings. The immunohistochemical rankings in the IC at P22/P23 were also significantly correlated or demonstrated a trend with both FA and MD values.

Conclusions

This study demonstrates the feasibility of employing DTI on the brain in experimental hydrocephalus in neonatal rats and reveals impairments in multiple regions of interest in both grey and white matter. A strong correlation was found between the immunohistochemical results and the changes in anisotropic diffusion properties.

Abstract

Background

Adiponectin, a circulating adipocyte protein, is associated with lower obesity. We have previously shown that adiponectin is present in human milk. This study determined whether higher milk adiponectin is associated with infant growth and investigated milk adiponectin's oligomeric form.

Design and Methods

This is a study of two parallel longitudinal cohorts of breastfed infants born between 1998 and 2005. Forty-five mother–infant pairs from Cincinnati, OH and 277 mother–infant pairs from Mexico City, Mexico were analyzed. All participants were healthy, term infants breastfed at least 1 month who completed 6 months of follow-up. Monthly milk samples (n = 1,379) up to 6 months were assayed for adiponectin by radioimmunoassay. Infant weight-for-age, length-for-age, and weight-for-length Z-scores up to 6 months of age were calculated using World Health Organization standards. Repeated-measures analysis was conducted. The structural form of human milk adiponectin was assessed by western blot.

Results

In the population studies, initial milk adiponectin was 24.0 ± 8.6 μg/L and did not differ by cohort. Over the first 6 months, higher milk adiponectin was associated with lower infant weight-for-age Z-score (−0.20 ± 0.04, p < 0.0001) and weight-for-length Z-score (−0.29 ± 0.08, p = 0.0002) but not length-for-age Z-score, adjusted for covariates, with no difference by cohort. By western blot, human milk adiponectin was predominantly in the biologically active high-molecular-weight form.

Conclusions

Our data suggest milk adiponectin may play a role in the early growth and development of breastfed infants.

Objective

The expansion of home visitation programs for at-risk, first-time mothers and their young children has drawn attention to the potential impact of depression on program outcomes, yet little research has examined depression in the context of home visitation. The purpose of this study was to determine the prevalence of and changes in depressive symptoms in mothers enrolled in home visitation and identify predictors of change in symptoms over the first 9 months of service.

Methods

Subjects consisted of 806 at-risk, first-time mothers enrolled in a home visitation program. Self-reported depression was measured at enrollment and again 9 months later. Established clinical cutoffs were used to identify clinically elevated levels of depression. Additional measures were taken of interpersonal trauma history, concurrent intimate partner violence, and social support.

Results

Results indicated that (1) 45.3% of mothers had clinically elevated symptoms of depression at some point during the first 9 months of service, (2) 25.9% of mothers had elevated symptoms at both time points or at the 9 month assessment, and (3) 74.1% experienced an interpersonal trauma prior to enrollment. Lack of improvement or worsening of depressive symptoms from enrollment to 9 months was best predicted by pre-enrollment interpersonal trauma history, young maternal age, being African American, and symptoms severe enough to have led to mental health treatment.

Conclusions

Findings suggest that maternal depressive symptoms are a significant problem in home visitation. The role of interpersonal trauma in depressive symptoms, and how to best address these clinical issues in home visitation, warrants further examination.

Practice Implications

Maternal depression is prevalent in home visitation programs, and many mothers exhibit elevated symptoms at multiple time points over the first year of service. Interpersonal trauma history is also prevalent, and is predictive of increased depressive symptoms over time. Home visitation programs should note that mothers with interpersonal trauma history, young maternal age, and being African American have an increased likelihood of persistent depressive symptoms, which may in turn pose significant challenges to providing services.

Spatial normalization and segmentation of infant brain MRI data based on adult or pediatric reference data may not be appropriate due to the developmental differences between the infant input data and the reference data. In this study we have constructed infant templates and a priori brain tissue probability maps based on the MR brain image data from 76 infants ranging in age from 9 to 15 months. We employed two processing strategies to construct the infant template and a priori data: one processed with and one without using a priori data in the segmentation step. Using the templates we constructed, comparisons between the adult templates and the new infant templates are presented. Tissue distribution differences are apparent between the infant and adult template, particularly in the gray matter (GM) maps. The infant a priori information classifies brain tissue as GM with higher probability than adult data, at the cost of white matter (WM), which presents with lower probability when compared to adult data. The differences are more pronounced in the frontal regions and in the cingulate gyrus. Similar differences are also observed when the infant data is compared to a pediatric (age 5 to 18) template. The two-pass segmentation approach taken here for infant T1W brain images has provided high-quality tissue probability maps for GM, WM, and CSF, in infant brain images. These templates may be used as prior probability distributions for segmentation and normalization; a key to improving the accuracy of these procedures in special populations.

Objective

Recent morphometric studies suggest that children with ADHD may demonstrate differential or delayed brain development than children without ADHD. Further, the regions that appear to be affected are regions that control attention and executive functioning. This study examines the developmental course of brain activation patterns during an attention task.

Method

Ten adolescents with ADHD and 14 normal controls performed a continuous performance task twice one year apart. fMRI scans were collected at each timepoint.

Results

In the absence of performance differences, children with ADHD and normal controls activated frontal-parietal regions while performing an attention task at initial testing. One year later, the normal control group evidenced no task-related areas of activation while performing the same task while the children with ADHD showed less activation at the second testing but continued to evidence task-related activations in bilateral frontal areas and left parietal lobe at the time of the second testing. In particular, children with ADHD appeared to require continued use of the right middle frontal gyrus during administration of testing one year apart while normal controls did not activate this region at the time of the second testing.

Conclusions

Children with ADHD appear to maintain the use of right prefrontal regions during attentional tasks beyond what is observed among normal controls. Given observed cortical thinning in corresponding brain regions, future research must address the recipocal effects of volumetric reductions and a continued need for using these regions to perform basic attentional tasks.

Purpose

Head motion during functional MRI scanning can lead to signal artifact, a problem often more severe with children. However, the documentation for the characteristics of head motion in children during various language functional tasks is very limited in the current literature. This report characterizes head motion in children during fMRI as a function of age, sex, and task.

Methods

Head motion during four different fMRI language tasks was investigated in a group of 323 healthy children between the age of 5 and 18 years. A repeated measures ANOVA analysis was used to study the impact of age, sex, task, and the interaction of these factors on the motion.

Results

Pediatric subjects demonstrated significantly different amounts of head motion during fMRI when different language tasks were used. Word-Picture Matching, the only task that involved visual engagement, suffered the least amount of motion, which was significantly less than in any of the other three tasks; the latter were not significantly different from each other. Further examination revealed that the main effect of language task on motion was significantly affected by age, sex, and their interaction.

Conclusion

Our results suggest that age, sex, and task are all associated with the degree of head motion in children during fMRI experiments. Investigators working with pediatric patients may increase their success by using task components associated with less motion (e.g., visual stimuli), or by using this large scale dataset to estimate the effects of sex and age on motion for planning purposes.

Purpose

To use functional MRI methods to visualize a network of auditory and language-processing brain regions associated with processing an aurally-presented story. We compare a passive listening (PL) story paradigm to an active-response (AR) version including on-line performance monitoring and a sparse acquisition technique.

Materials/Methods

Twenty children (ages 11−13) completed PL and AR story processing tasks. The PL version presented alternating 30-second blocks of stories and tones; the AR version presented story segments, comprehension questions, and 5s tone sequences, with fMRI acquisitions between stimuli. fMRI data was analyzed using a general linear model approach and paired t-test identifying significant group activation.

Results

Both tasks activated in primary auditory cortex, superior temporal gyrus bilaterally, left inferior frontal gyrus. The AR task demonstrated more extensive activation, including dorsolateral prefrontal cortex and anterior/posterior cingulate cortex. Comparison of effect size in each paradigm showed a larger effect for the AR paradigm in a left inferior frontal ROI.

Conclusion

Activation patterns for story processing in children are similar in passive listening and active-response tasks. Increases in extent and magnitude of activation in the AR task are likely associated with memory and attention resources engaged across acquisition intervals.

Quantifying change in brain activation patterns associated with post-stroke recovery and reorganization of language function over time requires accurate understanding of inter-scan and inter-subject variability. Here we report inter-scan variability measures for fMRI activation patterns associated with verb generation (VG) and semantic decision/tone decision (SDTD) tasks in 4 healthy controls and 4 aphasic left middle cerebral artery (LMCA) stroke subjects. A series of 10 fMRI scans was completed on a 4T Varian scanner for each task for each subject, except for one stroke subject who completed 5 and 6 scans for SDTD and VG, thus yielding 35 and 36 total stroke subject scans for SDTD and VG, respectively. Group composite and intraclass correlation coefficient (ICC) maps were computed across all subjects and trials for each task. The patterns of reliable activation for the VG and SDTD tasks correspond well to those regions typically activated by these tasks in healthy and aphasic subjects. ICCs for activation were consistently high (R0.05 ≈ 0.8) for individual tasks among both control and aphasic subjects. These voxel-wise measures of reliability highlight regions of low inter-scan variability within language circuitry for control and post-recovery stroke subjects. ICCs computed from the combination of the SDTD/VG data were markedly reduced for both control and aphasic subjects as compared with the ICCs for the individual tasks. These quantitative measures of inter-scan variability support the proposed use of these fMRI paradigms for longitudinal mapping of neural reorganization of language processing following left hemispheric insult.

Background

Although environmental lead exposure is associated with significant deficits in cognition, executive functions, social behaviors, and motor abilities, the neuroanatomical basis for these impairments remains poorly understood. In this study, we examined the relationship between childhood lead exposure and adult brain volume using magnetic resonance imaging (MRI). We also explored how volume changes correlate with historic neuropsychological assessments.

Methods and Findings

Volumetric analyses of whole brain MRI data revealed significant decreases in brain volume associated with childhood blood lead concentrations. Using conservative, minimum contiguous cluster size and statistical criteria (700 voxels, unadjusted p < 0.001), approximately 1.2% of the total gray matter was significantly and inversely associated with mean childhood blood lead concentration. The most affected regions included frontal gray matter, specifically the anterior cingulate cortex (ACC). Areas of lead-associated gray matter volume loss were much larger and more significant in men than women. We found that fine motor factor scores positively correlated with gray matter volume in the cerebellar hemispheres; adding blood lead concentrations as a variable to the model attenuated this correlation.

Conclusions

Childhood lead exposure is associated with region-specific reductions in adult gray matter volume. Affected regions include the portions of the prefrontal cortex and ACC responsible for executive functions, mood regulation, and decision-making. These neuroanatomical findings were more pronounced for males, suggesting that lead-related atrophic changes have a disparate impact across sexes. This analysis suggests that adverse cognitive and behavioral outcomes may be related to lead's effect on brain development producing persistent alterations in structure. Using a simple model, we found that blood lead concentration mediates brain volume and fine motor function.

Using magnetic resonance imaging to assess brain volumes, Kim Cecil and colleagues find that inner-city children with higher blood lead levels showed regions of decreased gray matter as adults.

Editors' Summary

Background.

Lead is a highly toxic metal that is present throughout the environment because of various human activities. In particular, for many years, large amounts of lead were used in paint, in solder for water pipes, in gasoline, and in ceramic glazes. But, as the harmful health effects of lead have become clear, its use in these and other products has been gradually phased out. Breathing air, drinking water, or eating food that contains lead can damage almost every organ in the human body. The organ that is most sensitive to lead exposure is the brain, and children's brains are particularly vulnerable because they are still developing. Children who swallow large amounts of lead can develop widespread brain damage that causes convulsions and sometimes death. Children who are repeatedly exposed to low to moderate amounts of lead (e.g., through accidentally swallowing residues of old lead paint or contaminated soil) can develop learning or behavioral problems.

Why Was This Study Done?

Lead exposure has been linked with various types of brain damage. These include problems with thinking (cognition); difficulties with organizing actions, decisions, and behaviors (executive functions); abnormal social behavior (including aggression); and difficulties in coordinating fine movements, such as picking up small objects (fine motor control). However, we know little about how lead damages the brain in this way and little about which brain regions are affected by exposure to low to moderate levels of lead during childhood. In this study, the researchers wanted to test the possibility that childhood lead exposure might lead to shrinking (“volume loss”) parts of the brain, particularly the parts that are crucial to cognition and behavior. They therefore studied the relationship between childhood lead exposure and adult brain volume. They also explored whether there is a relationship between brain volume and measures of brain functioning, such as fine motor control, memory, and learning assessed during adolescence.

What Did the Researchers Do and Find?

Between 1979 and 1984, the researchers recruited babies born in poor areas of Cincinnati, where there were many old, lead-contaminated houses, into the Cincinnati Lead Study. They measured their blood lead levels regularly from birth until they were 78 months old and calculated each child's average blood lead level over this period. They then used brain scans (known as magnetic resonance imaging, or MRI) to measure the brain volumes of the participants when they were 19–24 years old. The researchers found that exposure to lead as a child was linked with brain volume loss in adulthood, particularly in men. There was a “dose-response” effect—in other words, the greatest brain volume loss was seen in participants with the greatest lead exposure in childhood. The brain volume loss was most noticeable in a part of the brain called the prefrontal cortex—especially a region called the “anterior cingulate cortex.” When they examined the relationship between brain volume and measures of brain functioning, they found a link between brain volume and fine motor control, but not with the other measures.

What Do These Findings Mean?

These findings indicate that childhood lead exposure is associated with brain volume loss in adults, in specific regions of the brain. These brain regions are responsible for executive functions, regulating behavior, and fine motor control. Lead exposure has a larger effect on brain volumes in men than in women, which might help to explain the higher incidence of antisocial behaviors among men than women. Overall, these findings may explain why children and adults who have a history of lead exposure have behavioral and other problems, and support ongoing efforts to reduce childhood lead exposure in the US and other countries.

Additional Information.

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050112.

A PLoS Medicine Perspective article by David Bellinger further discusses this study and a related paper on child exposure to lead and criminal arrests in adulthood

Toxtown, an interactive site from the US National Library of Medicine, provides information on environmental health concerns including exposure to lead (in English and Spanish)

The US Environmental Protection Agency provides information on lead in paint, dust, and soil and on protecting children from lead poisoning (in English and Spanish)

Medline Plus and the US National Library of Medicine Specialized Information Services provide lists of links to information on lead and human health (in English and Spanish)

The US Centers for Disease Control and Prevention provides information about its Childhood Lead Poisoning Prevention Program

The UK Health Protection Agency also provides information about lead and its health hazards

Objective

Language skills continue to develop rapidly in children during the school-age years and the “snapshot” view of the neural substrates of language provided by current neuroimaging studies cannot capture the dynamic changes associated with brain development. The aim of this study was to conduct a five-year longitudinal investigation of language development using fMRI in healthy children.

Methods

Thirty subjects enrolled at ages 5, 6, or 7 were examined annually for 5 years using a 3T MRI scanner and a verb generation task. Data analysis was conducted based on a general linear model that was modified to investigate developmental changes while minimizing the potential for missing data.

Results

With increasing age, there is progressive participation in language processing by the inferior/middle frontal, middle temporal, and angular gyri of the left hemisphere and the lingual and inferior temporal gyri of the right hemisphere and regression of participation of the left posterior insula/extrastriate cortex, left superior frontal and right anterior cingulate gyri, and left thalamus.

Conclusion

The age-related changes observed in this study provide evidence of increased neuroplasticity of language in this age group and may have implications for further investigations of normal and aberrant language development.