Benjamin E. Yerys

Replication and Comparison of the Newly Proposed ADOS-2, Module 4 Algorithm in ASD Without ID: A Multi-site Study

Recent updates have been proposed to the Autism Diagnostic Observation Schedule-2 Module 4 diagnostic algorithm. This new algorithm, however, has not yet been validated in an independent sample without intellectual disability (ID). This multi-site study compared the original and revised algorithms in individuals with ASD without ID. The revised algorithm demonstrated increased sensitivity, but lower specificity in the overall sample. Estimates were highest for females, individuals with a verbal IQ below 85 or above 115, and ages 16 and older. Best practice diagnostic procedures should include the Module 4 in conjunction with other assessment tools. Balancing needs for sensitivity and specificity depending on the purpose of assessment (e.g., clinical vs. research) and demographic characteristics mentioned above will enhance its utility.

Striatal Development in Autism: Repetitive Behaviors and the Reward Circuitry

Autism spectrum disorder (ASD) is defined by two essential features – impaired social communication abilities, including deficits with social reciprocity, nonverbal communication and establishing relationships, and by the presence of restricted and repetitive behaviors and interests (RRBIs). Social deficits get the majority of attention both in science and in the popular media, but RRBIs are equally important in understanding autism. Although RRBIs are also seen in typically developing preschoolers, as well as in other psychiatric disorders such as obsessive-compulsive disorder, their impairing and persisting character is a hallmark of ASD1. n nRepetitive behaviors are among the first signs of ASD, with significant elevations by the childs first birthday2. Individuals with ASD of all ages and cognitive ability levels display RRBIs to variable degrees, with males usually being more severely affected than females3. Caregivers of individuals with ASD commonly emphasize that RRBIs are among the most challenging facets of the disorder on an everyday basis1. They negatively impact social, cognitive, family functioning and well-being, often leading to increased levels of parental stress and negative parenting styles. While the clinical description and natural history of RRBIs is becoming clear, an understanding of the biological bases of this set of features has only recently begun to emerge4. Better insight into the ontogenesis of RRBIs and their underlying neurobiology is needed not only to inform models of the etiology of ASD, but also to foster the development of new interventions. n nIn this issue of Biological Psychiatry, Langen et al.5 examine differences in the rate of basal ganglia growth in ASD relative to typically developing children (TDC). Their volumetric analyses focused on developmental trajectories of the ventral striatum (with nucleus accumbens) and dorsal striatum (with caudate nucleus and putamen). These components of the basal ganglia are the major subcortical targets within the frontostriatal behavior control loops that are recognized as likely subserving RRBIs4. This current study is a follow up of this same groups earlier work showing cross sectional differences in growth trajectory. While several labs have previously reported enlargement of the caudate nucleus in ASD, this current study is the first to make repeat morphology measurements, thus overcoming limitations associated with cross sectional analyses. This study involved 86 seven to seventeen year old cases and controls who had 2 MRI anatomical scans approximately 2 and a half years apart on average, allowing a direct test of differential striatal growth. The rate of basal ganglia growth was correlated with the severity of RRBIs as assessed by parent interview at the time of the first MRI scan, corroborating earlier work on the role of the striatum in repetitive behaviors among children with ASD. n nSpecifically the caudate nucleus showed a growth rate in ASD that was twice as high as the growth rate in TDC (i.e., 4.6% vs. 2.3%). This was independent of overall brain growth, use of psychotropic medications, or other major confounds. Most importantly, more severe RRBIs early in life, particularly insistence on sameness behaviors, such as avoiding trivial changes in routines and environments as well as adhering to compulsions and rituals, were related to faster striatal growth between average ages of about 9 and 12 year old, with large effect sizes (e.g., caudate nucleus: Cohens d = 0.86). While Langen et al. discuss several complementary explanations for their findings, they conclude that the divergent trajectory of caudate development in relation to RRBIs most likely results from early, and possibly continuing, patterns of repetitive behaviors that shape striatal development – not the other way around. n nThis new set of data elegantly adds to the notion that the striatum plays a central role in core ASD phenomenology6. However, one question lingers: what cause RRBIs, like insistence on sameness, compulsions and rituals, to become such a force so as to impact the growth trajectory of an evolutionarily ancient brain structure like the caudate nucleus? This question ties in with a long-standing debate among clinicians and scientists concerning the potential functions that the myriad of RRBIs might serve in individuals with ASD. While several plausible ideas have been advanced7, convincing support for any specific one is lacking. n nOne hypothesis that is gaining increased research attention, however, involves the effects of alterations of the balance between social and nonsocial motivation in reward circuitry on RRBIs8. This model suggests that ASD is in part a disorder of “behavioral dependency” to RRBIs because of the rewarding effects they induce1. Indeed, insistence on sameness and preoccupying restricted interests are reported to be quite pleasurable by affected individuals1. The dorsal striatum with caudate nucleus, in particular, is believed to mediate reward value for purposeful actions5. Functional imaging studies show that the brains reward circuitry in ASD, particularly striatum and ventral prefrontal cortices, selectively over-reacts to objects that may comprise an intense special interest, whereas it under-reacts to more typical desires such as social reward and money6. This may indicate that the brain in ASD cares less for conventional rewards. It is not yet known if an initial lack of social reward motivation opens the door for enhanced rewarding effects of certain circumscribed objects, topics, and routines, or whether the reverse is true – that the dominating reward effects of nonsocial objects, topic and routines diminishes the reward value of social engagement. n nThe rewarding effects of RRBIs are thought to be fueled by the preference of those with ASD for predictability in their environment, where they can exercise more control; social encounters are in many ways the antithesis of this, as these are often rapid, hard to control and offer much more variable reinforcement contingencies. When RRBIs are rewarding, their pursuit may be strengthened through reinforcement mechanisms that progressively turn them into rigid and strongly desired habits that are performed almost automatically with little conscious oversight. With this heuristic model, RRBIs are self-reinforcing, and they begin to hijack the normal developmental trajectory of entire repertoires of behaviors. The dorsal (associative) striatum with caudate nucleus dominates these processes4. Thus, an accelerated growth rate of the caudate related to RRBIs, as reported by Langen et al.5, could reflect atypical brain specialization in individuals with ASD9. From early in life the caudate nucleus mediates habitual processes for a wide range of different stimuli and contexts. Across development, however, the caudate may become co-opted by the most rewarding aspects of the environment. This interactive and self-sustaining biobehavioral process – in concert with other mesocorticolimbic functions4 – may shape the growth trajectory of the caudate nucleus and strengthens the occurrence of RRBIs in ASD (Figure 1). On a day-to-day basis, RRBIs interfere with social development and functioning as they may absorb resources typically dedicated to other learning opportunities, including social ones6. n n n nFigure 1 n nBased on data from the longitudinal study by Langen et al.5, we suggest a working model on the ontogenesis of higher-order restricted and repetitive behaviors and interests, such as resistance to change behaviors, among children with autism spectrum disorders. ... n n n nThe observation that RRBIs in ASD involve plasticity of the caudate nucleus – one major hub within the frontostriatal circuits that control behavior – is a fascinating advance for our field. It brings us closer to the neurobiological roots of how and why affected individuals develop and maintain this set of challenging behaviors. Follow-up research will need to address several issues to improve upon the approach of the Langen et al study. One critical issue is that researchers need to use more precise behavioral measurement tools10. This could involve item rating scales with greater item density around key concepts, as it is clear to all the ADI-R is sorely lacking in this regard. Also, quantitative motion capture tools are now widely available; deploying these in natural environments seems to us to be extremely promising adjuncts to standard rating scales. Repeat behavioral measurement across time, in sync with repeat brain measurement is an important next step that will enable better characterization of the interplay between RRBIs and brain dynamics. In this regard, multimodal imaging in the same sample is called for, as structural imaging will surely only capture portions of the story. The findings by Langen et al.5 call attention to the importance of RRBIs in autism. Because RRBIs may be rooted in the powerful reward circuitries that motivate a great deal of behavior, strategically targeting the role of reward mechanisms promises to improve treatment practices for limiting the life interfering aspects of RRBIs among individuals with ASD and their families.

What About the Girls? Sex-Based Differences in Autistic Traits and Adaptive Skills

There is growing evidence of a camouflaging effect among females with autism spectrum disorder (ASD), particularly among those without intellectual disability, which may affect performance on gold-standard diagnostic measures. This study utilized an age- and IQ-matched sample of school-aged youth (nu2009=u2009228) diagnosed with ASD to assess sex differences on the ADOS and ADI-R, parent-reported autistic traits, and adaptive skills. Although females and males were rated similarly on gold-standard diagnostic measures overall, females with higher IQs were less likely to meet criteria on the ADI-R. Females were also found to be significantly more impaired on parent reported autistic traits and adaptive skills. Overall, the findings suggest that some autistic females may be missed by current diagnostic procedures.

Linguistic camouflage in girls with autism spectrum disorder

BackgroundAutism spectrum disorder (ASD) is diagnosed more frequently in boys than girls, even when girls are equally symptomatic. Cutting-edge behavioral imaging has detected “camouflaging” in girls with ASD, wherein social behaviors appear superficially typical, complicating diagnosis. The present study explores a new kind of camouflage based on language differences. Pauses during conversation can be filled with words like UM or UH, but research suggests that these two words are pragmatically distinct (e.g., UM is used to signal longer pauses, and may correlate with greater social communicative sophistication than UH). Large-scale research suggests that women and younger people produce higher rates of UM during conversational pauses than do men and older people, who produce relatively more UH. Although it has been argued that children and adolescents with ASD use UM less often than typical peers, prior research has not included sufficient numbers of girls to examine whether sex explains this effect. Here, we explore UM vs. UH in school-aged boys and girls with ASD, and ask whether filled pauses relate to dimensional measures of autism symptom severity.MethodsSixty-five verbal school-aged participants with ASD (49 boys, 16 girls, IQ estimates in the average range) participated, along with a small comparison group of typically developing children (8 boys, 9 girls). Speech samples from the Autism Diagnostic Observation Schedule were orthographically transcribed and time-aligned, with filled pauses marked. Parents completed the Social Communication Questionnaire and the Vineland Adaptive Behavior Scales.ResultsGirls used UH less often than boys across both diagnostic groups. UH suppression resulted in higher UM ratios for girls than boys, and overall filled pause rates were higher for typical children than for children with ASD. Higher UM ratios correlated with better socialization in boys with ASD, but this effect was driven by increased use of UH by boys with greater symptoms.ConclusionsPragmatic language markers distinguish girls and boys with ASD, mirroring sex differences in the general population. One implication of this finding is that typical-sounding disfluency patterns (i.e., reduced relative UH production leading to higher UM ratios) may normalize the way girls with ASD sound relative to other children, serving as “linguistic camouflage” for a naïve listener and distinguishing them from boys with ASD. This first-of-its-kind study highlights the importance of continued commitment to understanding how sex and gender change the way that ASD manifests, and illustrates the potential of natural language to contribute to objective “behavioral imaging” diagnostics for ASD.

Evaluation of the ADHD Rating Scale in Youth with Autism

Scientists and clinicians regularly use clinical screening tools for attention deficit/hyperactivity disorder (ADHD) to assess comorbidity without empirical evidence that these measures are valid in youth with autism spectrum disorder (ASD). We examined the prevalence of youth meeting ADHD criteria on the ADHD rating scale fourth edition (ADHD-RS-IV), the relationship of ADHD-RS-IV ratings with participant characteristics and behaviors, and its underlying factor structure in 386, 7–17xa0year olds with ASD without intellectual disability. Expected parent prevalence rates, relationships with age and externalizing behaviors were observed, but confirmatory factor analyses revealed unsatisfactory fits for one-, two-, three-factor models. Exploratory analyses revealed several items cross-loading on multiple factors. Implications of screening ADHD in youth with ASD using current diagnostic criteria are discussed.

Negative Valence in Autism Spectrum Disorder: The Relationship Between Amygdala Activity, Selective Attention, and Co-occurring Anxiety

BACKGROUNDnA critical agenda of the National Institutes of Health Research Domain Criteria (RDoC) initiative is establishing whether domains within the RDoC matrix are truly transdiagnostic. Rates of anxiety disorders are elevated in autism spectrum disorder (ASD), but it is unclear whether the same mechanisms contribute to anxiety in individuals with and without ASD. As changes in selective attention are a hallmark of anxiety disorders in non-ASD samples, the identification of these changes in ASD would support the transdiagnostic nature of anxiety.nnnMETHODSnThis functional magnetic resonance imaging study focused on the negative valence domain from RDoC (manifest as anxiety symptoms) in youth with ASD (nxa0= 38) and typically developing control participants (nxa0= 25). The task required selective attention toward and away from social information (faces) with negative and neutral affect. Participants underwent in-depth characterization for both anxiety and ASD symptoms.nnnRESULTSnDimensional and categorical measures of anxiety were significantly related to increased amygdala activation-evidence of enhanced attentional capture by social information.nnnCONCLUSIONSnThis pattern fits with decades of research among non-ASD samples using selective attention and attentional bias paradigms, suggesting that anxiety in ASD shares mechanisms with anxiety alone. Overall, results from this study support the transdiagnostic nature of the negative valence domain from RDoC and increase the likelihood that anxiety in ASD should be responsive to interventions targeting maladaptive responses to negative information.

Social-Emotional Inhibition of Return in Children with Autism Spectrum Disorder Versus Typical Development

AbstractnIn typical development there is a bias to orient visual attention to social information. Children with ASD do not reliably demonstrate this bias, and the role of attention orienting has not been well studied. We examined attention orienting via the inhibition of return (IOR) mechanism in a spatial cueing task using social-emotional cues; we studied 8- to 17-year-old children with ASD (nxa0=xa041) and typically developing controls (TDC) (nxa0=xa025). The ASD group exhibited a significantly stronger IOR effect than the TDC group, and the IOR effect correlated positively with social impairments but was unrelated to co-occurring ADHD or anxiety symptoms. The results provide evidence of an early altered attention mechanism that is associated with to core social deficits in ASD.

Brief Report: Generalization Weaknesses in Verbally Fluent Children and Adolescents with Autism Spectrum Disorder

AbstractnIndividuals with autism spectrum disorder (ASD) have difficulty generalizing—i.e., relating new stimuli to past experiences. Few experimental studies have addressed this weakness, despite its impact on intervention effects. In a reanalysis of data (de Marchena et al. Cognition 119(1):96–113, 2011), we tested a novel form of generalization—the ability to transfer a strategy used in one context to a similar context—in verbally fluent youth with ASD and matched typically developing controls. Participants with ASD were subtly less likely to learn from experience; their generalizations were less consistent. Generalization in ASD correlated with receptive vocabulary but not age, suggesting a link to language development. A richer understanding of how to promote generalization in ASD will advance both theory and practice.

Multimodal Imaging in Autism: an Early Review of Comprehensive Neural Circuit Characterization

There is accumulating evidence that the neurobiology of autism spectrum disorders (ASD) is linked to atypical neural communication and connectivity. This body of work emphasizes the need to characterize the function of multiple regions that comprise neural circuits rather than focusing on singular regions as contributing to deficits in ASD. Multimodal neuroimaging — the formal combination of multiple functional and structural measures of the brain — is extremely promising as an approach to understanding neural deficits in ASD. This review provides an overview of the multimodal imaging approach, and then provides a snapshot of how multimodal imaging has been applied in the study of ASD to date. This body of work is separated into two categories: one concerning whole brain connectomics and the other focused on characterizing neural circuits implicated as altered in ASD. We end this review by highlighting emerging themes from the existing body of literature, and new resources that will likely influence future multimodal imaging studies.

Altered reward system reactivity for personalized circumscribed interests in autism

BackgroundNeurobiological research in autism spectrum disorders (ASD) has paid little attention on brain mechanisms that cause and maintain restricted and repetitive behaviors and interests (RRBIs). Evidence indicates an imbalance in the brain’s reward system responsiveness to social and non-social stimuli may contribute to both social deficits and RRBIs. Thus, this study’s central aim was to compare brain responsiveness to individual RRBI (i.e., circumscribed interests), with social rewards (i.e., social approval), in youth with ASD relative to typically developing controls (TDCs).MethodsWe conducted a 3T functional magnetic resonance imaging (fMRI) study to investigate the blood-oxygenation-level-dependent effect of personalized circumscribed interest rewards versus social rewards in 39 youth with ASD relative to 22 TDC. To probe the reward system, we employed short video clips as reinforcement in an instrumental incentive delay task. This optimization increased the task’s ecological validity compared to still pictures that are often used in this line of research.ResultsCompared to TDCs, youth with ASD had stronger reward system responses for CIs mostly within the non-social realm (e.g., video games) than social rewards (e.g., approval). Additionally, this imbalance within the caudate nucleus’ responsiveness was related to greater social impairment.ConclusionsThe current data support the idea of reward system dysfunction that may contribute to enhanced motivation for RRBIs in ASD, accompanied by diminished motivation for social engagement. If a dysregulated reward system indeed supports the emergence and maintenance of social and non-social symptoms of ASD, then strategically targeting the reward system in future treatment endeavors may allow for more efficacious treatment practices that help improve outcomes for individuals with ASD and their families.