Brain Network Activation Patterns in Autism Due to Genomic Copy Number Variation
Abstract
Background: The potential causes of autism spectrum disorder (ASD) are manifold and extremely complex. In the genetics field alone, more than 700 autism genes have been identified to date. Whether genetic complexity converges in common pathways and patterns that affect brain activity has yet to be determined. Brain Network Activation (BNA) is a novel, Food and Drug Administration (FDA)-approved method that can analyze networks of neurons that are active in response to outside stimuli. Data are recorded with a noninvasive system, similar to an EEG (electroencephalogram). Preliminary Data: We have conducted BNA testing on 10 individuals with a specific genetic alteration (15q13.3 deletion), five of whom met research-reliable criteria for ASD (both by ADI-R [Autism Diagnostic Interview, revised], and ADOS-2 [Autism Diagnostic Observation Schedule, Second Edition] testing). All individuals were able to complete the testing successfully, and tolerated the procedure well. Alterations in several brain networks were found, when compared to age-matched controls. One brain network altered in the groups of patients was able to predict the presence of autism with a sensitivity of 100% and a specificity of 67%. We hypothesize that analysis of brain network activity can be used to identify signatures of altered brain network function in subsets of ASD. These signatures may then provide outcome measures for future clinical trials in ASD, allowing the investigation of effects of pharmacological compounds in a quantifiable way. Approach: We will enroll 28 individuals with ASD of unknown cause, and 56 individuals with specific genetic alterations that predispose to ASD. Of these, 28 individuals will have a deletion (missing piece of chromosome material) on chromosome 15q13.3, and 28 individuals will have a duplication (extra piece of chromosome material) of the same location. BNA testing will be performed twice on each individual, using two tests, both of which use auditory stimuli (sounds presented via headphone). The study participants will also undergo rigorous testing for autism and cognitive abilities, including the ADI-R, ADOS-2, and the Stanford-Binet Intelligence Scales, 5th Edition. Questions to Be Answered: (1) Do individuals with the deletion have specific brain network alterations? (2) Do individuals with the duplication have brain network alterations, and are they in the same or opposite direction compared to the individuals with the deletion? (3) Are there BNA changes that are generally seen in all individuals with ASD? Can these changes be used to predict ASD? (4) Do BNA changes correlate with cognition or specific behaviors? Autism Research Program Areas of Interest Addressed: Our proposal promises to identify quantifiable outcome measures for future clinical trials. In addition, it relates to the question of heterogeneous clinical expression of ASD: How do both deletion and duplication of the same chromosome area predispose to ASD, yet with different severity? Are there patterns of brain activity that are shared by all individuals with ASD or are these patterns specific to the underlying genetic cause? Innovation: This represents the first application of a novel, FDA-approved system to study brain activity patterns in the context of ASD. From a genetic perspective, investigating deletions and duplications of the same site, and testing their functional consequences side by side, is novel. Impact: This study sets out to address several key questions and challenges in the field of ASD research. We will investigate the brain network patterns of ASD and test whether these depend on the underlying genetic cause. Second, we will assess BNA?s potential as a quantifiable outcome measure for future clinical trials, both for 15q13.3 copy number variants, but also for ASD in general. In summary, our proposal addresses ASD mechanistically, its heterogeneous causes and clinical expressions,
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710369
Entities
People
- Christian Schaaf
Organizations
- Baylor College of Medicine
- United States Army