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1.  Neural substrate differences in language networks and associated language-related behavioral impairments in children with TBI: A preliminary fMRI investigation 
NeuroRehabilitation  2007;22(5):355-369.
The present study examined whether functional MRI (fMRI) can identify changes in the neural substrates of language in young children following traumatic brain injury (TBI).
Eight children with TBI (F/M = 3/5, age (Mean ± SD) = 7.98 ± 1 years, range = 6–9 years) and a comparison group of nine children with orthopedic injuries (OI) (F/M = 4/5, age (Mean ± SD) = 7.4 ± 1 years, range = 6–9 years) participated in an fMRI study of covert verb generation (VG). Results revealed significantly different BOLD signal activation in perisylvian language areas between the groups, after accounting for potential confounders such as verbal fluency and executive function. We also found significant associations between the BOLD signal activation and performance on language-specific neuropsychological tests (NEPSY verbal fluency score, Verbal IQ) and Glasgow Coma Scale (GCS) score.
This study suggests that children with TBI have significantly different brain activation patterns in language circuitry compared to children with orthopedic injuries. Although we found clear differences in brain activation between the two groups, conventional MR images showed no evidence of structural abnormalities in five of eight children with TBI. Our study demonstrates the feasibility and potential utility of fMRI as a means of quantifying changes associated with language deficits in future pediatric TBI studies.
PMCID: PMC4280792  PMID: 18162699
2.  A Functional MRI Study of Language Function in International Adoptees 
The Journal of pediatrics  2013;163(5):10.1016/j.jpeds.2013.06.026.
To test the hypothesis that international adoption of Chinese and Eastern European girls after 9 months of age results in long term changes in the neural circuitry supporting monolingual English in later childhood.
Study design
Functional MRI (fMRI) was used to test this hypothesis by comparison with a control group of American-born English speakers (n=13). Girls now age 6–10 years adopted from China (n = 13) and Eastern Europe (n = 12) by English-speaking families were recruited through a pediatric hospital-based international adoption center after spending more than 6 months in an orphanage or other institution, a measure of early environmental deprivation. FMRI scans were performed on a 3 Tesla MRI scanner using a verb generation language fluency task. Composite activation maps were computed for each group using a general linear model with random effects analysis.
Chinese born adoptees demonstrate atypical lateralization of language function with an apparent shift of Temporal-Parietal and Frontal areas of brain activity toward the right hemisphere. Eastern European adoptees exhibited a rightward shift relative to controls in both Frontal and Temporal-Parietal brain regions.
Significant differences in lateralization between the Chinese and American-born groups in Temporal-Parietal language areas highlight the possible impact of early tonal Asian language exposure on neural circuitry. Findings suggest that exposure to an Asian language during infancy can leave a long-term imprint on the neural circuitry supporting English language development.
PMCID: PMC3812411  PMID: 23896183
international adoption; functional MRI; neural circuitry; language; lateralization indices; Chinese; Eastern European
3.  Diffusion tensor Imaging Properties and Neurobehavioral Outcomes in Children with Hydrocephalus 
Background and Purpose
White matter structural alterations and the correlation with neuropsychological deficits in children with hydrocephalus have not been well investigated. In this prospective study, the objectives were to: (1) apply DTI to detect in vivo white matter alterations based on diffusion properties in children with acute hydrocephalus; (2) quantify early neuropsychological deficits; and (3) explore the correlation between potential neuropsychological deficits and abnormalities in functionally related white matter.
A total of 44 children, 24 with hydrocephalus and 20 controls, were enrolled in the study. DTI indices, FA, MD, AD, RD were evaluated in the gCC, sCC, PLIC, and ALIC. The ABAS-II was used as a broad screener of development, including conceptual, social, practical and motor skills. The correlation between the Motor scale and DTI indices in the PLIC was analyzed.
DTI analyses showed that the gCC and sCC in children with hydrocephalus had lower FA and higher MD driven by the increased RD with statistical significance (p<0.05) or trend level significance (p=0.06). The PLIC and ALIC had significantly higher AD in children with hydrocephalus (p<0.05). On the ABAS-II, parent ratings of general adaptive skills, conceptual skills and motor skills were significantly lower in children with hydrocephalus (all at p level <0.05). The MD and RD value in the PLIC were found to have trend level or significant correlation with the Motor scale (p=0.057, 0.041, respectively).
DTI reveals alterations in white matter structure in children with hydrocephalus with preliminary findings suggesting correlation with clinical motor deficits.
PMCID: PMC4168017  PMID: 22899790
4.  White matter microstructural abnormality in children with hydrocephalus detected by probabilistic diffusion tractography 
Background and Purpose
Hydrocephalus is a severe pathologic condition in which WM damage is a major factor associated with poor outcomes. The goal of the study was to investigate tract-based WM connectivity and DTI measurements in children with hydrocephalus using PDT method.
Twelve children with hydrocephalus and 16 age matched controls were included in the study. PDT was conducted to generate tract-based connectivity distribution and DTI measures for the gCC and mCST. Tract-based summary measurements, included connectivity index and DTI measures (FA, MD, AD, and RDs) were calculated and compared between the two study groups.
Tract-based summary measurement showed that there was a higher percentage of voxels with lower normalized CI values in the WM tracts from children with hydrocephalus. In gCC, left mCST and right mCST, the normalized CI value in children with hydrocephalus was found to be significantly lower (p<0.05, corrected). The tract based DTI measures showed that the children with hydrocephalus had significantly higher MD, AD, and RD in gCC, left mCST, and right mCST, and lower FA in gCC (p<0.05, corrected).
The analysis of WM connectivity showed that PDT method is a sensitive tool to detect the decreased continuity in WM tracts that are under the direct influence of mechanical distortion and increased intracranial pressure in hydrocephalus. This voxel-based connectivity method can provide quantitative information complementary to the standard DTI summary measures.
PMCID: PMC4168018  PMID: 24072621
Tractography; Hydrocephalus; Connectivity Index; Fractional Anisotropy
5.  Antibody persistence in mothers one year after pneumococcal immunization in pregnancy 
Vaccine  2012;30(34):5063-5066.
Pneumococcal infections are a significant cause of morbidity and mortality, and young infants are particularly vulnerable to infection. Maternal immunization can protect infants, but there are limited data on the duration of pneumococcal vaccine antibody in pregnant women. We report on maternal antibody concentrations one year after immunization with 23-valent pneumococcal polysaccharide (23vPPS) vaccine.
The Mother's Gift study randomly assigned 340 pregnant Bangladeshi mothers between ages 18 and 36 to receive either inactivated influenza vaccine (Fluarix®) or the 23vPPS vaccine (Pneumovax®) during the third trimester. Sera were collected before immunization, at delivery, and at one year post-delivery. We determined anti-capsular IgG antibody to 9 pneumococcal serotypes by a multiplex Luminex ELISA. We report antibody geometric mean concentrations (GMCs) for 9 serotypes, 12 month/delivery geometric mean ratios (GMRs) and proportions seroprotected (>0.35 mcg/mL) in 23vPPS vaccine recipients and controls at delivery and at 12 months.
Among pneumococcal vaccinees, GMCs remained stable, with an overall 12 month/delivery GMR of 0.83 (95% CI, 0.75–0.92). In the control group, GMCs increased with a mean ratio of 1.98 (95% CI, 1.81–2.17; P < 0.0001). GMCs in these vaccinees did not decline significantly in the 12 months after antenatal immunization.
GMCs in these adult vaccinees and controls did not decline significantly in the 12 months after antenatal immunization. Interestingly, mothers who did not receive 23vPPS in pregnancy show a substantial increase of GMC for most serotypes in the first year after immunization. Further studies are needed to determine the need for repeat doses of 23vPPS vaccine in subsequent pregnancies more than a year later.
PMCID: PMC4133759  PMID: 22709949
Pneumococcal vaccine; Maternal immunization; Antibody titers
6.  Treatment of depressed mothers in home visiting: Impact on psychological distress and social functioning☆ 
Child abuse & neglect  2013;37(8):544-554.
Depression is prevalent in mothers receiving home visiting. Little is known about the impact of treatment on associated features of maternal depression in this population. The purpose of this study was to examine the impact of a novel, adapted treatment for depressed mothers in home visiting on psychological distress and social functioning.
In-Home Cognitive Behavioral Therapy (IH-CBT) was developed to treat depressed mothers in home visiting. A randomized clinical trial design was used in which subjects were 93 new mothers in a home visiting program. Mothers with major depressive disorder identified at 3 months postpartum were randomized into IH-CBT and ongoing home visiting (n = 47) or standard home visiting (SHV; n = 46) in which they received home visitation alone and could obtain treatment in the community. Measures of psychological distress, social support, and social network were measured at pre-treatment, post-treatment, and three-month follow-up. Clinical features of depression and home visiting parameters were examined as potential moderators.
Subjects receiving IH-CBT reported decreased psychological distress at post-treatment (ES = 0.77) and follow-up (ES = 0.73). Examination of types of psychological distress indicated broad improvements at both time points. Those receiving IH-CBT reported increased social support over time relative to those in the SHV condition. Effect sizes were modest at post-treatment (ES = 0.38) but increased at follow-up (ES = 0.65). Improvements were seen in affiliative and belonginess aspects of social support, in contrast to tangible support which was statistically non-significant. Findings were not moderated by clinical features of depression or home visiting parameters. No group differences were found in size of and involvement with social networks.
IH-CBT is effective in reducing psychological distress and improving perceived social support in depressed mothers receiving home visiting. To the extent that mothers are better adjusted and feel socially supported, they are more available to their children and more amenable to home visiting services. IH-CBT is a feasible, readily adopted treatment that is compatible with multiple home visiting models. As a result it is a promising approach to help depressed mothers in home visiting. Additional interventions may be needed to support depressed mothers in building sizable and stable social networks.
PMCID: PMC3742640  PMID: 23623623
Home visiting; Maternal depression; Cognitive behavioral therapy; Psychological distress; Social functioning
7.  Data on the safety of repeated MRI in healthy children 
NeuroImage : Clinical  2014;4:526-530.
To address the question of the safety of MRI for research in normal, healthy children. We examined MRI, neurocognitive and biometric data collected in a group of healthy, normally developing children who have participated in a 10 year longitudinal fMRI study.
Materials and methods
Thirty-one healthy children ranging in age from 5 to 7 years were enrolled between 2000 and 2002 and were tested yearly as part of a longitudinal study of normal language development. Twenty-eight of these children have completed multiple neuroimaging, neurocognitive and biometric exams. These children ranged in age from 5 to 18 years during the course of the study and were exposed to up to 10 annual MRI scans. Linear regression of the IQ (WISC-III) (Wechsler, 1991), executive function (BRIEF) (Gioia et al., 2002), and language (OWLS) (Carrow-Woolfolk, 1995) measures was performed against the number of years of exposure to MRI in the study. Body mass index (BMI) (Ogden et al., 2006) was also examined as a function of years and compared with normative values.
The WISC-III Full Scale (FSIQ) in our longitudinal cohort was higher than the average at baseline. There was no significant change over time in mean FSIQ p = 0.80, OWLS p = 0.16, or BRIEF p = 0.67. Similarly, over 10 years there were no significant changes in the Coding subtest of WISC III and height and body mass index did not deviate from norms (50th percentile).
Examination of neurocognitive and biometric data from a decade-long, longitudinal fMRI study of normal language development in this small, longitudinal sample of healthy children in the age range of 5 to 18 years, who received up to 10 MRI scans, provides scientific evidence to support the belief that MRI poses minimal risk for use in research with healthy children.
•We examined the safety of MRI for research in normal, healthy children.•We looked the change overtime of neurocognitive data in a longitudinal fMRI study.•There was no significant change over time in measured neurocognitive tests.•Body mass index of these children did not deviate from norms.•MRI poses minimal risk for use in research with healthy children.
PMCID: PMC4052465  PMID: 24936408
MRI; Safety healthy children repeated; IQ; BMI; OWLS; BRIEF; Longitudinal
8.  Follistatin-like Protein 1 and the Ferritin/Erythrocyte Sedimentation Rate Ratio Are Potential Biomarkers for Dysregulated Gene Expression and Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis 
The Journal of rheumatology  2013;40(7):10.3899/jrheum.121131.
Follistatin-like protein 1 (FSTL-1) is a secreted glycoprotein overexpressed in certain inflammatory diseases. Our objective was to correlate FSTL-1 levels with gene expression, known biomarkers, and measures of disease activity in systemic juvenile idiopathic arthritis (sJIA), including macrophage activation syndrome (MAS).
FSTL-1 serum levels were measured by ELISA in 28 patients with sJIA, including 7 patients who developed MAS, and 30 healthy controls. Levels were correlated with erythrocyte sedimentation rate (ESR), ferritin, and soluble interleukin-2 receptor-α (sIL-2Rα). Gene expression based on FSTL-1 levels was analyzed in peripheral blood mononuclear cells (PBMC).
Serum levels of FSTL-1 were elevated at time of presentation of sJIA (mean 200.7 ng/ml) and decreased to normal (mean 133.7 ng/ml) over 24 months (p < 0.01). FSTL-1 levels were markedly elevated during acute MAS (mean 279.8 ng/ml) and decreased to normal following treatment (p < 0.001). FSTL-1 levels correlated with serum markers of inflammation, including sIL-2Rα and ferritin. Ferritin/ESR ratio was superior to ferritin, sIL-2Rα, and FSTL-1 in discriminating MAS from new-onset sJIA. PBMC from patients with FSTL-1 levels > 200 ng/ml showed altered expression of genes related to innate immunity, erythropoiesis, and natural killer cell dysfunction. Two patients with the highest FSTL-1 levels at disease onset (> 300 ng/ml) ultimately developed MAS.
Elevated pretreatment serum FSTL-1 levels in sJIA are associated with dysregulated gene expression suggestive of occult MAS, and may have utility in predicting progression to overt MAS. Ferritin/ESR ratio may be superior to ferritin alone in discriminating overt MAS from new-onset sJIA. (First Release May 15 2013; J Rheumatol 2013;40:1191–9; doi:10.3899/jrheum.121131)
PMCID: PMC3885333  PMID: 23678162
9.  A 10-year longitudinal fMRI study of narrative comprehension in children and adolescents 
NeuroImage  2012;63(3):1188-1195.
Comprehension of spoken narratives requires coordination of multiple language skills. As such, for normal children narrative skills develop well into the school years and, during this period, are particularly vulnerable in the face of brain injury or developmental disorder. For these reasons, we sought to determine the developmental trajectory of narrative processing using longitudinal fMRI scanning. 30 healthy children between the ages of 5 and 18 enrolled at ages 5, 6, or 7, were examined annually for up to 10 years. At each fMRI session, children were presented with a set of five, 30s–long, stories containing 9, 10, or 11 sentences designed to be understood by a 5 year old child. FMRI data analysis was conducted based on a hierarchical linear model (HLM) that was modified to investigate developmental changes while accounting for missing data and controlling for factors such as age, linguistic performance and IQ. Performance testing conducted after each scan indicated well above the chance (p < 0.002) comprehension performance. There was a linear increase with increasing age in bilateral superior temporal cortical activation (BA 21 and 22) linked to narrative processing. Conversely, age-related decreases in cortical activation were observed in bilateral occipital regions, cingulate and cuneus, possibly reflecting changes in the default mode networks. The dynamic changes observed in this longitudinal fMRI study support the increasing role of bilateral BAs 21 and 22 in narrative comprehension, involving non-domain-specific integration in order to achieve final story interpretation. The presence of a continued linear development of this area throughout childhood and teenage years with no apparent plateau, indicates that full maturation of narrative processing skills has not yet occurred and that it may be delayed to early adulthood.
PMCID: PMC3476849  PMID: 22951258
longitudinal language development; narrative comprehension; language; fMRI; child; brain; development; functional MRI
10.  Sex differences in white matter development during adolescence: A DTI study 
Brain research  2012;1478:1-15.
Adolescence is a complex transitional period in human development, composing physical maturation, cognitive and social behavioral changes. The objective of this study is to investigate sex differences in white matter development and the associations between intelligence and white matter microstructure in the adolescent brain using diffusion tensor imaging (DTI) and tract-based spatial statistics (TBSS). In a cohort of 16 typically-developing adolescents aged 13 to 17 years, longitudinal DTI data were recorded from each subject at two time points that were one year apart. We used TBSS to analyze the diffusion indices including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). Our results suggest that boys (13–18 years) continued to demonstrate white matter maturation, whereas girls appeared to reach mature levels earlier. In addition, we identified significant positive correlations between FA and full-scale intelligence quotient (IQ) in the right inferior fronto-occipital fasciculus when both sexes were looked at together. Only girls showed significant positive correlations between FA and verbal IQ in the left cortico-spinal tract and superior longitudinal fasciculus. The preliminary evidence presented in this study supports that boys and girls have different developmental trajectories in white matter microstructure.
PMCID: PMC3592389  PMID: 22954903
Adolescence; Diffusion tensor imaging; Sex differences; Tract based spatial statistics; White matter development
11.  Impact of low-level gestational exposure to organophosphate pesticides on neurobehavior in early infancy: a prospective study 
Environmental Health  2013;12:79.
National data suggest widespread gestational exposure to organophosphate pesticides (OPs) based on the detection of OP metabolites in the urine of pregnant women. Associations with early infant neurobehavior are largely understudied, with only two studies reporting abnormal reflexes in newborns in association with gestational exposure to OPs. Our objective was to utilize biological markers of OP metabolites in pregnant women and a comprehensive assessment of infant neurobehavior to determine the association of gestational exposure to OPs with neurobehavioral outcomes during early infancy.
Among a cohort of 350 mother/infant pairs, we measured six common dialkylphosphate metabolites of OP pesticides in maternal urine, at two times during pregnancy (16 w & 26 w gestation), then calculated aggregate concentrations of diethylphosphate, dimethylphosphate, and total dialkyphosphate metabolites. We measured infant neurobehavior at about five weeks of age using the NICU Network Neurobehavioral Scale (NNNS), a comprehensive assessment of neurobehavior in young infants. Analyses of associations between gestational exposure to OPs and neurobehavior at five weeks included multiple linear and logistic regression.
After adjustment for covariates, higher creatinine-corrected urinary concentrations of diethylphosphate metabolites were associated with improved attention and reduced lethargy and hypotonia in young infants. Higher creatinine-corrected urinary concentrations of total dialkylphosphate metabolites were associated with fewer signs of autonomic stress. Women who were white, married, had advanced education, and reported more frequent consumption of fresh fruits and vegetables had higher concentrations of OP metabolites during pregnancy.
In this sample of pregnant women whose urinary concentrations of dialkylphosphate metabolites are representative of national exposure levels, we found no detrimental effects of gestational exposure to OPs on neurobehavioral outcomes among young infants. These results are important as they suggest there may be minimal to no detectable adverse impact of low level prenatal OP exposure on the neurobehavior of young infants.
PMCID: PMC3848803  PMID: 24034442
NNNS; Organophosphates; Pesticides; Neurobehavior; Infancy; Prenatal exposure
12.  A Clinical Trial of In-Home CBT for Depressed Mothers in Home Visitation 
Behavior therapy  2013;44(3):359-372.
Despite negative outcomes for depressed mothers and their children, no treatment specifically designed to address maternal depression in the context of home visitation has emerged. In-Home Cognitive Behavioral Therapy (IH-CBT) is an adapted treatment that is delivered in the home, focuses on the needs of new mothers, and leverages ongoing home visiting to optimize engagement and outcomes. This study examined the efficacy of IH-CBT using a randomized clinical trial. Subjects were 93 new mothers in a home visiting program. Mothers with major depressive disorder identified at 3 months postpartum were randomized into IH-CBT and ongoing home visitation (n=47) or standard home visitation (SHV; n=46) in which they received home visitation alone and could obtain treatment in the community. Depression was measured at pre- and posttreatment, and 3-month follow-up using interviews, clinician ratings, and self-report. Mothers receiving IH-CBT showed improvements in all indicators of depression relative to the SHV condition and these gains were maintained at follow-up. For example, 70.7% of mothers receiving IH-CBT were no longer depressed at posttreatment in terms of meeting criteria for major depressive disorder compared to 30.2% in the SHV group. These findings suggest that IH-CBT is an efficacious treatment for depressed mothers in home visitation programs.
PMCID: PMC3693767  PMID: 23768664
home visitation; maternal depression; cognitive behavioral therapy; adapted treatment
13.  Early microbial and metabolomic signatures predict later onset of necrotizing enterocolitis in preterm infants 
Microbiome  2013;1:13.
Necrotizing enterocolitis (NEC) is a devastating intestinal disease that afflicts 10% of extremely preterm infants. The contribution of early intestinal colonization to NEC onset is not understood, and predictive biomarkers to guide prevention are lacking. We analyzed banked stool and urine samples collected prior to disease onset from infants <29 weeks gestational age, including 11 infants who developed NEC and 21 matched controls who survived free of NEC. Stool bacterial communities were profiled by 16S rRNA gene sequencing. Urinary metabolomic profiles were assessed by NMR.
During postnatal days 4 to 9, samples from infants who later developed NEC tended towards lower alpha diversity (Chao1 index, P = 0.086) and lacked Propionibacterium (P = 0.009) compared to controls. Furthermore, NEC was preceded by distinct forms of dysbiosis. During days 4 to 9, samples from four NEC cases were dominated by members of the Firmicutes (median relative abundance >99% versus <17% in the remaining NEC and controls, P < 0.001). During postnatal days 10 to 16, samples from the remaining NEC cases were dominated by Proteobacteria, specifically Enterobacteriaceae (median relative abundance >99% versus 38% in the other NEC cases and 84% in controls, P = 0.01). NEC preceded by Firmicutes dysbiosis occurred earlier (onset, days 7 to 21) than NEC preceded by Proteobacteria dysbiosis (onset, days 19 to 39). All NEC cases lacked Propionibacterium and were preceded by either Firmicutes (≥98% relative abundance, days 4 to 9) or Proteobacteria (≥90% relative abundance, days 10 to 16) dysbiosis, while only 25% of controls had this phenotype (predictive value 88%, P = 0.001). Analysis of days 4 to 9 urine samples found no metabolites associated with all NEC cases, but alanine was positively associated with NEC cases that were preceded by Firmicutes dysbiosis (P < 0.001) and histidine was inversely associated with NEC cases preceded by Proteobacteria dysbiosis (P = 0.013). A high urinary alanine:histidine ratio was associated with microbial characteristics (P < 0.001) and provided good prediction of overall NEC (predictive value 78%, P = 0.007).
Early dysbiosis is strongly involved in the pathobiology of NEC. These striking findings require validation in larger studies but indicate that early microbial and metabolomic signatures may provide highly predictive biomarkers of NEC.
PMCID: PMC3971624  PMID: 24450576
Microbiome; Premature infants; Necrotizing enterocolitis; Dysbiosis
14.  Materials Organization, Planning, and Homework Completion in Middle School Students with ADHD: Impact on Academic Performance 
School mental health  2011;3(2):93-101.
This study evaluated the homework functioning of middle school students with ADHD to determine what aspects are most predictive of school grades and the best source (e.g., parents or teachers) for obtaining this information. Students with ADHD in grades 5–8 (N = 57) and their parents and teachers completed the Children’s Organization Skills Scales (COSS) to measure materials organization, planning, and time-management, and parents completed the Homework Problems Checklist (HPC) to examine homework completion and homework materials management behaviors. Regression analyses revealed that parent-rated homework materials management and teacher-rated memory and materials management were the best predictors of school grades. These findings suggest that organization of materials is a critical component of the homework completion process for students with ADHD and an important target for intervention. Teachers were the best source of information regarding materials organization and planning, whereas parents were a valuable source of information for specific homework materials management problems.
PMCID: PMC3619433  PMID: 23577045
ADHD; Adolescents; Organization; Time-Management; Homework
15.  Left-Handedness and Language Lateralization in Children 
Brain research  2011;1433C:85-97.
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.
PMCID: PMC3249496  PMID: 22177775
Language lateralization; language development; handedness; fMRI
16.  Pediatric Sports-Related Concussion Produces Cerebral Blood Flow Alterations 
Pediatrics  2012;129(1):28-37.
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.
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.
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.
PMCID: PMC3255471  PMID: 22129537
concussion; pediatrics; MRI; cerebral blood flow; magnetic resonance spectroscopy
17.  Evidence for higher reaction time variability for children with ADHD on a range of cognitive tasks including reward and event rate manipulations 
Neuropsychology  2011;25(4):427-441.
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.
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.
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.
High RT variability is a ubiquitous and robust phenomenon in children with ADHD.
PMCID: PMC3522094  PMID: 21463041
attention deficit hyperactivity disorder; intra-individual variability; reward; event rate; subtypes
18.  Use of an Internet Portal to Improve Community-Based Pediatric ADHD Care: A Cluster Randomized Trial 
Pediatrics  2011;128(5):e1201-e1208.
To determine the effectiveness of a quality improvement program to improve pediatricians' adherence to existing, evidence-based, attention-deficit/hyperactivity disorder (ADHD) practice guidelines.
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.
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).
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.
PMCID: PMC3208964  PMID: 22007005
attention-deficit/hyperactivity disorder; pediatricians; American Academy of Pediatrics guidelines; quality improvement
19.  Prenatal Exposure to Bisphenol A and Phthalates and Infant Neurobehavior 
Neurotoxicology and teratology  2011;33(5):558-566.
To examine the association of prenatal exposure to bisphenol A and select common phthalates with infant neurobehavior measured at 5 weeks.
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.
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).
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.
PMCID: PMC3183357  PMID: 21854843
Bisphenol A; Infant neurobehavior; Phthalates; Prenatal exposure
21.  Morphometric Differences in the Heschl's Gyrus of Hearing Impaired and Normal Hearing Infants 
Cerebral Cortex (New York, NY)  2010;21(5):991-998.
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.
PMCID: PMC3114550  PMID: 20841321
auditory cortex; brain imaging; deaf; neurodevelopment; pediatric
22.  Effects of Stimulant Medication, Incentives, and Event Rate on Reaction Time Variability in Children With ADHD 
Neuropsychopharmacology  2011;36(5):1060-1072.
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.
PMCID: PMC3059336  PMID: 21248722
ADHD; reaction time; stimulants; variability; incentive; event rate; psychostimulants; biological psychiatry; cognition; psychiatry & behavioral sciences; adhd; incentive; event rate; reaction time
23.  Patterns and Predictors of Adolescent Academic Achievement and Performance in a Sample of Children with Attention-Deficit/Hyperactivity Disorder (ADHD) 
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.
PMCID: PMC3132152  PMID: 21722025
ADHD; Academic; Predictors; Adolescence; Grades; Achievement
24.  Effects of stimulant medication, incentives, and event rate on reaction time variability in children with ADHD 
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.
PMCID: PMC3059336  PMID: 21248722
ADHD; reaction time; stimulants; variability; incentive; event rate
25.  The Transition to Middle School is Associated with Changes in the Developmental Trajectory of ADHD Symptomatology in Young Adolescents with ADHD 
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.
PMCID: PMC3096937  PMID: 18645755
ADHD; Middle School; Transition; Adolescents; MTA

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