Runner-Up Articles

Landefeld CS, Steinman MA. The Neurontin legacy--marketing through misinformation and manipulation. N Engl J Med. 2009 Jan 8;360(2):103-6.

A cautionary tale!

Rameckers EA, Speth LA, Duysens J, Vles JS, Smits-Engelsman BC. Botulinum toxin-a in children with congenital spastic hemiplegia does not improve upper extremity motor-related function over rehabilitation alone: a randomized controlled trial. Neurorehabil Neural Repair. 2009 Mar-Apr;23(3):218-25.

BACKGROUND: Rehabilitation of the upper extremity in children with hemiplegic cerebral palsy has not been compared to the same intensity of therapy combined with injected botulinum toxin (BTX). OBJECTIVE: To measure the short-term (2 weeks) and long-term (6 and 9 months) effects of a standardized functional training program versus without the addition of chemodenervation of forearm and hand muscles. METHODS: Twenty children with spastic hemiplegia, aged 4 to 16 years, were matched for baseline characteristics and then randomized to standardized functional physical and occupational therapies for 6 months (PT/OT group) or to the same therapies plus multimuscle BTX-A (BTX+ group). MAIN OUTCOME MEASURES: were isometric generated force, overshoot and undershoot (force production error), active and passive range of motion by goniometry (ROM), stretch restricted angle (SRA) of joints, Ashworth scores at the elbow and wrist, and the Melbourne assessment of unilateral upper limb function. All measures were performed at baseline, 2 weeks after BTX-A, 6 months (end of therapy), and then 3 months after termination of the therapy. RESULTS: Clinical measures (muscle tone, active ROM of wrist and elbow) showed improvement in both groups. However, no significant differences emerged between groups on functional measures. Generated force decreased directly after the BTX-A injection but increased during the therapy period. The PT/OT group, however, showed a significantly higher increase in force and accuracy with therapy compared with the BTX+ therapy group. CONCLUSIONS: Functional rehabilitation therapies for the upper extremity increase manual isometric flexor force at the wrist and ROM, but BTX injections cause weakness and do not lead to better outcomes than therapy alone.

Tedroff K, Granath F, Forssberg H, Haglund-Akerlind Y. Long-term effects of botulinum toxin A in children with cerebral palsy. Dev Med Child Neurol. 2009 Feb;51(2):120-7.

The long-term effects of botulinum toxin A (BoNT-A) treatment in children with cerebral palsy (CP) are still elusive. We studied a prospective clinical cohort of 94 children with different subtypes (50% spastic diplegic CP, 22% hemiplegic CP, 25% tetraplegic CP, 3% dyskinetic CP), sex (55% male, 45% female), severity according to Gross Motor Function Classification System (29% Level I, 15% Level II, 16% Level III, 17% Level IV, 23% Level V), and age (median 5y 4mo, range 11mo-17y 8mo). The longest follow-up time was 3 years 7 months (median 1y 6mo) and included a maximum of eight injections per muscle (median two injections to a specific muscle). Outcome measurements were muscle tone (Modified Ashworth Scale) and joint range of motion (ROM). Assessments were made at a minimum before and 3 months after each injection. Ninety-five per cent confidence intervals for differences from baseline were used to identify significant changes. BoNT-A injections induced reduction of long-term spasticity in all muscle-groups examined: the gastrocnemius, hamstring, and adductor muscles. The reduction in tone was most distinct in the gastrocnemius muscle, and each repeated injection produced an immediate reduction in muscle tone. However, improvement in ROM was brief and measured only after the first injections, whereupon the ROM declined. Thus, the results suggest that BoNT-A can be effective in reducing muscle tone over a longer period, but not in preventing development of contractures in spastic muscles. The dissociation between the effects on muscle tone and ROM indicates that development of contractures is not coupled to increased muscle tone only, but might be caused by other mechanisms.

Ágnes Melinda Kovács* and Jacques Mehler. Flexible Learning of Multiple Speech Structures in Bilingual Infants. Science 31 July 2009: Vol. 325. no. 5940, pp. 611 - 612.

Children acquire their native language according to a well-defined time frame. Surprisingly, although children raised in bilingual environments have to learn roughly twice as much about language as their monolingual peers, the speed of acquisition is comparable in monolinguals and bilinguals. Here, we show that preverbal 12-month-old bilingual infants have become more flexible at learning speech structures than monolinguals. When given the opportunity to simultaneously learn two different regularities, bilingual infants learned both, whereas monolinguals learned only one of them. Hence, bilinguals may acquire two languages in the time in which monolinguals acquire one because they quickly become more flexible learners.

Conde-Agudelo A, Romero R. Antenatal magnesium sulfate for the prevention of cerebral palsy in preterm infants less than 34 weeks' gestation: a systematic review and metaanalysis. Am J Obstet Gynecol. 2009 Jun;200(6):595-609.

We conducted a systematic review and metaanalysis of randomized controlled trials to determine whether magnesium sulfate administered to women at risk of preterm delivery before 34 weeks of gestation may reduce the risk of cerebral palsy in their children. Six trials involving 4796 women and 5357 infants were included. Antenatal magnesium sulfate was associated with a significant reduction in the risk of cerebral palsy (relative risk [RR], 0.69; 95% confidence interval [CI], 0.55-0.88), moderate or severe cerebral palsy (RR, 0.64; 95% CI, 0.44-0.92), and substantial gross motor dysfunction (RR, 0.60; 95% CI, 0.43-0.83). There was no overall difference in the risk of total pediatric mortality (RR, 1.01; 95% CI, 0.89-1.14). Minor side effects were more frequent among women receiving magnesium sulfate. In conclusion, magnesium sulfate administered to women at risk of delivery before 34 weeks of gestation reduces the risk of cerebral palsy.

Salem Y, Godwin EM. Effects of task-oriented training on mobility function in children with cerebral palsy. NeuroRehabilitation. 2009;24(4):307-13.

Background/Purpose: Improvement in mobility function has been the primary goal in the rehabilitation of children with cerebral palsy. Few studies have examined the effectiveness of task-oriented strength training for children with cerebral palsy. The purpose of this study was to examine the effects of task-oriented strength training on mobility function in children with cerebral palsy. Study design: A single-blind, randomized controlled trial with pre-training and post-training evaluations. Materials and methods: Ten children with cerebral palsy (GMFCS levels I-III) were randomly assigned to an experimental group (N = 5) or control group (N = 5). Mobility function was assessed using the Gross Motor Function Measure (GMFM) and the Timed "Up and Go" (TUG) test. Participants in the control group received conventional physical therapy focused on improving walking and balance through facilitation and normalization of movement patterns. Participants in the experiment group received task-oriented strength training focused on strengthening the lower extremities and practicing functional tasks similar to those the child performs during daily activities. Results: After the 5-week training period there were significant improvements in the experimental group for dimension D (p = 0.009), and dimension E (p = 0.009) of the GMFM. The experimental group significantly reduced the time taken to complete the TUG (p = 0.017). Conclusion/Significance: This study supports the efficacy of task-oriented strength training for improving mobility function in children with cerebral palsy. The findings demonstrate that the application of a task-oriented strength training program is linked to positive functional outcomes. The results suggest that children with cerebral palsy may benefit from a task-oriented strength training program. Further studies with a larger randomized sample and longer post-intervention follow-up are necessary to document the long-term effects of participation in task-oriented strength training programs in the cerebral palsy population.

Kulkarni AV, Drake JM, Mallucci CL, Sgouros S, Roth J, Constantini S; Canadian Pediatric Neurosurgery Study Group. Endoscopic third ventriculostomy in the treatment of childhood hydrocephalus. J Pediatr. 2009 Aug;155(2):254-9.e1.

OBJECTIVE: To develop a model to predict the probability of endoscopic third ventriculostomy (ETV) success in the treatment for hydrocephalus on the basis of a child's individual characteristics. STUDY DESIGN: We analyzed 618 ETVs performed consecutively on children at 12 international institutions to identify predictors of ETV success at 6 months. A multivariable logistic regression model was developed on 70% of the dataset (training set) and validated on 30% of the dataset (validation set). RESULTS: In the training set, 305/455 ETVs (67.0%) were successful. The regression model (containing patient age, cause of hydrocephalus, and previous cerebrospinal fluid shunt) demonstrated good fit (Hosmer-Lemeshow, P = .78) and discrimination (C statistic = 0.70). In the validation set, 105/163 ETVs (64.4%) were successful and the model maintained good fit (Hosmer-Lemeshow, P = .45), discrimination (C statistic = 0.68), and calibration (calibration slope = 0.88). A simplified ETV Success Score was devised that closely approximates the predicted probability of ETV success. CONCLUSIONS: Children most likely to succeed with ETV can now be accurately identified and spared the long-term complications of CSF shunting.

Robert B. Hinton; Gregor Andelfinger; Priya Sekar; Andrea C. Hinton; Roxanne L. Gendron; Erik C. Michelfelder; Yves Robitaille; D Woodrow Benson. Prenatal Head Growth and White Matter Injury in Hypoplastic Left Heart Syndrome. Pediatric Research. October 2008, Volume 64, Issue 4. 364-9.

Children with hypoplastic left heart syndrome (HLHS) have an increased prevalence of central nervous system (CNS) abnormalities. The extent to which this problem is due to CNS maldevelopment, prenatal ischemia, postnatal chronic cyanosis and/or multiple exposures to cardiopulmonary bypass is unknown. To better understand the etiology of CNS abnormalities in HLHS, we evaluated 68 neonates with HLHS; in 28 cases, both fetal ultrasound and echocardiogram data were available to assess head size, head growth and aortic valve anatomy (atresia or stenosis). In addition, we evaluated neuropathology in 11 electively aborted HLHS fetuses. The mean head circumference percentile in HLHS neonates was significantly smaller than HLHS fetuses (22 ? 2% versus 40 ? 4%, p < 0.001). A significant decrease in head growth, defined as a 50% reduction in head circumference percentile, was observed in half (14/28) of HLHS fetuses and nearly a quarter (6/28) were already growth restricted (<=10%) at the time of initial evaluation. Brains from HLHS fetuses demonstrated chronic diffuse white matter injury of varying severity. These patterns of prenatal head growth and brain histopathology identify a spectrum of abnormal CNS development and/or injury in HLHS fetuses.

Isaacs EB, Morley R, Lucas A. Early diet and general cognitive outcome at adolescence in children born at or below 30 weeks gestation. J Pediatr. 2009 Aug;155(2):229-34.

OBJECTIVE: To test the hypothesis that effects of early diet on cognition observed at age 8 years persist in adolescents born preterm at < or = 30 weeks gestational age. STUDY DESIGN: A subgroup from a preterm infant cohort recruited for a randomized trial studying the effects of early dietary intervention was assessed at age 16 years. IQ scores were compared between those assigned a high-nutrient diet (n = 49) or standard-nutrient diet (n = 46) in infancy at both 8 and 16 years. RESULTS: At age 8 years, the high-nutrient group had higher mean Verbal IQ (VIQ; P = .03), Performance IQ (P = .01), and Full-Scale IQ (P = .02) scores compared with the standard-nutrient group; the VIQ difference persisted at adolescence (P = .02). This effect was accounted for principally by a significant difference in the mean Verbal Comprehension Index score (P < .008). CONCLUSIONS: A brief period of dietary intervention after preterm birth, principally between 26 and 34 weeks of gestation, affected IQ at age 16 years. A standard-nutrient diet was associated with lower VIQ, accounted for mainly by differences in verbal comprehension, which persisted after control of social factors.

Molina BS, Hinshaw SP, Swanson JM, Arnold LE, Vitiello B, Jensen PS, Epstein JN, Hoza B, Hechtman L, Abikoff HB, Elliott GR, Greenhill LL, Newcorn JH, Wells KC, Wigal T, Gibbons RD, Hur K, Houck PR; MTA Cooperative Group. The MTA at 8 years: prospective follow-up of children treated for combined-type ADHD in a multisite study. J Am Acad Child Adolesc Psychiatry. 2009 May;48(5):484-500.

OBJECTIVES: To determine any long-term effects, 6 and 8 years after childhood enrollment, of the randomly assigned 14-month treatments in the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA; N = 436); to test whether attention-deficit/hyperactivity disorder (ADHD) symptom trajectory through 3 years predicts outcome in subsequent years; and to examine functioning level of the MTA adolescents relative to their non-ADHD peers (local normative comparison group; N = 261). METHOD: Mixed-effects regression models with planned contrasts at 6 and 8 years tested a wide range of symptom and impairment variables assessed by parent, teacher, and youth report. RESULTS: In nearly every analysis, the originally randomized treatment groups did not differ significantly on repeated measures or newly analyzed variables (e.g., grades earned in school, arrests, psychiatric hospitalizations, other clinically relevant outcomes). Medication use decreased by 62% after the 14-month controlled trial, but adjusting for this did not change the results. ADHD symptom trajectory in the first 3 years predicted 55% of the outcomes. The MTA participants fared worse than the local normative comparison group on 91% of the variables tested. CONCLUSIONS: Type or intensity of 14 months of treatment for ADHD in childhood (at age 7.0-9.9 years) does not predict functioning 6 to 8 years later. Rather, early ADHD symptom trajectory regardless of treatment type is prognostic. This finding implies that children with behavioral and sociodemographic advantage, with the best response to any treatment, will have the best long-term prognosis. As a group, however, despite initial symptom improvement during treatment that is largely maintained after treatment, children with combined-type ADHD exhibit significant impairment in adolescence. Innovative treatment approaches targeting specific areas of adolescent impairment are needed.

Robinson MN, Peake LJ, Ditchfield MR, Reid SM, Lanigan A, Reddihough DS. Magnetic resonance imaging findings in a population-based cohort of children with cerebral palsy. Dev Med Child Neurol. 2009 Jan;51(1):39-45. Epub 2008 Oct 17.

The purpose of this study was to investigate the frequency and spectrum of magnetic resonance imaging (MRI) abnormalities in a population of children with cerebral palsy (CP) who were born in the years 2000 and 2001 in Victoria, Australia. In 2000 and 2001, 221 children (126 males, 95 females; mean age 6y [SD 7mo], range 5-7y) with CP, excluding those with CP due to postneonatal causes (6% of all cases), were identified through the Victorian Cerebral Palsy Register. All medical records were systematically reviewed and all available brain imaging was comprehensively evaluated by a single senior MRI radiologist. MRI was available for 154 (70%) individuals and abnormalities were identified in 129 (84%). The study group comprised 88% with a spastic motor type CP; the distribution was hemiplegia in 33.5%, diplegia in 28.5%, and quadriplegia in 37.6% of children. Overall, pathological findings were most likely to be identified in children with spastic hemiplegia (92%) and spastic quadriplegia (84%). Abnormalities were less likely to be identified in non-spastic motor types (72%) and spastic diplegia (52%). The most common abnormalities identified on MRI were periventricular white matter injury (31%), focal ischaemic/haemorrhagic lesions (16%), diffuse encephalopathy (14%), and brain malformations (12%). Dual findings were seen in 3% of patients. This is the first study to document comprehensively the neuroimaging findings of all children identified with CP born over a consecutive 24-month period in a large geographical area.

Goldman S, Wang C, Salgado MW, Greene PE, Kim M, Rapin I. Motor stereotypies in children with autism and other developmental disorders. Dev Med Child Neurol. 2009 Jan;51(1):30-8.

The purpose of the study was to count and characterize the range of stereotypies--repetitive rhythmical, apparently purposeless movements--in developmentally impaired children with and without autism, and to determine whether some types are more prevalent and diagnostically useful in children with autism. We described each motor stereotypy recorded during 15 minutes of archived videos of standardized play sessions in 277 children (209 males, 68 females; mean age 4y 6mo [SD 1y 5mo], range 2y 11mo-8y 1mo), 129 with autistic disorder (DSM-III-R), and 148 cognitively-matched non-autistic developmentally disordered (NADD) comparison children divided into developmental language disorder and non-autism, low IQ (NALIQ) sub-groups. The parts of the body involved and characteristics of all stereotypies were scored blind to diagnosis. More children with autism had stereotypies than the NADD comparison children. Autism and, to a lesser degree, nonverbal IQ (NVIQ) <80, especially in females contributed independently to the occurrence, number, and variety of stereotypies, with non-autistic children without cognitive impairment having the least number of stereotypies and children with autism and low NVIQ the most. Autism contributed independently to gait and hand/finger stereotypies and NVIQ <80 to head/trunk stereotypies. Atypical gazing at fingers and objects was rare but virtually limited to autism. Stereotypies are environmentally modulated movement disorders, some highly suggestive, but not pathognomonic, of autism. Their underlying brain basis and genetic correlates need investigation.

Northam EA, Rankins D, Lin A, Wellard RM, Pell GS, Finch SJ, Werther GA, Cameron FJ. Central nervous system function in youth with type 1 diabetes 12 years after disease onset. Diabetes Care. 2009 Mar;32(3):445-50.

OBJECTIVE: In this study, we used neurocognitive assessment and neuroimaging to examine brain function in youth with type 1 diabetes studied prospectively from diagnosis. RESEARCH DESIGN AND METHODS: We studied type 1 diabetic (n = 106) and control subjects (n = 75) with no significant group difference on IQ at baseline 12 years previously by using the Wechsler Abbreviated Scale of General Intelligence, magnetic resonance spectroscopy and imaging, and metabolic control data from diagnosis. RESULTS: Type 1 diabetic subjects had lower verbal and full scale IQs than control subjects (both P < 0.05). Type 1 diabetic subjects had lower N-acetylaspartate in frontal lobes and basal ganglia and higher myoinositol and choline in frontal and temporal lobes and basal ganglia than control subjects (all P < 0.05). Type 1 diabetic subjects, relative to control subjects, had decreased gray matter in bilateral thalami and right parahippocampal gyrus and insular cortex. White matter was decreased in bilateral parahippocampi, left temporal lobe, and middle frontal area (all P < 0.0005 uncorrected). T2 in type 1 diabetic subjects was increased in left superior temporal gyrus and decreased in bilateral lentiform nuclei, caudate nuclei and thalami, and right insular area (all P < 0.0005 uncorrected). Early-onset disease predicted lower performance IQ, and hypoglycemia was associated with lower verbal IQ and volume reduction in thalamus; poor metabolic control predicted elevated myoinositol and decreased T2 in thalamus; and older age predicted volume loss and T2 change in basal ganglia. CONCLUSIONS: This study documents brain effects 12 years after diagnosis in a type 1 diabetic sample whose IQ at diagnosis matched that of control subjects. Findings suggest several neuropathological processes including gliosis, demyelination, and altered osmolarity.

Cohen GL, Garcia J, Purdie-Vaughns V, Apfel N, Brzustoski P. Recursive processes in self-affirmation: intervening to close the minority achievement gap. Science. 2009 Apr 17;324(5925):400-3.

A 2-year follow-up of a randomized field experiment previously reported in Science is presented. A subtle intervention to lessen minority students' psychological threat related to being negatively stereotyped in school was tested in an experiment conducted three times with three independent cohorts (N = 133, 149, and 134). The intervention, a series of brief but structured writing assignments focusing students on a self-affirming value, reduced the racial achievement gap. Over 2 years, the grade point average (GPA) of African Americans was, on average, raised by 0.24 grade points. Low-achieving African Americans were particularly benefited. Their GPA improved, on average, 0.41 points, and their rate of remediation or grade repetition was less (5% versus 18%). Additionally, treated students' self-perceptions showed long-term benefits. Findings suggest that because initial psychological states and performance determine later outcomes by providing a baseline and initial trajectory for a recursive process, apparently small but early alterations in trajectory can have long-term effects. Implications for psychological theory and educational practice are discussed.

Brody GH, Beach SRH, Philibert RA, Chen Y, Murry VM. Prevention Effects Moderate the Association of 5-HTTLPR and Youth Risk Behavior Initiation: Gene ? Environment Hypotheses Tested via a Randomized Prevention Design. Child Development 2009; 80(3):645-61.

A randomized prevention design was used to investigate a moderation effect in the association between a polymorphism in the SCL6A4(5HTT) gene at 5-HTTLPR and increases in youths' risk behavior initiation. Participation in the Strong African American Families (SAAF) program was hypothesized to attenuate the link between 5-HTTLPR status and risk behavior initiation. Youths (N = 641, M age = 11.2 years) were assigned randomly to a SAAF or control condition. Risk behavior initiation across 29 months was linked positively with the 5-HTTLPR genotype and negatively with SAAF participation. Control youths at genetic risk initiated risk behavior at twice the rate of SAAF youths at genetic risk and youths not at genetic risk in either condition.

There have been many discussions of how genes and environment might interact in the context of human behavior. Brody et al. have studied the effects of a randomized behavioral intervention on adolescents who have a genetic polymorphism associated with the initiation of risky behavior. Roughly 600 11-year-olds were randomly assigned to the Strong African American Families (SAAF) program or to a control group. The SAAF group (and their caregivers, usually mothers) participated in separate and joint training sessions on parenting practices, stress management, dealing with racism, setting goals, and norms for the use of alcohol and other substances. Sessions occurred over the course of 1 year, and the initiation of risky behaviors was assessed at the beginning of the program and for the next 2.5 years. Two years later, saliva samples were collected to look for a polymorphism in the promoter region of the serotonin transporter. Possession of a short form of the allele has been associated previously with impulsivity, substance abuse, and early sexual activity. In the control group, adolescents with the short allele were twice as likely to have engaged in risky behaviors as those assigned to the SAAF group or those with the long allele in either group. Only one genetic polymorphism was examined, and the results need to be confirmed in a variety of populations; however, this provides further evidence of the value of this intervention and the mutability of the effects of genetic predisposition.

Ethofer T, Van De Ville D, Scherer K, Vuilleumier P. Decoding of Emotional Information in Voice-Sensitive Cortices. Curr Biol. 2009 May 13. [Epub ahead of print]

The ability to correctly interpret emotional signals from others is crucial for successful social interaction. Previous neuroimaging studies showed that voice-sensitive auditory areas [1-3] activate to a broad spectrum of vocally expressed emotions more than to neutral speech melody (prosody). However, this enhanced response occurs irrespective of the specific emotion category, making it impossible to distinguish different vocal emotions with conventional analyses [4-8]. Here, we presented pseudowords spoken in five prosodic categories (anger, sadness, neutral, relief, joy) during event-related functional magnetic resonance imaging (fMRI), then employed multivariate pattern analysis [9, 10] to discriminate between these categories on the basis of the spatial response pattern within the auditory cortex. Our results demonstrate successful decoding of vocal emotions from fMRI responses in bilateral voice-sensitive areas, which could not be obtained by using averaged response amplitudes only. Pairwise comparisons showed that each category could be classified against all other alternatives, indicating for each emotion a specific spatial signature that generalized across speakers. These results demonstrate for the first time that emotional information is represented by distinct spatial patterns that can be decoded from brain activity in modality-specific cortical areas.

The widespread adoption of multiple technologies for distinct channels of data communication—text, voice, and video—has made it abundantly clear to even the casual user that more bandwidth allows for higher rates of information transfer. But what happens on the receiving end? Presumably, recipients of phone calls are processing a lot more information, such as emotional overtones, than just the words that are spoken. Does this emotional content register in their brains? Ethofer et al. apply the method of multivariate pattern analysis and show that pseudowords spoken with five distinct emotional melodies (anger, sadness, relief, joy, or neutrality) do evoke recognizable neural responses within the auditory cortex. Each of these emotions could be discriminated against the others, and decoding algorithms trained on any nine of the speakers' voices were accurate in classifying the emotional identity of the tenth speaker's speech. Furthermore, the five distributed maps of neuronal activity segregated more closely to levels of arousal than valence, suggesting a possible affective organization within the auditory cortex.

Atladóttir HO, Pedersen MG, Thorsen P, Mortensen PB, Deleuran B, Eaton WW, Parner ET. Association of family history of autoimmune diseases and autism spectrum disorders. Pediatrics. 2009 Aug;124(2):687-94. Epub 2009 Jul 5.

OBJECTIVES: Recent studies suggest that familial autoimmunity plays a part in the pathogenesis of ASDs. In this study we investigated the association between family history of autoimmune diseases (ADs) and ASDs/infantile autism. We perform confirmatory analyses based on results from previous studies, as well as various explorative analyses. METHODS: The study cohort consisted of all of the children born in Denmark from 1993 through 2004 (689 196 children). Outcome data consisted of both inpatient and outpatient diagnoses reported to the Danish National Psychiatric Registry. Information on ADs in parents and siblings of the cohort members was obtained from the Danish National Hospital Register. The incidence rate ratio of autism was estimated by using log-linear Poisson regression. RESULTS: A total of 3325 children were diagnosed with ASDs, of which 1089 had an infantile autism diagnosis. Increased risk of ASDs was observed for children with a maternal history of rheumatoid arthritis and celiac disease. Also, increased risk of infantile autism was observed for children with a family history of type 1 diabetes. CONCLUSIONS: Associations regarding family history of type 1 diabetes and infantile autism and maternal history of rheumatoid arthritis and ASDs were confirmed from previous studies. A significant association between maternal history of celiac disease and ASDs was observed for the first time. The observed associations between familial autoimmunity and ASDs/infantile autism are probably attributable to a combination of a common genetic background and a possible prenatal antibody exposure or alteration in fetal environment during pregnancy.

Courtney C Haswell, Jun Izawa1, Lauren R Dowell, Stewart H Mostofsky & Reza Shadmehr. Representation of internal models of action in the autistic brain. Nature Neuroscience. Published online: 5 July 2009 | doi:10.1038

Children with autism spectrum disorder (ASD) have deficits in motor control, imitation and social function. Does a dysfunction in the neural basis of representing internal models of action contribute to these problems? We measured patterns of generalization as children learned to control a novel tool and found that the autistic brain built a stronger than normal association between self-generated motor commands and proprioceptive feedback; furthermore, the greater the reliance on proprioception, the greater the child's impairments in social function and imitation.

McGibbon NH; Benda W; Duncan BR; Silkwood-Sherer D. Immediate and long-term effects of hippotherapy on symmetry of adductor muscle activity and functional ability in children with spastic cerebral palsy. Arch Phys Med Rehabil. 2009; 90(6):966-74.

OBJECTIVES: To investigate the immediate effects of 10 minutes of hippotherapy, compared with 10 minutes of barrel-sitting, on symmetry of adductor muscle activity during walking in children with cerebral palsy (CP) (phase I). To investigate the long-term effects of 12 weeks of hippotherapy on adductor activity, gross motor function, and self-concept (phase II). DESIGN: Pretest/posttest randomized controlled trial plus clinical follow-up. SETTING: Outpatient therapy center. PARTICIPANTS: Children with spastic CP (phase I: n=47; phase II: n=6). INTERVENTIONS: Phase I: 10 minutes of hippotherapy or 10 minutes of barrel-sitting; phase II: 12 weekly hippotherapy sessions. MAIN OUTCOME MEASURES: Phases I and II: adductor muscle activity measured by surface electromyography. Phase II: gross motor function and self-perception profiles. RESULTS: Phase I: hippotherapy significantly improved adductor muscle asymmetry (P<.001; d=1.32). Effects of barrel-sitting were not significant (P>.05; d=.10). Phase II: after 12 weeks of hippotherapy, testing in several functional domains showed improvements over baseline that were sustained for 12 weeks posttreatment. CONCLUSIONS: Hippotherapy can improve adductor muscle symmetry during walking and can also improve other functional motor skills.

Kanovský P, Bares M, Severa S, Richardson A; Dysport Paediatric Limb Spasticity Study Group Long-term efficacy and tolerability of 4-monthly versus yearly botulinum toxin type A treatment for lower-limb spasticity in children with cerebral palsy. Dev Med Child Neurol. 2009 Jun;51(6):436-45.

In this study, we compared the long-term efficacy and tolerability of two dosage regimens of the potent botulinum toxin type A (BoNT-A; Dysport; Ipsen Ltd, Slough, UK) in children with cerebral palsy (CP) and lower-limb spasticity. Children aged 1 to 8 years with diplegic CP who were able to walk (aided or unaided) were randomized (1:1) to 30 LD(50) units/kg total body weight of BoNT-A (injected into gastrocnemius muscles) every 4 months or once yearly for 2 years in this multicentre, assessor-blinded, parallel-group study. In the 4-monthly group (n=110, 39 males, 71 females), mean age was 3 years 8 months (SD 1 y 6 mo, range 1-8 y). In the yearly group (n=104, 47 males, 57 females), mean age was 4 years 4 months (SD 1 y 6 mo, range 2-8 y). Both treatment groups had similar baseline Gross Motor Function Measure scores. At month 28 (primary endpoint; intention-to-treat group), median maximum passive ankle dorsiflexion was 12.00 degrees in the 4-monthly and 11.00 degrees in the yearly group. Between-group difference of 1.67 degrees was not statistically significant (p=0.055). Other efficacy endpoints showed no significant difference between the regimens. The results of the study do not allow a clear conclusion of the preferred injection regimen.

Bloch MH, Panza KE, Landeros-Weisenberger A, Leckman JF. Meta-analysis: treatment of attention-deficit/hyperactivity disorder in children with comorbid tic disorders. J Am Acad Child Adolesc Psychiatry. 2009 Sep;48(9):884-93.

OBJECTIVE: The Food and Drug Administration currently requires the package inserts of most psychostimulant medications to list the presence of a tic disorder as a contraindication to their use. Approximately half of children with Tourette's syndrome experience comorbid attention-deficit/hyperactivity disorder (ADHD). We sought to determine the relative efficacy of different medications in treating ADHD and tic symptoms in children with both Tourette's syndrome and ADHD. METHOD: We conducted a PubMed search to identify all double-blind, randomized, placebo-controlled trials examining the efficacy of medications in the treatment of ADHD in the children with comorbid tics. We used a random effects meta-analysis with standardized mean difference as our primary outcome to estimate the effect size of pharmaceutical agents in the treatment of ADHD symptoms and tics. RESULTS: Our meta-analysis included nine studies involving 477 subjects. We assessed the efficacy of six medications-dextroamphetamine, methylphenidate, alpha-2 agonists (clonidine and guanfacine), desipramine, atomoxetine, and deprenyl. Methylphenidate, alpha-2 agonists, desipramine, and atomoxetine demonstrated efficacy in improving ADHD symptoms in children with comorbid tics. Alpha-2 agonists and atomoxetine significantly improved comorbid tic symptoms. Although there was evidence that supratherapeutic doses of dextroamphetamine worsens tics, there was no evidence that methylphenidate worsened tic severity in the short term. CONCLUSIONS: Methylphenidate seems to offer the greatest and most immediate improvement of ADHD symptoms and does not seem to worsen tic symptoms. Alpha-2 agonists offer the best combined improvement in both tic and ADHD symptoms. Atomoxetine and desipramine offer additional evidence-based treatments of ADHD in children with comorbid tics. Supratherapeutic doses of dextroamphetamine should be avoided.

Newcorn JH, Sutton VK, Weiss MD, Sumner CR. Clinical responses to atomoxetine in attention-deficit/hyperactivity disorder: the Integrated Data Exploratory Analysis (IDEA) study. J Am Acad Child Adolesc Psychiatry. 2009 May;48(5):511-8.

OBJECTIVE: Clinical experience suggests that some (but not all) patients with attention-deficit/hyperactivity disorder (ADHD) are highly responsive to the nonstimulant atomoxetine. We conducted a retrospective analysis of randomized controlled trials (RCTs) to identify potential baseline (moderator) and on-treatment (mediator) predictors of responses. METHOD: Data from 6 U.S. RCTs among patients aged 6 to 18 years were pooled (N = 1,069; subjects treated with atomoxetine, n = 618). Subjects were categorized as much improved (> or = 40% decrease in ADHD Rating Scale-IV-Parent Version: Investigator Administered and Scored total score), minimally improved (25%-< 40% decline), or nonresponders (< 25% decrease). Logistic regression, analyses of variance, and repeated-measures analyses were used to explore associations between baseline and on-treatment variables, achieving a much improved response at trial endpoint (6-9 weeks). RESULTS: Forty-seven percent of patients showed a much improved clinical response, and 40% did not respond. Only 13% of the patients had a minimal response. No baseline characteristics predicted achieving a much improved clinical response; the only predictor of achieving this response was being at least minimally improved by treatment week 4 (sensitivity = 81%, specificity = 72%, positive predictive value = 75%, and negative predictive value = 79%). CONCLUSIONS: Clinical response to atomoxetine was bimodal, with most subjects being either responders who were much improved or nonresponders. There were no demographic or clinical predictors of response. However, subjects who ultimately achieved a much improved response were likely to be at least minimal responders by week 4. The recommendation to consider either augmenting or switching treatment in patients who do not achieve at least this level of response to atomoxetine by 4 weeks offers a method for limiting the extended duration of titration to subjects who are most likely to benefit further, while minimizing the duration of exposure in those less likely to achieve an excellent response.

Waldman M, Nicholson S, Adilov N, Williams J. Autism prevalence and precipitation rates in California, Oregon, and Washington counties. Arch Pediatr Adolesc Med. 2008 Nov;162(11):1026-34.

OBJECTIVE: To investigate empirically the possibility of an environmental trigger for autism among genetically vulnerable children that is positively associated with precipitation. DESIGN: We used regression analysis to investigate autism prevalence rates and counts first in relation to mean annual county-level precipitation and then to the amount of precipitation a birth cohort was exposed to when younger than 3 years, controlling for time trend, population size, per capita income, and demographic characteristics. In some models, we included county fixed-effects rather than a full set of covariates. SETTING: Counties in California, Oregon, and Washington. PARTICIPANTS: Children born in California, Oregon, and Washington between 1987 and 1999. Main Exposure County-level precipitation. MAIN OUTCOME MEASURES: County-level autism prevalence rates and counts. RESULTS: County-level autism prevalence rates and counts among school-aged children were positively associated with a county's mean annual precipitation. Also, the amount of precipitation a birth cohort was exposed to when younger than 3 years was positively associated with subsequent autism prevalence rates and counts in Oregon counties and California counties with a regional developmental services center. CONCLUSIONS: These results are consistent with the existence of an environmental trigger for autism among genetically vulnerable children that is positively associated with precipitation. Further studies focused on establishing whether such a trigger exists and identifying the specific trigger are warranted.

Gould MS, Walsh BT, Munfakh JL, Kleinman M, Duan N, Olfson M, Greenhill L, Cooper T. Sudden death and use of stimulant medications in youths. Am J Psychiatry. 2009 Sep;166(9):992-1001. Epub 2009 Jun 15.

OBJECTIVE: The authors sought to determine whether a significant association exists between the use of stimulants and the rare event of sudden unexplained death in children and adolescents. METHOD: A matched case-control design was performed. Mortality data from 1985-1996 state vital statistics were used to identify 564 cases of sudden death occurring at ages 7 through 19 years across the United States along with a matched group of 564 young people who died as passengers in motor vehicle traffic accidents. The primary exposure measure was the presence of amphetamine, dextroamphetamine, methamphetamine, or methylphenidate according to informant reports or as noted in medical examiner records, toxicology results, or death certificates. RESULTS: In 10 (1.8%) of the sudden unexplained deaths it was determined that the youths were taking stimulants, specifically methylphenidate; in contrast, use of stimulants was found in only two subjects in the motor vehicle accident comparison group (0.4%), with only one involving methylphenidate use. A significant association of stimulant use with sudden unexplained death emerged from the primary analysis, which was based on exact conditional logistic regression (odds ratio=7.4, 95% CI=1.4 to 74.9). A comprehensive series of sensitivity analyses yielded qualitatively similar findings. CONCLUSIONS: This case-control study provides support for an association between the use of stimulants and sudden unexplained death among children and adolescents. Although sudden unexplained death is a rare event, this finding should be considered in the context of other data about the risk and benefit of stimulants in medical treatment.

Meador KJ, Baker GA, Browning N, Clayton-Smith J, Combs-Cantrell DT, Cohen M, Kalayjian LA, Kanner A, Liporace JD, Pennell PB, Privitera M, Loring DW; NEAD Study Group. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med. 2009 Apr 16;360(16):1597-605.

BACKGROUND: Fetal exposure of animals to antiepileptic drugs at doses lower than those required to produce congenital malformations can produce cognitive and behavioral abnormalities, but cognitive effects of fetal exposure of humans to antiepileptic drugs are uncertain. METHODS: Between 1999 and 2004, we enrolled pregnant women with epilepsy who were taking a single antiepileptic agent (carbamazepine, lamotrigine, phenytoin, or valproate) in a prospective, observational, multicenter study in the United States and the United Kingdom. The primary analysis is a comparison of neurodevelopmental outcomes at the age of 6 years after exposure to different antiepileptic drugs in utero. This report focuses on a planned interim analysis of cognitive outcomes in 309 children at 3 years of age. RESULTS: At 3 years of age, children who had been exposed to valproate in utero had significantly lower IQ scores than those who had been exposed to other antiepileptic drugs. After adjustment for maternal IQ, maternal age, antiepileptic-drug dose, gestational age at birth, and maternal preconception use of folate, the mean IQ was 101 for children exposed to lamotrigine, 99 for those exposed to phenytoin, 98 for those exposed to carbamazepine, and 92 for those exposed to valproate. On average, children exposed to valproate had an IQ score 9 points lower than the score of those exposed to lamotrigine (95% confidence interval [CI], 3.1 to 14.6; P=0.009), 7 points lower than the score of those exposed to phenytoin (95% CI, 0.2 to 14.0; P=0.04), and 6 points lower than the score of those exposed to carbamazepine (95% CI, 0.6 to 12.0; P=0.04). The association between valproate use and IQ was dose dependent. Children's IQs were significantly related to maternal IQs among children exposed to carbamazepine, lamotrigine, or phenytoin but not among those exposed to valproate. CONCLUSIONS: In utero exposure to valproate, as compared with other commonly used antiepileptic drugs, is associated with an increased risk of impaired cognitive function at 3 years of age. This finding supports a recommendation that valproate not be used as a first-choice drug in women of childbearing potential.

Jepsen JR, Fagerlund B, Mortensen EL. Do attention deficits influence IQ assessment in children and adolescents with ADHD? J Atten Disord. 2009 May;12(6):551-62.

OBJECTIVE: To characterize the relationship between IQ and attention deficits in children with ADHD and to estimate the inattention-related mean influence on IQ when children are tested before stimulant drug treatment has been initiated. METHOD: Studies of various methodologies are reviewed. RESULTS: Correlation studies show mostly weak associations between IQ scores and attention deficits. Meta-analyses report the average short-term stimulant treatment effect on IQ in children with ADHD to be 2 to 7 IQ points. CONCLUSION: The associations between IQ and attention deficits in ADHD are generally modest, with the mean influence on IQ probably amounting to 2 to 5 IQ points. This may serve as a benchmark when clinicians interpret the validity of IQ in this clinical population.

Davis E, Davies B, Wolfe R, Raadsveld R, Heine B, Thomason P, Dobson F, Graham HK. A randomized controlled trial of the impact of therapeutic horse riding on the quality of life, health, and function of children with cerebral palsy. Dev Med Child Neurol. 2009 Feb;51(2):111-9; discussion 88.

This randomized controlled trial examined whether therapeutic horse riding has a clinically significant impact on the physical function, health and quality of life (QoL) of children with cerebral palsy (CP). Ninety-nine children aged 4 to 12 years with no prior horse riding experience and various levels of impairment (Gross Motor Function Classification System Levels I-III) were randomized to intervention (10wks therapeutic programme; 26 males, 24 females; mean age 7y 8mo [SD 2y 5mo] or control (usual activities, 27 males, 22 females; mean age 8y 2mo [SD 2y 6mo]). Pre- and post-measures were completed by 72 families (35 intervention and 37 control). Children's gross motor function (Gross Motor Function Measure [GMFM]), health status (Child Health Questionnaire [CHQ]), and QoL (CP QoL-Child, KIDSCREEN) were assessed by parents and QoL was assessed by children before and after the 10-week study period. On analysis of covariance, there was no statistically significant difference in GMFM, CP QoL-Child (parent report and child self-report), and CHQ scores (except family cohesion) between the intervention and control group after the 10-week study period, but there was weak evidence of a difference for KIDSCREEN (parent report). This study suggests that therapeutic horse riding does not have a clinically significant impact on children with CP. However, a smaller effect cannot be ruled out and the absence of evidence might be explained by a lack of sensitivity of the instruments since the QoL and health measures have not yet been demonstrated to be sensitive to change for children with CP.

Robert J Palisano, Steven E Hanna, Peter L Rosenbaum, Beth Tieman Probability of walking, wheeled mobility, and assisted mobility in children and adolescents with cerebral palsy. DMCN–online.

Aim Our aim was to describe how the probability of walking, wheeled mobility, and assisted mobility changes with environmental setting and age in children and adolescents with cerebral palsy (CP).

Method The parents of a population-based sample of 642 children and adolescents (360 males, 282 females; age range 16mo–21y) reported their children's mobility at home, school, and outdoors at 6- or 12-month intervals a mean of 5.2 times. Generalized mixed-effects analyses were used to model the probabilities.

Results By age 3 years, children with motor function classified as level I according to the Gross Motor Function Classification System (GMFCS) walked in all three settings. Children/adolescents classified as level V used assisted mobility, with a small number using wheeled mobility. In the case of children classified as GMFCS level II, the probability of walking varied with the environmental setting, which, at age 18, is outdoors 90% of the time. Among children classified as GMFCS level III, the probability of walking was highest at age 9 at school (68%), and at age 18 was approximately 50% in all three settings. Among children/adolescents rated as GMFCS level IV, the probability of wheeled mobility increased with age and, at age 18, 57% of mobility took place outdoors.

Interpretation The results provide evidence that age and environmental setting influence method of mobility of children/adolescents with CP. The method that is preferred in one setting may not be preferred in another setting or at another age.

Lundy CT, Doherty GM, Fairhurst CB. Botulinum toxin type A injections can be an effective treatment for pain in children with hip spasms and cerebral palsy. Dev Med Child Neurol. 2009 Sep;51(9):705-10.

AIM: Botulinum toxin type A (BoNT-A) injections were used in the treatment of lower-limb spasticity in children with cerebral palsy (CP). Anecdotal evidence suggests a reduction in pain after this treatment in children who had pain localized to a displaced hip joint. We report on our current clinical practice. METHOD: Twenty-six children with non-ambulant quadriplegic CP (Gross Motor Function Classification System level V) were assessed as having significant spasticity and pain at the hip level. Twelve were males and 14 females, with an age range of 2 to 19 years (mean age 11y 6mo, SD 4y 9mo). Ten had functional difficulties secondary to predominant spasticity and 16 had a mix of a high-background peripheral tone with superimposed dystonia. Of the 26 children assessed, 10 had at least one hip which was dislocated and three had at least one hip which was subluxed. As part of their spasticity management programme they received targeted BoNT-A injections to the adductor magnus, medial hamstrings and iliopsoas muscle groups. The Paediatric Pain Profile was used as the primary outcome measure. RESULTS: All had highly significant improvement in their recorded pain profile scores measured at 3 months after treatment (p<0.001). There was equal efficacy in response to treatment in the children with subluxed or dislocated hips. In addition, families commented on improved quality of life for the children across several areas, including sleep, postural management, and activities of daily living. INTERPRETATION: This report demonstrates that targeted BoNT-A injections reduced pain in children with significant spasticity and pain at the hip level. They may also improve quality of life of non-ambulant children with CP and a hip problem.

Li J, Vestergaard M, Obel C, Precht DH, Christensen J, Lu M, Olsen J. Prenatal stress and cerebral palsy: a nationwide cohort study in Denmark. Psychosom Med. 2009 Jul;71(6):615-8.

OBJECTIVES: Exposure to prenatal stress may affect neurodevelopment of the fetus, but whether this exposure increases the risk of cerebral palsy (CP) later in life is unknown. We aimed to examine the association between maternal bereavement during the prenatal time period and CP in childhood. METHODS: We conducted a nationwide cohort study by linking information from nationwide registers. All 1,501,894 singletons born in Denmark from 1979 to 2004 were followed up from birth to the end of 2006. We identified 39,601 children whose mothers lost a close relative (child, spouse, parent, sibling) during pregnancy or up to 1 year before pregnancy and they were classified as the exposed group. The outcome of interest was the diagnosis of CP as registered in the National Hospital Register. We used Cox Regression to estimate the hazard ratios (HRs). RESULTS: Exposure to maternal bereavement after the loss of a child during the prenatal period was associated with an increased risk of CP among children born preterm without intrauterine growth retardation (HR 2.26, 95% CI, 1.09-3.79) and among children born at term with intrauterine growth retardation (HR 2.01, 95% CI, 1.04-3.89). Prenatal stress after maternal bereavement by loss of other relatives was not associated with an increased risk of CP. CONCLUSIONS: Our data suggest that extremely severe stress in prenatal life could increase the susceptibility for CP among children born preterm or with impaired fetal growth.

Di Martino A, Shehzad Z, Kelly C, Roy AK, Gee DG, Uddin LQ, Gotimer K, Klein DF, Castellanos FX, Milham MP. Relationship between cingulo-insular functional connectivity and autistic traits in neurotypical adults. Am J Psychiatry. 2009 Aug;166(8):891-9.

OBJECTIVE: The Social Responsiveness Scale-Adult Version (SRS-A) measures autistic traits that are continuously distributed in the general population. Based on increased recognition of the dimensional nature of autistic traits, the authors examined the neural correlates of these traits in neurotypical individuals using the SRS-A and established a novel approach to assessing the neural basis of autistic characteristics, attempting to directly relate SRS-A scores to patterns of functional connectivity observed in the pregenual anterior cingulate cortex, a region commonly implicated in social cognition. METHOD: Resting state functional magnetic resonance imaging scans were collected for 25 neurotypical adults. All participants provided SRS-A ratings completed by an informant who had observed them in natural social settings. Whole brain-corrected connectivity analyses were then conducted using SRS-A scores as a covariate of interest. RESULTS: Across participants, a significant negative relationship between SRS-A scores and the functional connectivity of the pregenual anterior cingulate cortex with the anterior portion of the mid-insula was found. Specifically, low levels of autistic traits were observed when a substantial portion of the anterior mid-insula showed positive connectivity with the pregenual anterior cingulate cortex. In contrast, elevated levels of autistic traits were associated with negative connectivity between these two regions. CONCLUSIONS: Resting state functional connectivity of the pregenual anterior cingulate cortex-insula social network was related to autistic traits in neurotypical adults. Application of this approach in samples with autism spectrum disorders is needed to confirm whether this circuit is dimensionally related to the severity of autistic traits in clinical populations.

Biederman J, Monuteaux MC, Spencer T, Wilens TE, Faraone SV. Do stimulants protect against psychiatric disorders in youth with ADHD? A 10-year follow-up study. Pediatrics. 2009 Jul;124(1):71-8.

OBJECTIVE: Little is known about the effect of stimulant treatment in youth with attention-deficit/hyperactivity disorder (ADHD) on the subsequent development of comorbid psychiatric disorders. We tested the association between stimulant treatment and the subsequent development of psychiatric comorbidity in a longitudinal sample of patients with ADHD. METHODS: We conducted a case-control, 10-year prospective follow-up study into young-adult years of youth with ADHD. At baseline, we assessed consecutively referred white male children with (n = 140) and without (n = 120) ADHD, aged 6 to 18 years. At the 10-year follow-up, 112 (80%) and 105 (88%) of the children in the ADHD and control groups, respectively, were reassessed (mean age: 22 years). We examined the association between stimulant treatment in childhood and adolescence and subsequent comorbid disorders and grade retention by using proportional hazards survival models. RESULTS: Of the 112 participants with ADHD, 82 (73%) were previously treated with stimulants. Participants with ADHD who were treated with stimulants were significantly less likely to subsequently develop depressive and anxiety disorders and disruptive behavior and less likely to repeat a grade compared with participants with ADHD who were not treated. CONCLUSIONS: We found evidence that stimulant treatment decreases the risk for subsequent comorbid psychiatric disorders and academic failure in youth with ADHD.