State-Dependent Differences in Functional Connectivity in Young Children With Autism Spectrum Disorder

AbstractBackgroundWhile there is increasing evidence of altered brain connectivity in autism, the degree and direction of these alterations in connectivity and their uniqueness to autism has not been established. The aim of the present study was to compare connectivity in children with autism to that of typically developing controls and children with developmental delay without autism.MethodsWe assessed EEG spectral power, coherence, phase lag, Pearson and partial correlations, and epileptiform activity during the awake, slow wave sleep, and REM sleep states in 137 children aged 2 to 6years with autism (n=87), developmental delay without autism (n=21), or typical development (n=29).FindingsWe found that brain connectivity, as measured by coherence, phase lag, and Pearson and partial correlations distinguished children with autism from both neurotypical and developmentally delayed children. In general, children with autism had increased coherence which was most prominent during slow wave sleep.InterpretationFunctional connectivity is distinctly different in children with autism compared to samples with typical development and developmental delay without autism. Differences in connectivity in autism are state and region related. In this study, children with autism were characterized by a dynamically evolving pattern of altered connectivity

The treatment of severe child aggression (TOSCA) study: Design challenges

<p>Abstract</p> <p>Background</p> <p>Polypharmacy (the concurrent use of more than one psychoactive drug) and other combination interventions are increasingly common for treatment of severe psychiatric problems only partly responsive to monotherapy. This practice and research on it raise scientific, clinical, and ethical issues such as additive side effects, interactions, threshold for adding second drug, appropriate target measures, and (for studies) timing of randomization. One challenging area for treatment is severe child aggression. Commonly-used medications, often in combination, include psychostimulants, antipsychotics, mood stabilizers, and alpha-2 agonists, which vary considerably in terms of perceived safety and efficacy.</p> <p>Results</p> <p>In designing our NIMH-funded trial of polypharmacy, we focused attention on the added benefit of a second drug (risperidone) to the effect of the first (stimulant). We selected these two drugs because their associated adverse events might neutralize each other (e.g., sleep delay and appetite decrease from stimulant versus sedation and appetite increase from antipsychotic). Moreover, there was considerable evidence of efficacy for each drug individually for the management of ADHD and child aggression. The study sample comprised children (ages 6-12 years) with both diagnosed ADHD and disruptive behavior disorder (oppositional-defiant or conduct disorder) accompanied by severe physical aggression. In a staged sequence, the medication with the least problematic adverse effects (stimulant) was openly titrated in 3 weeks to optimal effect. Participants whose behavioral symptoms were not normalized received additional double-blind medication, either risperidone or placebo, by random assignment. Thus children whose behavioral symptoms were normalized with stimulant medication were not exposed to an antipsychotic. All families participated in an empirically-supported parent training program for disruptive behavior, so that the actual comparison was stimulant+parent training versus stimulant+antipsychotic+parent training.</p> <p>Conclusions</p> <p>We hope that the resolutions of the challenges presented here will be useful to other investigators and facilitate much-needed research on child psychiatric polypharmacy.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00796302">NCT00796302</a></p

Identification of developmental and behavioral markers associated with genetic abnormalities in Autism Spectrum Disorder

ObjectiveAside from features associated with risk of neurogenetic syndromes in general (e.g., cognitive impairment), limited progress has been made in identifying phenotype-genotype relationships in autism spectrum disorder (ASD). The objective of this study was to extend work in the Simons Simplex Collection by comparing the phenotypic profiles of ASD probands with or without identified de novo loss of function mutations or copy number variants in high-confidence ASD-associated genes or loci.MethodAnalyses preemptively accounted for documented differences in sex and IQ in affected individuals with de novo mutations by matching probands with and without these genetic events on sex, IQ, and age before comparing them on multiple behavioral domains.ResultsChildren with de novo mutations (N=112) had a greater likelihood of motor delay during early development (later age at walking), but they were less impaired on certain measures of ASD core symptoms (parent-rated social communication abnormalities and clinician-rated diagnostic certainty about ASD) in later childhood. These children also showed relative strengths in verbal and language abilities, including a smaller discrepancy between nonverbal and verbal IQ and a greater likelihood of having achieved fluent language (i.e., regular use of complex sentences).ConclusionsChildren with ASD with de novo mutations may exhibit a "muted" symptom profile with respect to social communication and language deficits relative to those with ASD with no identified genetic abnormalities. Such findings suggest that examining early milestone differences and standardized testing results may be helpful in etiologic efforts, and potentially in clinical differentiation of various subtypes of ASD, but only if developmental and demographic variables are properly accounted for first

Moderators, Mediators, and Other Predictors of Risperidone Response in Children with Autistic Disorder and Irritability

Objective/Background: The National Institute of Mental Health (NIMH) Research Units on Pediatric Psychopharmacology (RUPP) Autism Network found an effect size of d = 1.2 in favor of risperidone on the main outcome measure in an 8-week double-blind, placebo-controlled trial for irritabilityin autistic disorder. This paper explores moderators and mediators of this effect. Method: Intention-to-treat (ITT) analyses were conducted with suspected moderators and mediators entered into the regression equations. MacArthur Foundation Network subgroup guidelines were followed in the evaluation of the results. Results: Only baseline severity moderated treatment response: Higher severity showed greater improvement for risperidone but not for placebo. Weight gain mediated treatment response negatively: Those who gained more weight improved less with risperidone and more with placebo. Compliance correlated with outcome for risperidone but not placebo. Higher dose correlated with worse outcome for placebo, but not risperidone. Of nonspecific predictors, parent education, family income, and low baseline prolactin positively predicted outcome; anxiety, bipolar symptoms, oppositional-defiant symptoms, stereotypy, and hyperactivity negatively predicted outcome. Risperidone moderated the effect of change in 5'-nucleotidase, a marker of zinc status, for which decrease was associated with improvement only with risperidone, not with placebo. Conclusion: The benefit–risk ratio of risperidone is better with greater symptom severity. Risperidone can be individually titrated to optimal dosage for excellent response in the majority of children. Weight gain is not necessary for risperidone benefit and may even detract from it. Socioeconomic advantage, low prolactin, and absence of co-morbid problems non-specifically predict better outcome. Mineral interactions with risperidone deserve further study

Observable Symptoms of Anxiety in Individuals with Fragile X Syndrome: Parent and Caregiver Perspectives

Caregiver reports, clinical observations, and diagnostic assessments indicate that most individuals with fragile X syndrome experience high levels of chronic anxiety. However, anxiety is a challenging endpoint for outcome measurement in FXS because most individuals cannot reliably report internal emotional or body states. A comprehensive survey of the presence, frequency, and duration of anxiety-related symptoms and questions to elicit open-ended responses was completed by caregivers of 456 individuals with FXS, ages 2–81 years (87 female, 369 male) and 24 female and 2 male FXS self-advocates ages 15–66 years. Caregivers reported classic behavioral indicators of anxiety, such as avoidance, irritability, motor agitation, and physiological symptoms, as well as behavioral features in FXS such as repetitive behavior, aggression, and self-injury. Self-advocate accounts largely paralleled caregiver data. Factor analyses yielded four factors: (1) increased irritability, aggression, and self-injury; (2) increased physical movement, nervous activity, and restlessness; (3) physical and physiological features of anxiety; and (4) internalizing and gastrointestinal symptoms. Caregivers are capable of observing and reporting behaviors that are valid indicators of anxious states that are usually reported in self-report standardized assessments. These results support the development of an anxiety measure for FXS that minimizes problems with rater inference

Functional brain connectivity in electrical status epilepticus in sleep

Electrical status epilepticus in sleep (ESES) is an age-related, self-limited epileptic encephalopathy. The syndrome is characterized by cognitive and behavioral abnormalities and a specific EEG pattern of continuous spikes and waves during slow-wave sleep. While spikes and sharp waves are known to result in transient cognitive impairment during learning and memory tasks performed during the waking state, the effect of epileptiform discharges during sleep on cognition and behavior is unclear. There is increasing evidence that abnormalities of coherence, a measure of the consistency of the phase difference between two EEG signals when compared over time, is an important feature of brain oscillations and plays a role in cognition and behavior. The objective of this study was to determine whether coherence of EEG activity is altered during slow-wave sleep in children with ESES when compared to typically developing children. We examined coherence during epochs of ESES versus epochs when ESES was not present. In addition, we compared coherence during slow-wave sleep between typically developing children and children with ESES. ESES was associated with remarkably high coherences at all bandwidths and most electrode pairs. While the high coherence was largely attributed to the spikes and spike-and-wave discharge, activity between spikes and spike-and-wave discharge also demonstrated high coherence. This study indicates that EEG coherence during ESES is relatively high. Whether these increases in coherence correlate with the cognitive and behavioral abnormalities seen in children with this EEG pattern remains to be determined