Top Ten Articles for 2008/2009

10. Gibson CS, Maclennan AH, Dekker GA, Goldwater PN, Sullivan TR, Munroe DJ, Tsang S, Stewart C, Nelson KB. Candidate genes and cerebral palsy: a population-based study. Pediatrics. 2008 Nov;122(5):1079-85.

OBJECTIVE: The objective of this study was to examine whether selected genetic polymorphisms in the infant are associated with later-diagnosed cerebral palsy. METHODS: A population-based case-control study was conducted of 28 single-nucleotide polymorphisms measured in newborn screening blood spots. A total of 413 children with later-diagnosed cerebral palsy were born to white women in South Australia in 1986-1999, and there were 856 control children. Distributions of genotypic frequencies were examined in total cerebral palsy, in gestational age groups, and by types of cerebral palsy and gender. Genotyping was performed by using a TaqMan assay. RESULTS: For inducible nitric-oxide synthase, possession of the T allele was more common in all children with cerebral palsy and for heterozygotes who were born at term. For lymphotoxin alpha, homozygous variant status was associated with risk for cerebral palsy and with spastic hemiplegic or quadriplegic cerebral palsy. Among term infants, heterozygosity for the endothelial protein C receptor single-nucleotide polymorphism was more frequent in children with cerebral palsy. In preterm infants, the variant A allele of interleukin 8 and heterozygosity for the beta-2 adrenergic receptor were associated with cerebral palsy risk. Interleukin 8 heterozygote status was associated with spastic diplegia. Variants of several genes were associated with cerebral palsy in girls but not in boys. CONCLUSIONS: Two of the 28 single-nucleotide polymorphisms examined were associated with all types of spastic cerebral palsy in both gestational age groups and others with cerebral palsy in gestational age or cerebral palsy subgroups. Some of these associations support previous findings. There may be a genetic contribution to cerebral palsy risk, and additional investigation is warranted of genes and gene-environment interactions in cerebral palsy.

9. Zimmerman FJ, Gilkerson J, Richards JA, Christakis DA, Xu D, Gray S, Yapanel U. Teaching by listening: the importance of adult-child conversations to language development. Pediatrics. 2009 Jul;124(1):342-9.

OBJECTIVE: To test the independent association of adult language input, television viewing, and adult-child conversations on language acquisition among infants and toddlers. METHODS: Two hundred seventy-five families of children aged 2 to 48 months who were representative of the US census were enrolled in a cross-sectional study of the home language environment and child language development (phase 1). Of these, a representative sample of 71 families continued for a longitudinal assessment over 18 months (phase 2). In the cross-sectional sample, language development scores were regressed on adult word count, television viewing, and adult-child conversations, controlling for socioeconomic attributes. In the longitudinal sample, phase 2 language development scores were regressed on phase 1 language development, as well as phase 1 adult word count, television viewing, and adult-child conversations, controlling for socioeconomic attributes. RESULTS: In fully adjusted regressions, the effects of adult word count were significant when included alone but were partially mediated by adult-child conversations. Television viewing when included alone was significant and negative but was fully mediated by the inclusion of adult-child conversations. Adult-child conversations were significant when included alone and retained both significance and magnitude when adult word count and television exposure were included. CONCLUSIONS: Television exposure is not independently associated with child language development when adult-child conversations are controlled. Adult-child conversations are robustly associated with healthy language development. Parents should be encouraged not merely to provide language input to their children through reading or storytelling, but also to engage their children in two-sided conversations.

8a. Scheffler RM, Brown TT, Fulton BD, Hinshaw SP, Levine P, Stone S. Positive association between attention-deficit/ hyperactivity disorder medication use and academic achievement during elementary school. Pediatrics. 2009 May;123(5):1273-9.

OBJECTIVE: Approximately 4.4 million (7.8%) children in the United States have been diagnosed with attention-deficit/hyperactivity disorder, and 56% of affected children take prescription medications to treat the disorder. Attention-deficit/hyperactivity disorder is strongly linked with low academic achievement, but the association between medication use and academic achievement in school settings is largely unknown. Our objective was to determine if reported medication use for attention-deficit/hyperactivity disorder is positively associated with academic achievement during elementary school. METHOD: To estimate the association between reported medication use and standardized mathematics and reading achievement scores for a US sample of 594 children with attention-deficit/hyperactivity disorder, we used 5 survey waves between kindergarten and fifth grade from the nationally representative Early Childhood Longitudinal Study--Kindergarten Class of 1998-1999 to estimate a first-differenced regression model, which controlled for time-invariant confounding variables. RESULTS: Medicated children had a mean mathematics score that was 2.9 points higher than the mean score of unmedicated peers with attention-deficit/hyperactivity disorder. Children who were medicated for a longer duration (at >2 waves) had a mean reading score that was 5.4 points higher than the mean score of unmedicated peers with attention-deficit/hyperactivity disorder. The medication-reading association was lower for children who had an individualized education program than for those without such educational accommodation. CONCLUSIONS: The finding of a positive association between medication use and standardized mathematics and reading test scores is important, given the high prevalence of attention-deficit/hyperactivity disorder and its association with low academic achievement. The 2.9-point mathematics and 5.4-point reading score differences are comparable with score gains of 0.19 and 0.29 school years, respectively, but these gains are insufficient to eliminate the test-score gap between children with attention-deficit/hyperactivity disorder and those without the disorder. Long-term trials are needed to better understand the relationship between medication use and academic achievement.

8b. Winterstein AG, Gerhard T, Shuster J, Saidi A. Cardiac safety of methylphenidate versus amphetamine salts in the treatment of ADHD. Pediatrics. 2009 Jul;124(1):e75-80.

OBJECTIVES: Safety concerns about central nervous system stimulants for the treatment of attention-deficit/hyperactivity disorder (ADHD) include adverse cardiac effects. This study aimed to compare the risk for cardiac events in users of methylphenidate and amphetamine salts. METHODS: A retrospective cohort design using claims data from the Florida Medicaid fee-for-service program representing a total of 2131953 children and adolescents was used. The analysis included all beneficiaries who were between 3 and 20 years of age, enrolled between July 1994 and June 2004, had at least 1 physician diagnosis of ADHD and were newly started on methylphenidate or amphetamine salts. Each month of follow-up was classified according to stimulant use into current use or former use. We defined cardiac events as first emergency department (ED) visit for cardiac disease or symptoms. Risk between current users of methylphenidate versus amphetamine salts and former users of drugs in these categories was compared by using a time-dependent Cox proportional hazard model that adjusted for differences in gender; race; age; year of the index date; disability; congenital anomalies; history of circulatory disease; history of hospital admission; and use of antidepressants, antipsychotics, and bronchodilators. RESULTS: A total of 456 youth visited the ED for cardiac reasons during 52783 years of follow-up. After adjustment for differences in covariates, the risk for cardiac ED visits was similar among current users of methylphenidate or amphetamines. Periods of former use had a similar risk between youth with an exposure history to methylphenidate or amphetamine. CONCLUSION: Exposure to methylphenidate and amphetamines salts showed similar risk for cardiac ED visits. Additional population-based studies that address manifestation of serious heart disease, especially after long-term use, dosage comparisons, and interactions with preexisting cardiac risk factors are needed to inform psychiatric treatment decisions.

7. Sakzewski L ; Ziviani J ; Boyd R Queensland Cerebral Palsy and Rehabilitation Research Centre, School of Medicine, University of Queensland, Victoria 3081, Australia. Systematic review and meta-analysis of therapeutic management of upper-limb dysfunction in children with congenital hemiplegia. Pediatrics. 2009; 123(6):e1111-22

CONTEXT: Rehabilitation for children with congenital hemiplegia to improve function in the impaired upper limb and enhance participation may be time-consuming and costly. OBJECTIVES: To systematically review the efficacy of nonsurgical upper-limb therapeutic interventions for children with congenital hemiplegia. METHODS: The Cochrane Central Register of Controlled Trials, Medline, CINAHL (Cumulative Index to Nursing and Allied Health Literature), AMED (Allied and Complementary Medicine), Embase, PsycINFO, and Web of Science were searched up to July 2008. Data sources were randomized or quasi-randomized trials and systematic reviews. RESULTS: Twelve studies and 7 systematic reviews met our criteria. Trials had strong methodologic quality (Physiotherapy Evidence Database [PEDro] scale > or = 5), and systematic reviews rated strongly (AMSTAR [Assessment of Multiple Systematic Reviews] score > or = 6). Four interventions were identified: intramuscular botulinum toxin A combined with upper-limb training; constraint-induced movement therapy; hand-arm bimanual intensive training; and neurodevelopmental therapy. Data were pooled for upper-limb, self-care, and individualized outcomes. There were small-to-medium treatment effects favoring intramuscular botulinum toxin A and occupational therapy, neurodevelopmental therapy and casting, constraint-induced movement therapy, and hand-arm bimanual intensive training on upper-limb outcomes. There were large treatment effects favoring intramuscular botulinum toxin A and upper-limb training for individualized outcomes. No studies reported participation outcomes. CONCLUSIONS: No one treatment approach seems to be superior; however, injections of botulinum toxin A provide a supplementary benefit to a variety of upper-limb-training approaches. Additional research is needed to justify more-intensive approaches such as constraint-induced movement therapy and hand-arm bimanual intensive training.

6a. Wu RR, Zhao JP, Jin H, Shao P, Fang MS, Guo XF, He YQ, Liu YJ, Chen JD, Li LH. Lifestyle intervention and metformin for treatment of antipsychotic-induced weight gain: a randomized controlled trial. JAMA. 2008 Jan 9;299(2):185-93.

CONTEXT: Weight gain, a common adverse effect of antipsychotic medications, is associated with medical comorbidities in psychiatric patients. OBJECTIVE: To test the efficacy of lifestyle intervention and metformin alone and in combination for antipsychotic-induced weight gain and abnormalities in insulin sensitivity. DESIGN, SETTING, AND PATIENTS: A randomized controlled trial (October 2004-December 2006) involving 128 adult patients with schizophrenia in the Mental Health Institute of the Second Xiangya Hospital, Central South University, China. Participants who gained more than 10% of their predrug weight were assigned to 1 of 4 treatment groups. INTERVENTIONS: Patients continued their antipsychotic medication and were randomly assigned to 12 weeks of placebo, 750 mg/d of metformin alone, 750 mg/d of metformin and lifestyle intervention, or lifestyle intervention only. MAIN OUTCOME MEASURES: Body mass index, waist circumference, insulin levels, and insulin resistance index. RESULTS: All 128 first-episode schizophrenia patients maintained relatively stable psychiatric improvement. The lifestyle-plus-metformin group had mean decreases in body mass index (BMI) of 1.8 (95% confidence interval [CI], 1.3-2.3), insulin resistance index of 3.6 (95% CI, 2.7-4.5), and waist circumference of 2.0 cm (95% CI, 1.5-2.4 cm). The metformin-alone group had mean decreases in BMI of 1.2 (95% CI, 0.9-1.5), insulin resistance index of 3.5 (95% CI, 2.7-4.4), and waist circumference of 1.3 cm (95% CI, 1.1-1.5 cm). The lifestyle-plus-placebo group had mean decreases in BMI of 0.5 (95% CI, 0.3-0.8) and insulin resistance index of 1.0 (95% CI, 0.5-1.5). However, the placebo group had mean increases in BMI of 1.2 (95% CI, 0.9-1.5), insulin resistance index of 0.4 (95% CI, 0.1-0.7), and waist circumference of 2.2 cm (95% CI, 1.7-2.8 cm). The lifestyle-plus-metformin treatment was significantly superior to metformin alone and to lifestyle plus placebo for weight, BMI, and waist circumference reduction. CONCLUSIONS: Lifestyle intervention and metformin alone and in combination demonstrated efficacy for antipsychotic-induced weight gain. Lifestyle intervention plus metformin showed the best effect on weight loss. Metformin alone was more effective in weight loss and improving insulin sensitivity than lifestyle intervention alone.

6b. Klein DJ, Cottingham EM, Sorter M, Barton BA, Morrison JA. A randomized, double-blind, placebo-controlled trial of metformin treatment of weight gain associated with initiation of atypical antipsychotic therapy in children and adolescents. Am J Psychiatry. 2006 Dec;163(12):2072-9.

OBJECTIVE: Second-generation, or atypical, antipsychotics effectively treat psychiatric illness in children and adolescents. However, weight gain and abnormalities in insulin sensitivity, including diabetes, complicate this therapy. METHOD: A 16-week double-blind, placebo-controlled trial was conducted to evaluate the effectiveness of metformin in managing weight gain in 39 subjects, ages 10-17, whose weight had increased by more than 10% during less than 1 year of olanzapine, risperidone, or quetiapine therapy. Body weight, body mass index (kilograms per square meter of height), and waist circumference were measured regularly, as were fasting insulin and glucose levels. RESULTS: Weight was stabilized in subjects receiving metformin, while those receiving placebo continued to gain weight (0.31 kg/week). Because the study was conducted with growing children, metformin treatment resulted in reduction in z scores for both weight and body mass index. The homeostasis model assessment, a surrogate indicator of insulin sensitivity, decreased in treated subjects. Overt diabetes was diagnosed in two subjects before treatment (elevated baseline fasting glucose and insulin values) and in two placebo-treated subjects (one at week 12 and the other after study completion). One subject taking placebo developed impaired fasting glucose. Placebo treatment was associated with the need to perform oral glucose tolerance testing upon study completion, by which three additional subjects were identified with impaired glucose tolerance. No serious adverse events resulted from metformin treatment. CONCLUSIONS: Metformin therapy is safe and effective in abrogating weight gain, decreased insulin sensitivity, and abnormal glucose metabolism resulting from treatment of children and adolescents with atypicals.

5. Hoon AH Jr, Stashinko EE, Nagae LM, Lin DD, Keller J, Bastian A, Campbell ML, Levey E, Mori S, Johnston MV. Sensory and motor deficits in children with cerebral palsy born preterm correlate with diffusion tensor imaging abnormalities in thalamocortical pathways. Dev Med Child Neurol. 2009 Sep;51(9):697-704.

AIM: Cerebral palsy (CP) is frequently linked to white matter injury in children born preterm. Diffusion tensor imaging (DTI) is a powerful technique providing precise identification of white matter microstructure. We investigated the relationship between DTI-observed thalamocortical (posterior thalamic radiation) injury, motor (corticospinal tract) injury, and sensorimotor function. METHOD: Twenty-eight children born preterm (16 males, 12 females; mean age 5y 10mo, SD 2y 6mo, range 16mo-13y; mean gestational age at birth 28wks, SD 2.7wks, range 23-34wks) were included in this case-control study. Twenty-one children had spastic diplegia, four had spastic quadriplegia, two had hemiplegia, and one had ataxic/hypotonic CP; 15 of the participants walked independently. Normative comparison data were obtained from 35 healthy age-matched children born at term (19 males, 16 females; mean age 5y 9mo, SD 4y 4mo, range 15mo-15y). Two-dimensional DTI color maps were created to evaluate 26 central white matter tracts, which were graded by a neuroradiologist masked to clinical status. Quantitative measures of touch, proprioception, strength (dynamometer), and spasticity (modified Ashworth scale) were obtained from a subset of participants. RESULTS: All 28 participants with CP had periventricular white-matter injury on magnetic resonance imaging. Using DTI color maps, there was more severe injury in the posterior thalamic radiation pathways than in the descending corticospinal tracts. Posterior thalamic radiation injury correlated with reduced contralateral touch threshold, proprioception, and motor severity, whereas corticospinal tract injury did not correlate with motor or sensory outcome measures. INTERPRETATION: These findings extend previous research demonstrating that CP in preterm children reflects disruption of thalamocortical connections as well as descending corticospinal pathways.

4. Beall PM, Moody EJ, McIntosh DN, Hepburn SL, Reed CL. Rapid facial reactions to emotional facial expressions in typically developing children and children with autism spectrum disorder. J Exp Child Psychol. 2008 Nov;101(3):206-23.

Typical adults mimic facial expressions within 1000 ms, but adults with autism spectrum disorder (ASD) do not. These rapid facial reactions (RFRs) are associated with the development of social-emotional abilities. Such interpersonal matching may be caused by motor mirroring or emotional responses. Using facial electromyography (EMG), this study evaluated mechanisms underlying RFRs during childhood and examined possible impairment in children with ASD. Experiment 1 found RFRs to happy and angry faces (not fear faces) in 15 typically developing children from 7 to 12 years of age. RFRs of fear (not anger) in response to angry faces indicated an emotional mechanism. In 11 children (8-13 years of age) with ASD, Experiment 2 found undifferentiated RFRs to fear expressions and no consistent RFRs to happy or angry faces. However, as children with ASD aged, matching RFRs to happy faces increased significantly, suggesting the development of processes underlying matching RFRs during this period in ASD.

3. Rossignol DA, Rossignol LW, Smith S, Schneider C, Logerquist S, Usman A, Neubrander J, Madren EM, Hintz G, Grushkin B, Mumper EA. Hyperbaric treatment for children with autism: a multicenter, randomized, double-blind, controlled trial. BMC Pediatr. 2009 Mar 13;9:21.

BACKGROUND: Several uncontrolled studies of hyperbaric treatment in children with autism have reported clinical improvements; however, this treatment has not been evaluated to date with a controlled study. We performed a multicenter, randomized, double-blind, controlled trial to assess the efficacy of hyperbaric treatment in children with autism. METHODS: 62 children with autism recruited from 6 centers, ages 2-7 years (mean 4.92 +/- 1.21), were randomly assigned to 40 hourly treatments of either hyperbaric treatment at 1.3 atmosphere (atm) and 24% oxygen ("treatment group", n = 33) or slightly pressurized room air at 1.03 atm and 21% oxygen ("control group", n = 29). Outcome measures included Clinical Global Impression (CGI) scale, Aberrant Behavior Checklist (ABC), and Autism Treatment Evaluation Checklist (ATEC). RESULTS: After 40 sessions, mean physician CGI scores significantly improved in the treatment group compared to controls in overall functioning (p = 0.0008), receptive language (p < 0.0001), social interaction (p = 0.0473), and eye contact (p = 0.0102); 9/30 children (30%) in the treatment group were rated as "very much improved" or "much improved" compared to 2/26 (8%) of controls (p = 0.0471); 24/30 (80%) in the treatment group improved compared to 10/26 (38%) of controls (p = 0.0024). Mean parental CGI scores significantly improved in the treatment group compared to controls in overall functioning (p = 0.0336), receptive language (p = 0.0168), and eye contact (p = 0.0322). On the ABC, significant improvements were observed in the treatment group in total score, irritability, stereotypy, hyperactivity, and speech (p < 0.03 for each), but not in the control group. In the treatment group compared to the control group, mean changes on the ABC total score and subscales were similar except a greater number of children improved in irritability (p = 0.0311). On the ATEC, sensory/cognitive awareness significantly improved (p = 0.0367) in the treatment group compared to the control group. Post-hoc analysis indicated that children over age 5 and children with lower initial autism severity had the most robust improvements. Hyperbaric treatment was safe and well-tolerated. CONCLUSION: Children with autism who received hyperbaric treatment at 1.3 atm and 24% oxygen for 40 hourly sessions had significant improvements in overall functioning, receptive language, social interaction, eye contact, and sensory/cognitive awareness compared to children who received slightly pressurized room air.

2. Vernes SC, Newbury DF, Abrahams BS, Winchester L, Nicod J, Groszer M, Alarcón M, Oliver PL, Davies KE, Geschwind DH, Monaco AP, Fisher SE. A functional genetic link between distinct developmental language disorders. N Engl J Med. 2008 Nov 27;359(22):2337-45.

BACKGROUND: Rare mutations affecting the FOXP2 transcription factor cause a monogenic speech and language disorder. We hypothesized that neural pathways downstream of FOXP2 influence more common phenotypes, such as specific language impairment. METHODS: We performed genomic screening for regions bound by FOXP2 using chromatin immunoprecipitation, which led us to focus on one particular gene that was a strong candidate for involvement in language impairments. We then tested for associations between single-nucleotide polymorphisms (SNPs) in this gene and language deficits in a well-characterized set of 184 families affected with specific language impairment. RESULTS: We found that FOXP2 binds to and dramatically down-regulates CNTNAP2, a gene that encodes a neurexin and is expressed in the developing human cortex. On analyzing CNTNAP2 polymorphisms in children with typical specific language impairment, we detected significant quantitative associations with nonsense-word repetition, a heritable behavioral marker of this disorder (peak association, P=5.0x10(-5) at SNP rs17236239). Intriguingly, this region coincides with one associated with language delays in children with autism. CONCLUSIONS: The FOXP2-CNTNAP2 pathway provides a mechanistic link between clinically distinct syndromes involving disrupted language.

1. Volkow ND, Wang GJ, Kollins SH, Wigal TL, Newcorn JH, Telang F, Fowler JS, Zhu W, Logan J, Ma Y, Pradhan K, Wong C, Swanson JM. Evaluating dopamine reward pathway in ADHD: clinical implications. JAMA. 2009 Sep 9;302(10):1084-91.

CONTEXT: Attention-deficit/hyperactivity disorder (ADHD)--characterized by symptoms of inattention and hyperactivity-impulsivity--is the most prevalent childhood psychiatric disorder that frequently persists into adulthood, and there is increasing evidence of reward-motivation deficits in this disorder. OBJECTIVE: To evaluate biological bases that might underlie a reward/motivation deficit by imaging key components of the brain dopamine reward pathway (mesoaccumbens). DESIGN, SETTING, AND PARTICIPANTS: We used positron emission tomography to measure dopamine synaptic markers (transporters and D(2)/D(3) receptors) in 53 nonmedicated adults with ADHD and 44 healthy controls between 2001-2009 at Brookhaven National Laboratory. MAIN OUTCOME MEASURES: We measured specific binding of positron emission tomographic radioligands for dopamine transporters (DAT) using [(11)C]cocaine and for D(2)/D(3) receptors using [(11)C]raclopride, quantified as binding potential (distribution volume ratio -1). RESULTS: For both ligands, statistical parametric mapping showed that specific binding was lower in ADHD than in controls (threshold for significance set at P < .005) in regions of the dopamine reward pathway in the left side of the brain. Region-of-interest analyses corroborated these findings. The mean (95% confidence interval [CI] of mean difference) for DAT in the nucleus accumbens for controls was 0.71 vs 0.63 for those with ADHD (95% CI, 0.03-0.13, P = .004) and in the midbrain for controls was 0.16 vs 0.09 for those with ADHD (95% CI, 0.03-0.12; P < or = .001); for D(2)/D(3) receptors, the mean accumbens for controls was 2.85 vs 2.68 for those with ADHD (95% CI, 0.06-0.30, P = .004); and in the midbrain, it was for controls 0.28 vs 0.18 for those with ADHD (95% CI, 0.02-0.17, P = .01). The analysis also corroborated differences in the left caudate: the mean DAT for controls was 0.66 vs 0.53 for those with ADHD (95% CI, 0.04-0.22; P = .003) and the mean D(2)/D(3) for controls was 2.80 vs 2.47 for those with ADHD (95% CI, 0.10-0.56; P = .005) and differences in D(2)/D(3) in the hypothalamic region, with controls having a mean of 0.12 vs 0.05 for those with ADHD (95% CI, 0.02-0.12; P = .004). Ratings of attention correlated with D(2)/D(3) in the accumbens (r = 0.35; 95% CI, 0.15-0.52; P = .001), midbrain (r = 0.35; 95% CI, 0.14-0.52; P = .001), caudate (r = 0.32; 95% CI, 0.11-0.50; P = .003), and hypothalamic (r = 0.31; CI, 0.10-0.49; P = .003) regions and with DAT in the midbrain (r = 0.37; 95% CI, 0.16-0.53; P < or = .001). CONCLUSION: A reduction in dopamine synaptic markers associated with symptoms of inattention was shown in the dopamine reward pathway of participants with ADHD.