Background: The genetic heterogeneity of autism spectrum disorder (ASD) is remarkable. Whether genetic complexity converges in common physiological alterations of neuronal networks has yet to be determined. Brain Network Activation (BNA) analysis represents a novel, Food and Drug Administration (FDA)-approved method of analyzing the activity of neuronal networks during specific brain processes evoked by a specific stimulus (evoked response potential or ERP). While the patient performs a task, his or her brain activity is recorded using a 64 electrode EEG (electroencephalogram). BNA applies advanced algorithmic analysis methods to the multichannel EEG-ERP data and provides quantitative scores as well as a map of network activity and connectivity. We propose to investigate BNA patterns in individuals with copy number changes at chromosome 15q13.3, who manifest ASD with high prevalence, as well as individuals with idiopathic ASD.Hypothesis: The analysis of brain network activity can be used to identify signatures of altered neural network function in subsets of ASD. These signatures can provide quantifiable outcome measures for future clinical trials, allowing the investigation of effects of pharmacological compounds.Specific Aims: (1) Identify alterations in brain network activity in individuals with 15q13.3 microdeletion, based on nine defined spatio-temporal brain activity patterns. Establish their predictive ability to discriminate between patients and controls. (2) Investigate the same for individuals with 15q13.3 microduplication. Determine whether neurophysiological alterations occur in the same direction as genomic copy number at that locus. (3) Analyze whether BNA patterns can be used to predict cognitive and behavioral phenotypes. Assess BNA data for association with ASD diagnosis. (4) Determine whether BNA alterations are specific to the underlying genetic etiology, or a general manifestation of ASD diagnosis, by comparing BNA findings of 15q13.3 deletion and duplication individuals with BNA findings of individuals affected with idiopathic ASD.Study Design: We propose to enroll 28 individuals with 15q13.3 microdeletion syndrome, 28 individuals with 15q13.3 microduplication, and 28 individuals with idiopathic ASD. Control individuals will be chosen from an internal database of individuals without neurobehavioral disease, controlling for age distribution and sex. All individuals will be subjected to two rounds of BNA testing, including baseline resting EEG, the Go/No-Go task (for cognitive function involving response inhibition, executive functions, and sustained attention), and the Oddball paradigm (for executive functions, attention, and memory processes). All study participants will be evaluated for ASD, using the Autism Diagnostic Interview, revised (ADI-R), and the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2). Cognitive ability will be assessed, using the Stanford-Binet Intelligence Scales, 5th Edition. For statistical analysis, pairwise group comparisons will be assessed using independent, two-sample t-tests and p-values will be adjusted for multiple hypotheses testing using Tukey’s method.Impact: This study sets out to address several key questions and challenges in the field of ASD research. First, we will investigate the neurophysiological signature of ASD and test whether this signature depends on the underlying genetic cause. Second, we will investigate why chromosomal copy number changes in opposite direction (deletions and duplications) frequently predispose to clinically overlapping cognitive and behavioral phenotypes. Third, we will assess BNA’s potential as a quantifiable outcome measure for future clinical trials of pharmacological intervention, both for 15q13.3 copy number variants and also for ASD in general. In summary, our proposal addresses ASD mechanistically, its heterogeneous causes and clinical expressions, as well as factors that will promote success of future clinical trials.Innovation: This represents the first application of BNA, a novel, FDA-approved system to study spatio-temporal brain activity patterns, in the context of ASD and intellectual disability. From a genetic perspective, investigating reciprocal deletions and duplications (both of which predispose to ASD) on a functional level, is both novel and important. This study investigates ASD in the context of a specific genetic etiology and beyond, assesses functional alterations at a network level, and drives discovery of quantifiable outcome measures for future clinical trials.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
