Prospective MEG biomarkers in ASD: pre-clinical evidence and clinical promise of electrophysiological signatures

Autism spectrum disorders (ASD) are characterized by social impairments and restricted/stereotyped behaviors and currently affect an estimated 1 in 68 children aged 8 years old. While there has been substantial recent focus on ASD in research, both the biological pathology and, perhaps consequently, a fully effective treatment have yet to be realized. What has remained throughout is the hypothesis that ASD has neurobiological underpinnings and the observation that both the phenotypic expression and likely the underlying etiology is highly heterogeneous. Given the neurodevelopmental basis of ASD, a biologically based marker (biomarker) could prove useful not only for diagnostic and prognostic purposes, but also for stratification and response indices for pharmaceutical development. In this review, we examine the current state of the field for MEG-related biomarkers in ASD. We describe several potential biomarkers (middle latency delays [M50/M100], mismatch negativity latency, gamma-band oscillatory activity), and investigate their relation to symptomology, core domains of dysfunction (e.g., language impairment), and putative biological underpinnings.

Keywords: ASD; Gamma; MEG; biomarker; latency delay; signature; translational.

We report the first study on pronoun use by an under-studied research population, children with autism spectrum disorder (ASD) exposed to American Sign Language from birth by their deaf parents. Personal pronouns cause difficulties for hearing children with ASD, who sometimes reverse or avoid them. Unlike speech pronouns, sign pronouns are indexical points to self and other. Despite this transparency, we find evidence from an elicitation task and parental report that signing children with ASD avoid sign pronouns in favor of names. An analysis of spontaneous usage showed that all children demonstrated the ability to point, but only children with better-developed sign language produced pronouns. Differences in language abilities and self-representation may explain these phenomena in sign and speech.

Objective: Converging evidence indicates that brain abnormalities in autism spectrum disorder (ASD) involve atypical network connectivity, but few studies have integrated functional with structural connectivity measures. This multimodal investigation examined functional and structural connectivity of the imitation network in children and adolescents with ASD, and its links with clinical symptoms.

Methods: Resting state functional magnetic resonance imaging and diffusion-weighted imaging were performed in 35 participants with ASD and 35 typically developing controls, aged 8 to 17 years, matched for age, gender, intelligence quotient, and head motion.

Results: Within-network analyses revealed overall reduced functional connectivity (FC) between distributed imitation regions in the ASD group. Whole brain analyses showed that underconnectivity in ASD occurred exclusively in regions belonging to the imitation network, whereas overconnectivity was observed between imitation nodes and extraneous regions. Structurally, reduced fractional anisotropy and increased mean diffusivity were found in white matter tracts directly connecting key imitation regions with atypical FC in ASD. These differences in microstructural organization of white matter correlated with weaker FC and greater ASD symptomatology.

Interpretation: Findings demonstrate atypical connectivity of the brain network supporting imitation in ASD, characterized by a highly specific pattern. This pattern of underconnectivity within, but overconnectivity outside the functional network is in contrast with typical development and suggests reduced network integration and differentiation in ASD. Our findings also indicate that atypical connectivity of the imitation network may contribute to ASD clinical symptoms, highlighting the role of this fundamental social cognition ability in the pathophysiology of ASD.

The intraparietal sulcus (IPS), a region in the dorsal attention network (DAN), has been implicated in multi-sensory attention and working memory. Working memory and attention develop across childhood; changes in functional connectivity within the DAN may relate to this maturation. Previous findings regarding fronto-parietal intrinsic functional connectivity age-effects were mixed. Our study aimed to circumvent limitations of previous work using a large cross-sectional sample, 183 typically developing participants 6.5-20 years, from the Autism Brain Imaging Data Exchange, and seed regions along the anterior-to-posterior axis of the IPS. These seeds, IPS0-4, were entered into functional connectivity models. Group-level models investigated differential connectivity along the IPS and relationships with age. Anterior IPS3/4 exhibited greater connectivity with sensorimotor/pre-motor regions. Posterior IPS0/1 demonstrated greater connectivity with dorsal and ventral visual regions. Positive age-effects were found between IPS3-4 and visual regions. Negative age-effects were found between IPS and superior parietal and medial orbitofrontal cortices. Follow-up region of interest analyses were used to estimate age-effects for DAN and anticorrelated default mode network regions. Results suggest age-effects on IPS functional connectivity are relatively modest, and may differ pre- and across-adolescence. Studying typical age-related connectivity variability within this network may help to understand neurodevelopmental disorders marked by impaired attention.

Keywords: Attention; Functional connectivity; IPS; Resting-state fMRI; Visual-spatial; Visuotopic.

We investigated the mechanisms by which Pivotal Response Treatment (PRT) improves social communication in a case series of 10 preschool-aged children with Autism Spectrum Disorder (ASD). Functional magnetic resonance imaging (fMRI) identified brain responses during a biological motion perception task conducted prior to and following 16 weeks of PRT treatment. Overall, the neural systems supporting social perception in these 10 children were malleable through implementation of PRT; following treatment, neural responses were more similar to those of typically developing children (TD). However, at baseline, half of the children exhibited hypoactivation, relative to a group of TD children, in the right posterior superior temporal sulcus (pSTS), and half exhibited hyperactivation in this region. Strikingly, the groups exhibited differential neural responses to treatment: The five children who exhibited hypoactivation at baseline evidenced increased activation in components of the reward system including the ventral striatum and putamen. The five children who exhibited hyperactivation at baseline evidenced decreased activation in subcortical regions critical for regulating the flow of stimulation and conveying signals of salience to the cortex-the thalamus, amygdala, and hippocampus. Our results support further investigation into the differential effects of particular treatment strategies relative to specific neural targets. Identification of treatment strategies that address the patterns of neural vulnerability unique to each patient is consistent with the priority of creating individually tailored interventions customized to the behavioral and neural characteristics of a given person.

Earlier autism diagnosis, the importance of early intervention, and development of specific interventions for young children have contributed to the emergence of similar, empirically supported, autism interventions that represent the merging of applied behavioral and developmental sciences. “Naturalistic Developmental Behavioral Interventions (NDBI)” are implemented in natural settings, involve shared control between child and therapist, utilize natural contingencies, and use a variety of behavioral strategies to teach developmentally appropriate and prerequisite skills. We describe the development of NDBIs, their theoretical bases, empirical support, requisite characteristics, common features, and suggest future research needs. We wish to bring parsimony to a field that includes interventions with different names but common features thus improving understanding and choice-making among families, service providers and referring agencies.

There is growing evidence that efficacious autism-related interventions rarely are adopted or successfully implemented in public schools, in part because of the lack of fit between the intervention and the needs and capacities of the school setting. There is little systematic information available regarding the barriers to implementation of complex interventions such as those addressing social engagement for children with autism.The present study used fieldnotes from an implementation trial to explore barriers that emerged during the training of school personnel and subsequent implementation of a social engagement intervention. A number of barriers at the individual (training) and school levels (policies surrounding recess, staffing, prioritization of competing demands, level of respect and support, and availability of resources) interfered with the continued use and sustainment of the intervention. We offer potential strategies to overcome these barriers and provide directions for future research in this critical area.

Keywords: autism; implementation; intervention; schools; social engagement.

This study sought to validate a new measure, the Classroom Cohesion Survey (CCS), designed to examine the relationship between teachers and classroom assistants in autism support classrooms. Teachers, classroom assistants, and external observers showed good inter-rater agreement on the CCS and good internal consistency for all scales. Simple factor structures were found for both teacher- and classroom assistant-rated scales, with one-factor solutions for both scales. Paired t tests revealed that on average, classroom assistants rated classroom cohesion stronger than teachers. The CCS may be an effective tool for measuring cohesion between classroom staff and may have an important impact on various clinical and implementation outcomes in school settings.

Keywords: autism; classroom cohesion; classroom team; teacher-staff relationship.

Schools have become the main provider of services to children with mental health needs. Although there is substantial literature on barriers to implementation of evidence-based practices (EBPs) in under-resourced school districts, less has been written on how to overcome those barriers. Providing mental health services in the school setting presents a tremendous opportunity to increase access to quality mental health care for underserved youth. This review provides a brief overview of the barriers to successful implementation and sustainment of EBPs in under-resourced public schools and provides recommendations for overcoming them. The discussion is organized around an established conceptual framework adapted for the delivery of services in under-resourced schools that focuses on interdependent factors that exist at the individual-, team, school-, and macro-levels. This manuscript explores some recommendations and strategies for effectively addressing challenges related to implementation of EBPs. Research ideas are offered to bridge the research-to-practice gap that impacts many under-resourced public school districts.

Keywords: Implementation; evidence-based practices; mental health services; sustainment; under-resourced schools.

Classroom assistants and one-to-one assistants are an important part of the staffing structure of many autism support classrooms. Limited studies, however, have examined how one-to-one assistants spend their time in the classroom. The purpose of this article was to examine the percentage of time one-to-one assistants were engaged in instruction or support of students with autism and to determine the factors associated with their engagement. Direct observations were conducted in 46 autism support classrooms. Teachers and classroom assistants were engaged in instruction or support 98% and 91% of the time, respectively. One-to-one assistants were engaged in instruction or support 57% of the time. Classroom assistants’ and one-to-one assistants’ engagement was significantly correlated. The low rate of one-to-one assistants’ engagement suggests an inefficient use of an important resource.

Keywords: autism; autism spectrum disorder; classroom staff engagement; one-to-one assistants; paraprofessionals.

evidence-based, CAM