Government initiatives in autism clinical trials

Randomized clinical trials remain the most valid method of testing the efficacy and safety of treatments. While efforts to elucidate the genetic and neurodevelopmental bases of autism are underway, clinicians and families are in need of scientifically valid information on how to best treat patients with autism. The effectiveness of many interventions currently used in communities has not been adequately tested. Given the high public health relevance of autism treatment research and the low interest of the pharmaceutical industry in autism, the role of the National Institutes of Health in supporting this research is paramount. Among recently launched initiatives in autism clinical trials, there are the Research Units on Pediatric Psychopharmacology Autism Network and the network of centers for Studies to Advance Autism Research and Treatment. These and other government activities in the area of autism clinical trials are here briefly reviewed.     

Outcome measures for clinical drug trials in autism

This paper identifies instruments and measures that may be appropriate for randomized clinical trials in participants with autism spectrum disorders (ASDs). The Clinical Global Impressions scale was recommended for all randomized clinical trials. At this point, however, there is no "perfect" choice of outcome measure for core features of autism, although we will discuss five measures of potential utility. Several communication instruments are recommended, based in part on suitability across the age range. In trials where the intention is to alter core features of ASDs, adaptive behavior scales are also worthy of consideration. Several "behavior complexes" common to ASDs are identified, and instruments are recommended for assessment of these. Given the prevalence of cognitive impairment in ASDs, it is important to assess any cognitive effects, although cognitive data from ASD randomized clinical trials, thus far, are minimal. Guidance from trials in related pharmacologic areas and behavioral pharmacology may be helpful. We recommend routine elicitation of side effects, height and weight, vital signs, and (in the case of antipsychotics) extrapyramidal side-effects assessment. It is often appropriate to include laboratory tests and assessments for continence and sleep pattern.     

Impact of recent findings on study design of future autism clinical trials

There are specific challenges to studying the design of pharmacologic trials in child/adolescent and adult autism, such as subject stratification and parallel versus crossover designs. This article describes how optimal study design is influenced by subject selection and outcome measures chosen. Lessons learned in study design from the Research Units on Pediatric Psychopharmacology Autism Network trial with risperidone, Seaver Center trials with fluoxetine and valproate, Dartmouth trials with amantadine, and National Institutes of Health secretin trials are highlighted. The Internet System for Assessing Autistic Children system for managing multicenter clinical trials in autism and statistical issues in autism research are also described.     

Expressive drawing ability in children with autism

The autistic impairments in emotional and social competence, imagination and generating ideas predict qualitative differences in expressive drawings by children with autism beyond that accounted by any general learning difficulties. In a sample of 60 5–19‐year‐olds, happy and sad drawings were requested from 15 participants with non‐savant autism and compared with those drawn by three control groups matched on either degree of learning difficulty (MLD), mental age (MA) or chronological age (CA). All drawings were rated by two artists on a 7‐point quality of expression scale. Contrary to our predictions, the drawings from the autistic group were rated similar to those of the MA and MLD groups. Analysis of the people and social content of the drawings revealed that although children with autism did not draw fewer people, they did draw more immature forms than mental age controls. Furthermore, there was tentative evidence that fewer social scenes were produced by the autism sample. We conclude that the overall merit of expressive drawing in autism is commensurate with their general learning difficulties, but the social/emotional impairment in autism affects their drawings of people and social scenes.     

Increasing response diversity in children with autism

Repetitive and invariant behavior is a diagnostic feature of autism. We implemented a lag reinforcement schedule to increase response diversity for 6 participants with autism aged 6 to 10 years, 4 of whom also received prompting plus additional training. These procedures appeared to increase the variety of building-block structures, demonstrating that an intervention that includes differential reinforcement can increase response diversity for children with an autism spectrum disorder.     

Attention and joint attention in preschool children with autism

Three experiments examined the role of attention in explaining dyadic (child-adult) and triadic (child-adult-object) joint attention difficulties in autism. Experiments 1 and 2 investigated children's ability to orient to an adult's attention bid and to follow the direction of a human or nonhuman cue. Experiment 3 tested ability to disengage and shift attention to objects. Results showed autism-specific difficulties at both dyadic and triadic levels. Children with autism were less responsive than developmentally delayed controls in orienting to attention bids and in following a human head-turn cue yet had no difficulty in shifting attention and were faster overall in orienting to targets. Results suggest a specific developmental delay in which children with autism rely on the presence of objects in the visual field to guide action. The relation between this problem and autistic children's difficulties with human communicative signals is discussed.     

Educational advocacy for children with autism

There exists a great divide between parents' demands for intensive behavioral interventions for their children with autism and the public education system's reluctance to support early intensive behavioral intervention programs. More and more, professionals with expertise in applied behavior analysis are being asked to advocate for effective, early behavioral intervention for autism in education litigation brought about by frustrated parents. The progress made in recent years in the behavioral treatment of children with autism and the schools' lack of adherence to the requirements of IDEA have made it possible for educational policy change through effective advocacy by behavioral interventionists. This paper discusses preparing for educational advocacy on behalf of young children with autism. We explore the personal and emotional reasons why parents choose to engage in the financially risky endeavor of educational litigation. We then outline an approach to developing expert testimony based upon evaluation of the target child and his/her educational history. Issues related to assessment, training, and ethical practice are addressed. Copyright © 2002 John Wiley & Sons, Ltd.     

Assessing and treating vocal stereotypy in children with autism

Previous research implies that stereotypic behavior tends to be maintained by the sensory consequences produced by engaging in the response. Few investigations, however, have focused on vocal stereotypy. The current study examined the noncommunicative vocalizations of 4 children with an autism spectrum disorder. First, functional analyses were conducted in an attempt to identify the function of each child's behavior. For each of the participants, it was found that vocal stereotypy was likely not maintained by the social consequences. Following assessment, response interruption and redirection (RIRD) was implemented in an ABAB design to determine whether vocal stereotypy could be successfully redirected. RIRD involved a teacher issuing a series of vocal demands the child readily complied with during regular academic programming. Vocal demands were presented contingent on the occurrence of vocal stereotypy and were continuously presented until the child complied with three consecutively issued demands without emitting vocal stereotypy. For each child, RIRD produced levels of vocal stereotypy substantially lower than those observed in baseline. For 3 of the children, an increase in appropriate communication was also observed. The children's teachers were trained to implement RIRD. Brief follow-up probes and anecdotal information implied that the treatment had a positive impact in the natural environment.     

Autism clinical trials: biological and medical issues in patient selection and treatment response

Biomedical measures are critical in the initial patient-screening and -selection phases of a clinical trial in autism and related disorders. These measures can also play an important role in the assessment and characterization of response and can provide an opportunity to study underlying etiologic and pathophysiologic processes. Thus, biomedical measures, including clinical laboratory analyses, metabolic screening, and chromosomal analysis, are used to screen for potential safety-related problems, to decrease biological and genetic heterogeneity, and to define subgroups. Neurobiological measures can be examined as possible predictors, modifiers or surrogates of therapeutic response, and adverse effects. Neurobiological research measures can also be used to study mechanisms and extent of drug action and to perform baseline and longitudinal investigations of possible pathophysiologic alterations. The potential utility and desirability of specific measures are considered and the general approach to choosing measures for incorporation is discussed.     

Development of motion processing in children with autism

Recent findings suggest that children with autism may be impaired in the perception of biological motion from moving point-light displays. Some children with autism also have abnormally high motion coherence thresholds. In the current study we tested a group of children with autism and a group of typically developing children aged 5 to 12 years of age on several motion perception tasks, in order to establish the specificity of the biological motion deficit in relation to other visual discrimination skills. The first task required the recognition of biological from scrambled motion. Three quasi-psychophysical tasks then established individual thresholds for the detection of biological motion in dynamic noise, of motion coherence and of form-from-motion. Lastly, individual thresholds for a task of static perception--contour integration (Gabor displays)--were also obtained. Compared to controls, children with autism were particularly impaired in processing biological motion in relation to any developmental measure (chronological or mental age). In contrast, there was some developmental overlap in ability to process other types of visual motion between typically developing children and the children with autism, and evidence of developmental change in both groups. Finally, Gabor display thresholds appeared to develop typically in children with autism.     

AEDs and psychotropic drugs in children with autism and epilepsy

The efficacy of antiepileptic drugs (AEDs) and psychotropic medications in children with autism is limited to the treatment of seizures or to specific behaviors such as irritability, impulsivity, hyperactivity, repetitive behaviors, or aggression. The reliability and value of the available data--to determine the efficacy of these medications in autism--are limited by lack of controlled clinical trials, the small number of subjects, the heterogeneity of the population studied, and the brief duration of most drug trials. Indeed, few controlled clinical trials using AEDs in autism, with or without seizures, have been conducted. Because some AEDs also have a positive effect on mood, the benefits that children with autism sometimes obtain from these medications may not be due to the treatment of the abnormal electrical activity or the seizures per se but to an effect on common neuronal systems responsible for both behavior and epilepsy. The relationship between epilepsy and autism, and specifically the effects that abnormal electrical activity may have on the developing brain, may provide some valuable insights into the type of studies that are needed to help us understand the pathophysiology of autism.     

Task-switching abilities in children with autism spectrum disorder

Task-switching performance is often used as a measure of executive control functions. Various task-switching studies in children with autism spectrum disorder (ASD) found, in contrast to expectations, no impairments in cognitive flexibility. Here, we studied whether the role of memory for arbitrary task rules can explain these findings, and how studying rule memory can help to generally better understand executive control. We designed a novel task-switching paradigm to separate cognitive flexibility from demand on memory for arbitrary rules, and we compared 19 children with ASD (9 to 16 years old) with an age- and IQ-matched control group. Children with ASD had increased difficulty with task switching only when memorizing arbitrary rules was required. When no arbitrary rules needed to be memorized, they performed accurately and quickly. Nevertheless, they showed less distraction from task-irrelevant stimulus features, suggesting that they represented tasks differently from the children in the comparison group. We conclude that children with ASD have a weaker capacity of forming rule representations, which only leads to performance impairment when they need to memorize arbitrary rules. Further, executive control impairments in ASD seem more complex than hitherto hypothesized due to mutual interactions between memory demand and task representations.     

The differential outcomes effect in children with autism

The differential outcomes procedure uses reinforcement unique to each alternative in a conditional discrimination, leading to faster and more accurate learning relative to non‐differential outcomes procedures. In this study, the differential outcomes procedure was used to teach novel tacts of musical instrument sounds to children with autism. For one set of instruments, response‐specific reinforcers were used in combination with social reinforcement. For the other set, reinforcers were provided non‐differentially. Two out of three participants showed enhanced learning in the differential outcomes condition, providing some support of the differential outcomes procedures as a useful tool for teaching individuals with autism. Future research into the differential outcomes effect is warranted to identify the procedural and individual factors that predict its effectiveness.     

Generalization of tacting actions in children with autism

This intervention compared the effects of two procedures on the generalization of a tacting repertoire (labeling) in 6 children with autism spectrum disorder. In one procedure the verbal antecedent stimulus “What is she doing?” appeared together with a person performing an action; in the other procedure, the antecedent stimulus was just the presence of the action. In initial tests, children emitted tacts only when the action was presented with the verbal antecedent. Thereafter, they learned to tact an action without the verbal antecedent and received tests to evaluate generalization to another action. Results indicated that in order to obtain generalization of tacting actions, it was necessary to learn to tact other actions without the verbal antecedent as well as learning to tact the action with the verbal antecedent. These findings have relevance for generalization of tacting actions from control by verbal antecedents to natural conditions and the production of spontaneous language.     

Evidence for syntactic alignment in children with autism

We report an experiment that examined whether children with Autistic Spectrum Disorder (ASD) spontaneously converge, or align, syntactic structure with a conversational partner. Children with ASD were more likely to produce a passive structure to describe a picture after hearing their interlocutor use a passive structure to describe an unrelated picture when playing a card game. Furthermore, they converged syntactic structure with their interlocutor to the same extent as did both chronological and verbal age-matched controls. These results suggest that the linguistic impairment that is characteristic of children with ASD, and in particular their difficulty with interactive language usage, cannot be explained in terms of a general deficit in linguistic imitation.     

Inner and outer face perception in children with autism.

Possible peculiarities in face perception in the autistic population were explored through two experiments. Fourteen autistic children (mean age=10 years 1 month) were individually matched to verbal mental age (VMA) and chronological age (CA) subjects. In a first experiment, subjects were to match faces on the basis of either their outer (hair, chin, ears) or their inner (eyes, nose, mouth) aspects. Autistic children performed equally well in both conditions, while VMA-matched children performed better in the outer than the inner part condition. In a second experiment, chimeric faces consisting of the outer part of an individual's face and the inner part of another individual's face were presented to the subjects. None of the groups showed a preference for neither the outer nor the inner part of the face in this condition. Results were discussed in terms of the existence of a local visual processing strategy in this population.