Constrained Multivariate Functional Principal Components Analysis for Novel Outcomes in Eye-Tracking Experiments.

Individuals with autism spectrum disorder (ASD) tend to experience greater difficulties with social communication and sensory information processing. Of particular interest in ASD biomarker research is the study of visual attention, effectively quantified in eye tracking (ET) experiments. Eye tracking offers a powerful, safe, and feasible platform for gaining insights into attentional processes by measuring moment-by-moment gaze patterns in response to stimuli.

A roadmap for SHANK3-related Epilepsy Research: recommendations from the 2023 strategic planning workshop.

On September 27, 2023, the CureSHANK nonprofit foundation sponsored a conference in Boston, Massachusetts, to identify gaps in knowledge surrounding SHANK3-related epilepsy with the goal of determining future research priorities and recommendations. In addition to patient families and members of the CureSHANK community, participants in the conference included a broad cross-section of preclinical and clinical researchers and clinicians with expertise in SHANK3-related epilepsy as well as representatives from the pharmaceutical industry. Here we summarize the outcomes from comprehensive premeeting deliberations and the final conference recommendations, including (1) gaps in knowledge related to clinical science, (2) gaps in knowledge related to preclinical science, and (3) research priorities moving forward.

Modeling intra-individual inter-trial EEG response variability in autism.

Autism spectrum disorder (autism) is a prevalent neurodevelopmental condition characterized by early emerging impairments in social behavior and communication. EEG represents a powerful and non-invasive tool for examining functional brain differences in autism. Recent EEG evidence suggests that greater intra-individual trial-to-trial variability across EEG responses in stimulus-related tasks may characterize brain differences in autism.

Clinically derived 12-factor structure and confirmatory factor analysis of the neurodevelopmental parent report for outcome monitoring.

Unlabelled: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication and social interaction impairments accompanied by restrictive and repetitive behaviors or interests. Co-occurring conditions may greatly impact overall functioning and intervention needs, and contribute to individual variability and etiologic subtypes. Clinical care of individuals with ASD requires gathering a breadth of information across multiple domains.

A functional model for studying common trends across trial time in eye tracking experiments.

Eye tracking (ET) experiments commonly record the continuous trajectory of a subject's gaze on a two-dimensional screen throughout repeated presentations of stimuli (referred to as trials). Even though the continuous path of gaze is recorded during each trial, commonly derived outcomes for analysis collapse the data into simple summaries, such as looking times in regions of interest, latency to looking at stimuli, number of stimuli viewed, number of fixations or fixation length. In order to retain information in trial time, we utilize functional data analysis (FDA) for the first time in literature in the analysis of ET data.

Evaluation of clinical assessments of social abilities for use in autism clinical trials by the autism biomarkers consortium for clinical trials.

Clinical trials in autism spectrum disorder (ASD) often rely on clinician rating scales and parent surveys to measure autism-related features and social behaviors. To aid in the selection of these assessments for future clinical trials, the Autism Biomarkers Consortium for Clinical Trials (ABC-CT) directly compared eight common instruments with respect to acquisition rates, sensitivity to group differences, equivalence across demographic sub-groups, convergent validity, and stability over a 6-week period. The sample included 280 children diagnosed with ASD (65 girls) and 119 neurotypical children (36 girls) aged from 6 to 11 years.

Associations Between Infant Screen Use, Electroencephalography Markers, and Cognitive Outcomes.

Importance: Research evidence is mounting for the association between infant screen use and negative cognitive outcomes related to attention and executive functions. The nature, timing, and persistence of screen time exposure on neural functions are currently unknown. Electroencephalography (EEG) permits elucidation of the neural correlates associated with cognitive impairments.

The role of aperiodic spectral slope in event-related potentials and cognition among children with and without attention deficit hyperactivity disorder.

Aperiodic spectral slope is a measure of spontaneous neural oscillatory activity that is believed to support regulation of brain responses to environmental stimuli. Compared to typically developing (TD) control participants, children with attention deficit hyperactivity disorder (ADHD) have been shown to have flatter aperiodic spectral slope at rest as well as attenuated event-related potential (ERP) amplitudes in response to environmental stimuli. A small body of research suggests that aperiodic slope may also explain differences in behavioral responses.

Concomitant medication use in children with autism spectrum disorder: Data from the Autism Biomarkers Consortium for Clinical Trials.

Children with autism spectrum disorder are prescribed a variety of medications that affect the central nervous system (psychotropic medications) to address behavior and mood. In clinical trials, individuals taking concomitant psychotropic medications often are excluded to maintain homogeneity of the sample and prevent contamination of biomarkers or clinical endpoints. However, this choice may significantly diminish the clinical representativeness of the sample.

The Autism Biomarkers Consortium for Clinical Trials: Initial Evaluation of a Battery of Candidate EEG Biomarkers.

Objective: Numerous candidate EEG biomarkers have been put forward for use in clinical research on autism spectrum disorder (ASD), but biomarker development has been hindered by limited attention to the psychometric properties of derived variables, inconsistent results across small studies, and variable methodology. The authors evaluated the basic psychometric properties of a battery of EEG assays for their potential suitability as biomarkers in clinical trials.

Methods: This was a large, multisite, naturalistic study in 6- to 11-year-old children who either had an ASD diagnosis (N=280) or were typically developing (N=119).

Absence of dynamic neural oscillatory response to environmental conditions marks childhood attention deficit hyperactivity disorder.

Background: Prior research suggests that symptoms of attention deficit hyperactivity disorder (ADHD) and related neurodevelopmental disorders may derive from alterations in the brain's ability to flexibly tune the balance between information integration and segregation and global versus local processing. This balance allows the brain to optimally filter salient stimuli in the environment and can be measured with electroencephalography (EEG) via calculation of the aperiodic spectral slope. A steeper aperiodic slope increases the capacity of global neural networks to process low-salience stimuli, while a flatter aperiodic slope reflects an emphasis on local neural networks that respond preferentially to high-salience input.

Identifying Age Based Maturation in the ERP Response to Faces in Children With Autism: Implications for Developing Biomarkers for Use in Clinical Trials.

Recent proposals have suggested the potential for neural biomarkers to improve clinical trial processes in neurodevelopmental conditions; however, few efforts have identified whether chronological age-based adjustments will be necessary (as used in standardized behavioral assessments). Event-related potentials (ERPs) demonstrate early differences in the processing of faces vs. objects in the visual processing system by 4 years of age and age-based improvement (decreases in latency) through adolescence.

Multilevel hybrid principal components analysis for region-referenced functional electroencephalography data.

Electroencephalography experiments produce region-referenced functional data representing brain signals in the time or the frequency domain collected across the scalp. The data typically also have a multilevel structure with high-dimensional observations collected across multiple experimental conditions or visits. Common analysis approaches reduce the data complexity by collapsing the functional and regional dimensions, where event-related potential (ERP) features or band power are targeted in a pre-specified scalp region.

A randomized controlled trial of everolimus for neurocognitive symptoms in PTEN hamartoma tumor syndrome.

PTEN hamartoma tumor syndrome (PHTS) is a complex neurodevelopmental disorder characterized by mechanistic target of rapamycin (mTOR) overactivity. Limited data suggest that mTOR inhibitors may be therapeutic. No placebo-controlled studies have examined mTOR inhibition on cognition and behavior in humans with PHTS with/without autism.

The autism biomarkers consortium for clinical trials: evaluation of a battery of candidate eye-tracking biomarkers for use in autism clinical trials.

Background: Eye tracking (ET) is a powerful methodology for studying attentional processes through quantification of eye movements. The precision, usability, and cost-effectiveness of ET render it a promising platform for developing biomarkers for use in clinical trials for autism spectrum disorder (ASD).

Methods: The autism biomarkers consortium for clinical trials conducted a multisite, observational study of 6-11-year-old children with ASD (n = 280) and typical development (TD, n = 119).

Neurobehavioral Biomarkers: An EEG Family Reunion.

The field of clinical EEG has had an uneasy relationship with the use of this technology for clinical cognitive applications and often for good reason. However, apart from its clinical use, EEG has had a tradition as a major tool in cognitive psychology and cognitive neuroscience dating back at least to the 1960s. Based on accumulated knowledge from its research application, EEG-based biomarkers are beginning to see applications in clinical trials and may eventually enter clinical care.

Parental Language Input Predicts Neuroscillatory Patterns Associated with Language Development in Toddlers at Risk of Autism.

In this study we investigated the impact of parental language input on language development and associated neuroscillatory patterns in toddlers at risk of Autism Spectrum Disorder (ASD). Forty-six mother-toddler dyads at either high (n = 22) or low (n = 24) familial risk of ASD completed a longitudinal, prospective study including free-play, resting electroencephalography, and standardized language assessments. Input quantity/quality at 18 months positively predicted expressive language at 24 months, and relationships were stronger for high-risk toddlers.

EEG Phase-Amplitude Coupling Strength and Phase Preference: Association with Age over the First Three Years after Birth.

Phase-amplitude coupling (PAC), the coupling of the phase of slower electrophysiological oscillations with the amplitude of faster oscillations, is thought to facilitate dynamic integration of neural activity in the brain. Although the brain undergoes dramatic change and development during the first few years of life, how PAC changes through this developmental period has not been extensively studied. Here, we examined PAC through electroencephalography (EEG) data collected during an awake, eyes-open EEG collection paradigm in 98 children between the ages of three months and three years.

Shifted phase of EEG cross-frequency coupling in individuals with Phelan-McDermid syndrome.

Background: Phelan-McDermid Syndrome (PMS) is a rare condition caused by deletion or mutation of the SHANK3 gene. Individuals with PMS frequently present with intellectual disability, autism spectrum disorder, and other neurodevelopmental challenges. Electroencephalography (EEG) can provide a window into network-level function in PMS.

Autism Spectrum Disorder Parent Report for Outcome Monitoring: A Preliminary Report of Development and Clinical Utility.

Objective: Children with autism spectrum disorder (ASD) face challenges across many functional domains. A tool that gathers relevant clinical information before visits, emphasizing symptoms that are likely to change over development and inform clinical interventions, could improve health care quality, allowing for more patient-centered and efficient care. This study evaluated the clinical utility and preliminary psychometrics of the ASD Parent Report for Outcome Monitoring (ASD-PROM), a web-based measure assessing competence in core features of ASD, along with the breadth of concerns and comorbidities that frequently co-occur with ASD.

Use of longitudinal EEG measures in estimating language development in infants with and without familial risk for autism spectrum disorder.

Language development in children with autism spectrum disorder (ASD) varies greatly among affected individuals and is a strong predictor of later outcomes. Younger siblings of children with ASD have increased risk of ASD, but also language delay. Identifying neural markers of language outcomes in infant siblings could facilitate earlier intervention and improved outcomes.

Day-to-Day Test-Retest Reliability of EEG Profiles in Children With Autism Spectrum Disorder and Typical Development.

Biomarker development is currently a high priority in neurodevelopmental disorder research. For many types of biomarkers (particularly biomarkers of diagnosis), reliability over short periods is critically important. In the field of autism spectrum disorder (ASD), resting electroencephalography (EEG) power spectral densities (PSD) are well-studied for their potential as biomarkers.

EEG-IP: an international infant EEG data integration platform for the study of risk and resilience in autism and related conditions.

Background: Establishing reliable predictive and diganostic biomarkers of autism would enhance early identification and facilitate targeted intervention during periods of greatest plasticity in early brain development. High impact research on biomarkers is currently limited by relatively small sample sizes and the complexity of the autism phenotype.

Methods: EEG-IP is an International Infant EEG Data Integration Platform developed to advance biomarker discovery by enhancing the large scale integration of multi-site data.

The Autism Biomarkers Consortium for Clinical Trials (ABC-CT): Scientific Context, Study Design, and Progress Toward Biomarker Qualification.

Clinical research in neurodevelopmental disorders remains reliant upon clinician and caregiver measures. Limitations of these approaches indicate a need for objective, quantitative, and reliable biomarkers to advance clinical research. Extant research suggests the potential utility of multiple candidate biomarkers; however, effective application of these markers in trials requires additional understanding of replicability, individual differences, and intra-individual stability over time.