Developmental sequelae and neurophysiologic substrates of sensory seeking in infant siblings of children with autism spectrum disorder.

It has been proposed that early differences in sensory responsiveness arise from atypical neural function and produce cascading effects on development across domains. This longitudinal study prospectively followed infants at heightened risk for autism spectrum disorder (ASD) based on their status as younger siblings of children diagnosed with ASD (Sibs-ASD) and infants at relatively lower risk for ASD (siblings of typically developing children; Sibs-TD) to examine the developmental sequelae and possible neurophysiological substrates of a specific sensory response pattern: unusually intense interest in nonsocial sensory stimuli or "sensory seeking." At 18 months, sensory seeking and social orienting were measured with the Sensory Processing Assessment, and a potential neural signature for sensory seeking (i.e., frontal alpha asymmetry) was measured via resting state electroencephalography. At 36 months, infants' social symptomatology was assessed in a comprehensive diagnostic evaluation. Sibs-ASD showed elevated sensory seeking relative to Sibs-TD, and increased sensory seeking was concurrently associated with reduced social orienting across groups and resting frontal asymmetry in Sibs-ASD. Sensory seeking also predicted later social symptomatology. Findings suggest that sensory seeking may produce cascading effects on social development in infants at risk for ASD and that atypical frontal asymmetry may underlie this atypical pattern of sensory responsiveness.

A Randomized, Placebo-Controlled Trial of Metformin for the Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorder: Open-Label Extension.

OBJECTIVE: A previous study reported on a 16-week placebo-controlled, randomized clinical trial (RCT) of metformin for weight stabilization in 61 children and adolescents 6 to 17 years old with autism spectrum disorder who were prescribed atypical antipsychotics. The present study describes the results of a 16-week open-label extension. METHOD: Fifty-two participants from the acute trial (85%) entered the extension; 22 had been on metformin during the initial RCT and 30 had been on placebo. Participants were re-titrated to 500 mg twice a day (6- to 9-year-olds) or 850 mg twice a day (10- to 17-year-olds) during the open-label extension. Primary outcome measure was change in body mass index (BMI) z-score after 16 weeks; secondary outcomes were change in additional body composition and metabolic parameters. RESULTS: After 16 weeks of open-label treatment, participants initially taking placebo during the RCT had lower BMI z-scores (mean 16-week change -0.10, p = .004). Statistically significant improvements also were noted in secondary body composition measures (weight z-score and BMI and weight percentile) but not in metabolic variables. Participants who initially had been taking metformin during the 16-week RCT maintained prior decreases in BMI z-scores but did not have additional weight loss. Three participants discontinued treatment because of an adverse event. No significant changes were noted on metabolic measures, although the decrease in hemoglobin A1c was large (∼1 mmol) and consistent across the acute and open-label phases. CONCLUSION: Metformin can be effective for decreasing weight gain associated with atypical antipsychotic use and maintaining prior improvement in children and adolescents with autism spectrum disorder. Clinical trial registration information-Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD); http://clinicaltrials.gov/; NCT01825798.

Metformin for Treatment of Overweight Induced by Atypical Antipsychotic Medication in Young People With Autism Spectrum Disorder: A Randomized Clinical Trial.

IMPORTANCE: Atypical antipsychotic medications are indicated for the treatment of irritability and agitation symptoms in children with autism spectrum disorder (ASD). Unfortunately, these medications are associated with weight gain and metabolic complications that are especially troubling in children and with long-term use. OBJECTIVE: To evaluate the efficacy of metformin for weight gain associated with atypical antipsychotic medications in children and adolescents with ASD (defined in the protocol as DSM-IV diagnosis of autistic disorder, Asperger disorder, or pervasive developmental disorder not otherwise specified), aged 6 to 17 years. DESIGN, SETTING, AND PARTICIPANTS: A 16-week, double-blind, placebo-controlled, randomized clinical trial was conducted at 4 centers in Toronto, Ontario, Canada; Columbus, Ohio; Pittsburgh, Pennsylvania; and Nashville, Tennessee. In all, 209 potential participants were screened by telephone, 69 individuals provided consent, and 61 participants were randomized to receive metformin or placebo between April 26, 2013, and June 24, 2015. INTERVENTIONS: Metformin or matching placebo titrated up to 500 mg twice daily for children aged 6 to 9 years and 850 mg twice daily for those 10 to 17 years. MAIN OUTCOMES AND MEASURES: The primary outcome measure was change in body mass index (BMI) z score during 16 weeks of treatment. Secondary outcomes included changes in additional body composition and metabolic variables. Safety, tolerability, and efficacy analyses all used a modified intent-to-treat sample comprising all participants who received at least 1 dose of medication. RESULTS: Of the 61 randomized participants, 60 participants initiated treatment (45 [75%] male; mean [SD] age, 12.8 [2.7] years). Metformin reduced BMI z scores from baseline to week 16 significantly more than placebo (difference in 16-week change scores vs placebo, -0.10 [95% CI, -0.16 to -0.04]; P = .003). Statistically significant improvements were also noted in secondary body composition measures (raw BMI, -0.95 [95% CI, -1.46 to -0.45] and raw weight, -2.73 [95% CI, -4.04 to -1.43]) but not in metabolic variables. Overall, metformin was well tolerated. Five participants in the metformin group discontinued treatment owing to adverse events (agitation, 4; sedation, 1). Participants receiving metformin vs placebo experienced gastrointestinal adverse events during a significantly higher percentage of treatment days (25.1% vs 6.8%; P = .005). CONCLUSIONS AND RELEVANCE: Metformin may be effective in decreasing weight gain associated with atypical antipsychotic use and is well tolerated by children and adolescents with ASD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01825798.

Early Predictors of Growth in Diversity of Key Consonants Used in Communication in Initially Preverbal Children with Autism Spectrum Disorder.

Diversity of key consonants used in communication (DKCC) is a value-added predictor of expressive language growth in initially preverbal children with autism spectrum disorder (ASD). Studying the predictors of DKCC growth in young children with ASD might inform treatment of this under-studied aspect of prelinguistic development. Eighty-seven initially preverbal preschoolers with ASD and their parents were observed at five measurement periods. In this longitudinal correlational investigation, we found that child intentional communication acts and parent linguistic responses to child leads predicted DKCC growth, after controlling for two other predictors and two background variables. As predicted, receptive vocabulary mediated the association between the value-added predictors and endpoint DKCC.

White matter correlates of sensory processing in autism spectrum disorders.

Autism spectrum disorder (ASD) has been characterized by atypical socio-communicative behavior, sensorimotor impairment and abnormal neurodevelopmental trajectories. DTI has been used to determine the presence and nature of abnormality in white matter integrity that may contribute to the behavioral phenomena that characterize ASD. Although atypical patterns of sensory responding in ASD are well documented in the behavioral literature, much less is known about the neural networks associated with aberrant sensory processing. To address the roles of basic sensory, sensory association and early attentional processes in sensory responsiveness in ASD, our investigation focused on five white matter fiber tracts known to be involved in these various stages of sensory processing: superior corona radiata, centrum semiovale, inferior longitudinal fasciculus, posterior limb of the internal capsule, and splenium. We acquired high angular resolution diffusion images from 32 children with ASD and 26 typically developing children between the ages of 5 and 8. We also administered sensory assessments to examine brain-behavior relationships between white matter integrity and sensory variables. Our findings suggest a modulatory role of the inferior longitudinal fasciculus and splenium in atypical sensorimotor and early attention processes in ASD. Increased tactile defensiveness was found to be related to reduced fractional anisotropy in the inferior longitudinal fasciculus, which may reflect an aberrant connection between limbic structures in the temporal lobe and the inferior parietal cortex. Our findings also corroborate the modulatory role of the splenium in attentional orienting, but suggest the possibility of a more diffuse or separable network for social orienting in ASD. Future investigation should consider the use of whole brain analyses for a more robust assessment of white matter microstructure.

Affective neural response to restricted interests in autism spectrum disorders.

BACKGROUND: Restricted interests are a class of repetitive behavior in autism spectrum disorders (ASD) whose intensity and narrow focus often contribute to significant interference with daily functioning. While numerous neuroimaging studies have investigated executive circuits as putative neural substrates of repetitive behavior, recent work implicates affective neural circuits in restricted interests. We sought to explore the role of affective neural circuits and determine how restricted interests are distinguished from hobbies or interests in typical development. METHODS: We compared a group of children with ASD to a typically developing (TD) group of children with strong interests or hobbies, employing parent report, an operant behavioral task, and functional imaging with personalized stimuli based on individual interests. RESULTS: While performance on the operant task was similar between the two groups, parent report of intensity and interference of interests was significantly higher in the ASD group. Both the ASD and TD groups showed increased BOLD response in widespread affective neural regions to the pictures of their own interest. When viewing pictures of other children's interests, the TD group showed a similar pattern, whereas BOLD response in the ASD group was much more limited. Increased BOLD response in the insula and anterior cingulate cortex distinguished the ASD from the TD group, and parent report of the intensity and interference with daily life of the child's restricted interest predicted insula response. CONCLUSIONS: While affective neural network response and operant behavior are comparable in typical and restricted interests, the narrowness of focus that clinically distinguishes restricted interests in ASD is reflected in more interference in daily life and aberrantly enhanced insula and anterior cingulate response to individuals' own interests in the ASD group. These results further support the involvement of affective neural networks in repetitive behaviors in ASD.

Response of neural reward regions to food cues in autism spectrum disorders.

BACKGROUND: One hypothesis for the social deficits that characterize autism spectrum disorders (ASD) is diminished neural reward response to social interaction and attachment. Prior research using established monetary reward paradigms as a test of non-social reward to compare with social reward may involve confounds in the ability of individuals with ASD to utilize symbolic representation of money and the abstraction required to interpret monetary gains. Thus, a useful addition to our understanding of neural reward circuitry in ASD includes a characterization of the neural response to primary rewards. METHOD: We asked 17 children with ASD and 18 children without ASD to abstain from eating for at least four hours before an MRI scan in which they viewed images of high-calorie foods. We assessed the neural reward network for increases in the blood oxygenation level dependent (BOLD) signal in response to the food images RESULTS: We found very similar patterns of increased BOLD signal to these images in the two groups; both groups showed increased BOLD signal in the bilateral amygdala, as well as in the nucleus accumbens, orbitofrontal cortex, and insula. Direct group comparisons revealed that the ASD group showed a stronger response to food cues in bilateral insula along the anterior-posterior gradient and in the anterior cingulate cortex than the control group, whereas there were no neural reward regions that showed higher activation for controls than for ASD. CONCLUSION: These results suggest that neural response to primary rewards is not diminished but in fact shows an aberrant enhancement in children with ASD.

Neurocognitive and behavioral outcomes of younger siblings of children with autism spectrum disorder at age five.

Later-born siblings of children with Autism Spectrum Disorders (ASD) are at increased risk for ASD as well as qualitatively similar traits not meeting clinical cutoffs for the disorder. This study examined age five neurocognitive and behavioral outcomes of 39 younger siblings of children with ASD (Sibs-ASD) and 22 younger siblings of typically developing children (Sibs-TD) previously assessed in a longitudinal investigation starting in the second year of life. There were few group differences between Sibs-TD and Sibs-ASD on global measures of IQ, language, or behavior problems. Sibs-ASD did show vulnerabilities on measures of executive functioning, social cognition, and repetitive behaviors. These results highlight the importance of following sibling risk groups over an extended time period and employing measures targeting broader aspects of development.