Qualitative Exploration Toward the Development of a Parent-Rated Scale for Insomnia in Children with Autism Spectrum Disorder.

Toward the development of a new parent-rating for insomnia, this multi-site qualitative study explored sleep problems and related impacts in children with autism spectrum disorder (ASD) and their families. To ensure content validity of the measure, we conducted six focus groups with caregivers (N = 25) of 24 children (age 3 to 18 years) with ASD. Based on parent report, all children had a history of mild or greater insomnia. The focus group transcripts were systematically coded to identify major themes. Verbatim comments from caretakers were used to generate 134 candidate items. Further review by the research team and an expert panel followed by individual cognitive interviews with 12 parents reduced the item bank to 40. The thematic analysis of focus group transcripts identified 7 categories: (1) Trouble falling asleep; (2) trouble staying asleep; (3) early morning waking; (4) bedtime routines; (5) parental strategies for bedtime management; (6) impact of sleep problems on the child; and (7) impact of sleep problems on the family. The Flesch Kincaid Grade Level of the 40-item version was 7.2 (seventh grade reading level). Insomnia in children with ASD shares features in common with insomnia in the general pediatric population. However, perhaps owing to autistic features such as insistence on sameness, sensory sensitivities, communication impairments, insomnia in children with ASD appears to have unique behavioral manifestations. Content validity and item clarity of the 40-item bank were supported by expert panel review and cognitive interviews with caregivers of children with ASD.

Feasibility of Actigraphy for Evaluating Sleep and Daytime Physical Activity in Children with Autism Spectrum Disorder.

This research evaluated the feasibility of actigraphy to measure sleep and physical activity in children (ages 2-8 years) with autism spectrum disorder (ASD). We also explored associations between sleep and physical activity. Validated screening measures established eligibility. Questionnaires, diaries, and 5 days and 5 nights of actigraphy monitoring were used to collect data. Of the 32 children enrolled, 27 (84.4%) completed actigraphy monitoring. Based on the median steps per day, children with high physical activity had lower total sleep time and more disruptive behaviors than children with low physical activity. Findings support the feasibility of using actigraphy to measure sleep and physical activity in children with ASD. Larger studies are needed to evaluate interactions of physical activity on sleep in this population.

Successful pharmacotherapy for the treatment of severe feeding aversion with mechanistic insights from cross-species neuronal remodeling.

Pediatric feeding disorders affect up to 5% of children, causing severe food intake problems that can result in serious medical and developmental outcomes. Behavioral intervention (BI) is effective in extinguishing feeding aversions, and also expert-dependent, time/labor-intensive and not well understood at a neurobiological level. Here we first conducted a double-blind, placebo-controlled trial comparing BI with BI plus d-cycloserine (DCS). DCS is a partial N-methyl-d-aspartate (NMDA) receptor agonist shown to augment extinction therapies in multiple anxiety disorders. We examined whether DCS enhanced extinction of feeding aversion in 15 children with avoidant/restrictive food intake disorder (ages 20-58 months). After five treatment days, BI improved feeding by 37%. By contrast, BI+DCS improved feeding by 76%. To gain insight into possible mechanisms of successful intervention, we next tested the neurobiological consequences of DCS in a murine model of feeding aversion and avoidance. In mice with conditioned food aversion, DCS enhanced avoidance extinction across a broad dose range. Confocal fluorescence microscopy and three-dimensional neuronal reconstruction indicated that DCS enlarged dendritic spine heads-the primary sites of excitatory plasticity in the brain-within the orbitofrontal prefrontal cortex, a sensory-cognition integration hub. DCS also increased phosphorylation of the plasticity-associated extracellular signal-regulated kinase 1/2. In summary, DCS successfully augments the extinction of food aversion in children and mice, an effect that may involve plasticity in the orbitofrontal cortex. These results warrant a larger-scale efficacy study of DCS for the treatment of pediatric feeding disorders and further investigations of neural mechanisms.

Positive effects of methylphenidate on hyperactivity are moderated by monoaminergic gene variants in children with autism spectrum disorders.

Methylphenidate (MPH) reduces hyperactive-impulsive symptoms common in children with autism spectrum disorders (ASDs), however, response and tolerability varies widely. We hypothesized monoaminergic gene variants may moderate MPH effects in ASD, as in typically developing children with attention-deficit/hyperactivity disorder. Genotype data were available for 64 children with ASD and hyperactivity who were exposed to MPH during a 1-week safety/tolerability lead-in phase and 58 who went on to be randomized to placebo and three doses of MPH during a 4-week blinded, crossover study. Outcome measures included the Clinical Global Impression-Improvement (CGI-I) scale and the Aberrant Behavior Checklist (ABC-hyperactivity index). A total of 14 subjects discontinued the study because of MPH side effects. Subjects were genotyped for variants in DRD1-DRD5, ADRA2A, SLC6A3, SLC6A4, MAOA and MAOB, and COMT. Forty-nine percent of the sample met positive responder criteria. In this modest but relatively homogeneous sample, significant differences by DRD1 (P=0.006), ADRA2A (P<0.02), COMT (P<0.04), DRD3 (P<0.05), DRD4 (P<0.05), SLC6A3 (P<0.05) and SLC6A4 (P<0.05) genotypes were found for responders versus non-responders. Variants in DRD2 (P<0.001) and DRD3 (P<0.04) were associated with tolerability in the 14 subjects who discontinued the trial. For this first MPH pharmacogenetic study in children with ASD, multiple monoaminergic gene variants may help explain individual differences in MPH's efficacy and tolerability.

Moderation of antipsychotic-induced weight gain by energy balance gene variants in the RUPP autism network risperidone studies.

Second-generation antipsychotic exposure, in both children and adults, carries significant risk for excessive weight gain that varies widely across individuals. We queried common variation in key energy balance genes (FTO, MC4R, LEP, CNR1, FAAH) for their association with weight gain during the initial 8 weeks in the two NIMH Research Units on Pediatric Psychopharmacology Autism Network trials (N=225) of risperidone for treatment of irritability in children/adolescents aged 4-17 years with autism spectrum disorders. Variants in the cannabinoid receptor (CNR)-1 promoter (P=1.0 × 10(-6)), CNR1 (P=9.6 × 10(-5)) and the leptin (LEP) promoter (P=1.4 × 10(-4)) conferred robust-independent risks for weight gain. A model combining these three variants was highly significant (P=1.3 × 10(-9)) with a 0.85 effect size between lowest and highest risk groups. All results survived correction for multiple testing and were not dependent on dose, plasma level or ethnicity. We found no evidence for association with a reported functional variant in the endocannabinoid metabolic enzyme, fatty acid amide hydrolase, whereas body mass index-associated single-nucleotide polymorphisms in FTO and MC4R showed only trend associations. These data suggest a substantial genetic contribution of common variants in energy balance regulatory genes to individual antipsychotic-associated weight gain in children and adolescents, which supersedes findings from prior adult studies. The effects are robust enough to be detected after only 8 weeks and are more prominent in this largely treatment naive population. This study highlights compelling directions for further exploration of the pharmacogenetic basis of this concerning multifactorial adverse event.

The Home Situations Questionnaire-PDD version: factor structure and psychometric properties.

BACKGROUND: The Home Situations Questionnaire (HSQ) is a caregiver-rated scale designed to assess behavioural non-compliance in everyday settings that has been used in several studies in typically developing children. Currently there is no accepted measure of behavioural non-compliance in children with pervasive developmental disorders (PDDs). METHODS: Investigators of the Research Units on Pediatric Psychopharmacology Autism Network modified the HSQ for children with PDDs by adding five items (making 25 total items), and used it as the primary outcome measure in a clinical trial. In the current investigation, we examined the factor structure and psychometric properties of the modified scale, the HSQ-PDD. RESULTS: An exploratory factor analysis with oblique rotations yielded two factors: 'Socially Inflexible' (14 items) and 'Demand-Specific' (six items). Item content of both factors appeared to fit well with the rubric of PDDs. Internal consistency, using Cronbach's alpha statistic, was 0.90 for 'Socially Inflexible', and 0.80 for 'Demand-Specific.' The obtained sub-scales and HSQ-PDD Total score showed moderate correlations with selected sub-scales of the Aberrant Behavior Checklist, Child and Adolescent Symptom Inventory, and Children's Yale-Brown Obsessive Compulsive Scale, and low correlations with the Vineland Adaptive Behavior sub-scales. CONCLUSIONS: The HSQ-PDD appears to be well suited for children with PDDs, although the Demand-Specific sub-scale may benefit from addition of more items. We provided sub-scale means and standard deviations for this relatively severe group of children with PDDs, and discussed the factor structure with respect to previous research.

The Dimensional Yale-Brown Obsessive-Compulsive Scale (DY-BOCS): an instrument for assessing obsessive-compulsive symptom dimensions.

Obsessive-compulsive disorder (OCD) encompasses a broad range of symptoms representing multiple domains. This complex phenotype can be summarized using a few consistent and temporally stable symptom dimensions. The objective of this study was to assess the psychometric properties of the Dimensional Yale-Brown Obsessive-Compulsive Scale (DY-BOCS). This scale measures the presence and severity of obsessive-compulsive (OC) symptoms within six distinct dimensions that combine thematically related obsessions and compulsions. The DY-BOCS includes portions to be used as a self-report instrument and portions to be used by expert raters, including global ratings of OC symptom severity and overall impairment. We assessed 137 patients with a Diagnostic and Statistical Manual-IV diagnosis of OCD, aged 6-69 years, from sites in the USA, Canada and Brazil. Estimates of the reliability and validity of both the expert and self-report versions of the DY-BOCS were calculated and stratified according to age (pediatric vs. adult subjects). The internal consistency of each of the six symptom dimensions and the global severity score were excellent. The inter-rater agreement was also excellent for all component scores. Self-report and expert ratings were highly intercorrelated. The global DY-BOCS score was highly correlated with the total Yale-Brown Obsessive-Compulsive Scale score (Pearson r = 0.82, P<0.0001). Severity scores for individual symptom dimensions were largely independent of one another, only modestly correlated with the global ratings, and were also differentially related to ratings of depression, anxiety and tic severity. No major differences were observed when the results were stratified by age. These results indicate that the DY-BOCS is a reliable and valid instrument for assessing multiple aspects of OCD symptom severity in natural history, neuroimaging, treatment response and genetic studies when administered by expert clinicians or their highly trained staff.

A placebo-controlled trial of risperidone in Tourette syndrome.

OBJECTIVE: To evaluate the efficacy and safety of risperidone in children and adults with Tourette syndrome. METHODS: This was an 8-week, randomized, double-blind, placebo-controlled trial. The primary outcome measure was the Total Tic score of the Yale Global Tic Severity Scale (YGTSS). RESULTS: Thirty-four medication-free subjects (26 children and 8 adults) ranging in age from 6 to 62 years (mean = 19.7 +/- 17.0 years) participated. YGTSS Total Tic scores were similar at baseline (26.0 +/- 5.1 for risperidone vs 27.4 +/- 8.5 for placebo). After 8 weeks of treatment (mean daily dose of 2.5 +/- 0.85), the 16 subjects on risperidone showed a 32% reduction in tic severity from baseline, compared to a 7% reduction for placebo patients (n = 18) (F[2,64] = 6.07; p = 0.004). The 12 children randomized to risperidone showed a 36% reduction in tic symptoms compared to an 11% decrease in the 14 children on placebo (F[2,48] = 6.38; p = 0.004). Two children on risperidone showed acute social phobia, which resolved with dose reduction in one subject but resulted in medication discontinuation in the other. A mean increase in body weight of 2.8 kg was observed in the risperidone group compared to no change in placebo (F[2,64] = 10.68; p = 0.0001). No extrapyramidal symptoms and no clinically significant alterations in cardiac conduction times or laboratory measures were observed. CONCLUSION: Risperidone appears to be safe and effective for short-term treatment of tics in children or adults with Tourette syndrome. Longer-term studies are needed to evaluate the durability of efficacy and safety over time.

Antibodies against neural, nuclear, cytoskeletal, and streptococcal epitopes in children and adults with Tourette's syndrome, Sydenham's chorea, and autoimmune disorders.

BACKGROUND: Some cases of Tourette's syndrome (TS) are hypothesized to be caused by autoantibodies that develop in response to a preceding group A beta hemolytic streptococcal infection. METHODS: To test this hypothesis, we looked for the presence ot total and IgG antibodies against neural, nuclear, cytoskeletal and streptococcal epitopes using indirect immunofluorescent assays and Western blot techniques in three patient groups: TS (n = 81), SC (n = 27), and a group of autoimmune disorders (n = 52) and in normal controls (n = 67). Subjects were ranked after titrations of autoantibodies from 0 to 227 according to their level of immunoreactivity. RESULTS: TS patients had a significantly higher mean rank for total antineural and antinuclear antibodies, as well as antistreptolysin O titers. However, among children and adolescents, only the total antinuclear antibodies were increased in TS patients compared to age matched controls. Compared to SC patients, TS patients had a significantly lower mean rank for total and IgG class antineural antibodies, significantly lower IgG class anticytoskeletal antibodies, and a significantly higher rank for total antinuclear antibodies. Compared to a mixed group of autoimmune disorders, the TS patients had a significantly lower mean rank for total and IgG class antineural antibodies, total and IgG class antinuclear antibodies, IgG class anticytoskeletal antibodies, and a significantly higher rank for antistreptococcal antibodies. CONCLUSIONS: TS patients had significantly higher levels of total antineural and antinuclear antibodies than did controls. Their relation to IgG class antineural and antinuclear antibodies, markers for prior streptococcal infection, and other clinical characteristics, especially chronological age, was equivocal.

A placebo-controlled study of guanfacine in the treatment of children with tic disorders and attention deficit hyperactivity disorder.

OBJECTIVE: This study evaluated the efficacy and safety of guanfacine in treating children with tic disorders and attention deficit hyperactivity disorder (ADHD). METHOD: Subjects from a specialty tic disorders clinic were randomly assigned to receive 8 weeks of treatment with guanfacine or placebo under double-blind conditions. Follow-up visits occurred every 2 weeks for safety monitoring and dose adjustment. RESULTS: Thirty-four medication-free subjects (31 boys and three girls with a mean age of 10.4 years) with ADHD, combined type, and a tic disorder participated. After 8 weeks of treatment, guanfacine was associated with a mean improvement of 37% in the total score on the teacher-rated ADHD Rating Scale, compared to 8% improvement for placebo. Nine of 17 subjects who received guanfacine were blindly rated on the Clinical Global Improvement scale as either much improved or very much improved, compared with none of 17 subjects who received placebo. The mean score on the parent-rated hyperactivity index improved by 27% in the guanfacine group and 21% in the placebo group, not a significant difference. On the Continuous Performance Test, commission errors decreased by 22% and omission errors by 17% in the guanfacine group, compared with increases of 29% in commission errors and of 31% in omission errors in the placebo group. Tic severity decreased by 31% in the guanfacine group, compared to 0% in the placebo group. One guanfacine subject with sedation withdrew at week 4. Guanfacine was associated with insignificant decreases in blood pressure and pulse. CONCLUSIONS: Guanfacine appears to be a safe and effective treatment for children with tic disorders and ADHD.

Regional brain and ventricular volumes in Tourette syndrome.

BACKGROUND: The pathophysiology of Tourette syndrome (TS) is thought to involve disturbances in cortico-striato-thalamo-cortical circuitry. The morphological characteristics of the cortical and associated white matter portions of these circuits have not been previously examined in TS subjects. METHODS: High-resolution anatomical magnetic resonance images were acquired in 155 TS and 131 healthy children and adults. The cerebrums and ventricles were isolated and then parcellated into subregions using standard anatomical landmarks. RESULTS: For analyses that included both children and adults, TS subjects were found to have larger volumes in dorsal prefrontal regions, larger volumes in parieto-occipital regions, and smaller inferior occipital volumes. Significant inverse associations of cerebral volumes with age were seen in TS subjects that were not seen in healthy controls. Sex differences in the parieto-occipital regions of healthy subjects were diminished in the TS group. The age-related findings were most prominent in TS children, whereas the diminished sex differences were most prominent in TS adults. Group differences in regional ventricular volumes were less prominent than in the cerebrum. Regional cerebral volumes were significantly associated with the severity of tic symptoms in orbitofrontal, midtemporal, and parieto-occipital regions. CONCLUSIONS: Broadly distributed cortical systems are involved in the pathophysiology of TS. Developmental processes, sexual dimorphisms, and compensatory responses in these cortical regions may help to modulate the course and severity of tic symptoms.

Thermal sensitivity in Tourette syndrome: preliminary report.

The effects of heat on tic symptoms were studied in a sample of 78 adults with Tourette syndrome. 62 men and 16 women completed a survey concerning the type, onset, and course of their tics. 10 adult male subjects also participated in a thermal challenge during which ambient temperature was raised from 22 degrees C to 35 degrees C following a control period. Of the 78, 24% or 19 reported increased tics upon exposure to heat. Compared to the remaining 59 subjects, there were no differences in sex distribution, current age, or overall course of illness. In the thermal challenge, there was general increase in tics that was correlated with sweat rate (r = .55, p = .001). This effect was prominent in 5 of 10 subjects (rs = .29 to .63). There were no mean differences in current age, age of onset, or current severity of symptoms between the five subjects of each group. Tic symptoms in a subgroup of patients with Tourette syndrome may be sensitive to heat. Abnormal heat regulation is not a likely explanation for the observed increase in tics. The increase may be due to normal heat-loss mechanisms through dopaminergic pathways.

Methodological issues in designing a multisite trial of risperidone in children and adolescents with autism.

OBJECTIVE: To describe the methodological challenges and decisions made in developing a multisite, controlled study of risperidone in children and adolescents with autism. METHODS: Review the design considerations for clinical trials in children with autistic disorder accompanied by severe tantrums, aggressive and/or self-injurious behaviors. These design considerations include the definition of inclusion criteria that are relevant to clinical practice and matching study design to the goal of evaluating short- and long-term effects. Additional ethical and scientific issues concern the length of trial and sample size. RESULTS: We undertook a short-term, placebo-controlled study to evaluate the efficacy and safety of risperidone in children and adolescents with autistic disorder. This trial design was followed by an extended open-label maintenance on risperidone to confirm durability of treatment effects and to monitor safety. Finally, a placebo-controlled discontinuation study tested the need for continuous treatment. CONCLUSIONS: In the absence of standard pharmacological treatment for children with autistic disorder, a placebo-controlled study remains the most appropriate method of testing efficacy and safety. The clinical relevance of this study is enhanced by the addition of an extended maintenance phase followed by a placebo discontinuation.

Assessment of children with pervasive developmental disorders.

TOPIC: Pervasive developmental disorders, a group of conditions marked by impaired social reciprocity, communication deficits, and restricted, repetitive behaviors. PURPOSE: Advanced practice nurses (APNs) are in a unique position to assess these children, make appropriate diagnoses, and refer parents for further consultation and intervention. SOURCES: Current literature, formal training on diagnostic instruments, and clinical experience. CONCLUSIONS: Diagnosis of pervasive developmental disorders requires knowledge of normal growth and development and other childhood psychiatric disorders. The role of the APN includes counseling parents regarding their child's legal right to intervention and guiding parents to make empirically based choices for intervention.