Individuals with profound autism have been historically underrepresented in research. Though profoundly autistic individuals make up roughly 27 percent of the ASD population, they represent only a small portion of research participants. Consequently, research findings in the field underrepresent profoundly autistic individuals. One of the most significant reasons for this underrepresentation is the need for research participants to follow spoken or written instructions and maintain engagement with a task. In this project researchers will test a novel interactive experimental delivery system that helps people participate in research without needing to understand complex instructions. The experiment uses computer vision systems that reward participants for sitting still and attending, rather than asking a participant to sit quietly and attend to a computer screen without incentive. Using this method, researchers will study two promising biomarkers, the balance of neural activity in the brain using electroencephalography (EEG) (which is associated with sensory sensitivity), and arousal using pupil diameter (which is associated with symptoms like disordered sleep and aggression). The goal is to develop a novel system for including profoundly autistic individuals in research.
Adapting Biomarker Assays for Profound Autism
Restricted and repetitive behaviors (RRBs) range from hand flapping to debilitating self-injury. This student will investigate the biological basis for the broad range of RRBs by examining the development of the circuits in an area of the brain called the striatum. Pictures of the brain will be collected and analyzed at multiple time points in individuals from 1-4 years of age and matched with the presence and type of RRBs and later outcomes, like real-world function or adaptive behavior. The results will help identify critical windows for brain development when intervention can be most beneficial.
The Autism Biomarkers Consortium for Clinical Trials (ABC-CT) is a multicenter research study based at Yale that also includes Duke University, Boston Children’s Hospital, the University of Washington/Seattle Children’s Research Institute and the University of California, Los Angeles. The aim of the consortium is to develop reliable and objective measurements of social function and communication in people with autism, based on underlying neurobiological signals rather than on behavior. To date, measuring several of these biological signals (by both the ABC-CT and other research groups) as objective markers, has only taken place in a laboratory environment by showing participants videos on computers.
Because many autistic individuals cannot sit still in a clinical setting, and because people normally don’t encounter the world in front of a computer, it is not known if these biomarkers are valid in real-life settings. The ASF accelerator grant will enable researchers to expand their study by going out into the community with mobile biomarker measuring devices that allow participants to move freely rather than be tethered to a computer. Data from this portion of the project will provide information about whether specific biomarkers are present in real-world settings. It will also enable researchers to access a broader diversity of participants.
Individuals with a mutation in ASH1L exhibit symptoms of profound autism, as well as several medical comorbidities. Building on this fellow’s expertise in pre-clinical models of ASH1L-related autism, the fellow will advance to a natural history study of human patients with this mutation, and their families. In addition, the fellow will collect EEG data from families and identify potential biomarkers of this gene mutation. These are critical steps that enable future drug development and seizure treatment. When the study is complete, the findings have potential to guide development of new drugs to treat symptoms of profound autism, including those with and without an ASH1L mutation.
Hypersensitivity to auditory stimuli, including even regular sounds and voices, is seen in a high percentage of people with autism. This project will expand on existing research at Vanderbilt looking at brain activity in autistic and non-autistic individuals with different levels of sound tolerance to understand the factors that play a role in the brain’s response to noise.
Even in cases of autism with a known genetic mutation, there can be differences in the presentation of symptoms, which is also known as “phenotypic heterogeneity.” One way to measure this variability across individuals with autism is by examining brainwave patterns. Earlier research in people with Fragile X Syndrome has shown that individuals have different patterns of brainwave activity, which may predict their response to treatments. Building on this research, the fellow will collect cells from individuals with Fragile X Syndrome and turn them into neurons. These cells will then be tested for their own electrical activity, validating the brainwave data collected earlier. This study will then take the research a step further by examining if and how different therapeutics affect these neurons in different ways, leading to more targeted therapeutics.
Genetic testing is recommended for all children with autism. However, many children receive test results that reveal mutations in genes that have not yet been associated with autism. Unfortunately, these variants of uncertain significance can cause confusion and problems for parents seeking clinical diagnoses and support. This study will utilize machine learning to integrate genetic findings with the child’s attainment of key developmental milestones, because often milestone delays are associated with rare genetic disorders. Eventually, this research could lead to a brief, low-cost clinical prediction tool that increases the diagnostic certainty of genetic testing in autism.
More and more evidence is pointing to sex-related differences in gene expression as a potential explanation of the male sex bias in autism diagnosis. This study will examine the role of a gene called MYT1L that has been linked to autism. Mouse models will examine the expression of this gene in the cortex (where there is no evidence of a sex difference in expression of MYT1L) and compare it to expression in the hypothalamus (where there are sex-specific differences linked to social behaviors). The fellow will also examine social learning in males and females and count neurons to look for both behavioral and cellular changes. This will determine where in the brain sex-differential effects in social behavior originate, providing evidence for more targeted intervention strategies in males and females with autism.
Recent research has implicated the gene PTCHD1 on the X chromosome as contributing to the causes of autism and intellectual disability, but there is still very little known about what it does and how it leads to changes in the brain. This project will be the first-ever attempt to determine the function of the PTCHD1 protein in its natural biological setting. Cells will be manipulated to create mutations in PTCHD1, then turned into neurons, and then the proteins that are expressed will be measured. Finally, the fellow will measure how these proteins interact in the brain. This will enhance our understanding of how this gene interacts with the rest of the brain and expand the range of therapeutic approaches intended to target specific types of dysfunction in people with autism.
Oversensitivity to touch is common in autism and can lead to discomfort and harm. In some cases, people with autism avoid other people’s touch but seek out tactile stimulation through self- stimulatory behaviors. Self-stimulation can be anything from finger tapping to headbanging, which is harmful and dangerous. While the differences in the brain’s response to different types of touch have been studied in neurotypical people, there is little information on the different responses in people with autism. This fellow will examine how the autistic brain responds to different types of touch, ultimately providing a biological basis for determining why some touch is avoided while some is sought out, which could improve therapy for dangerous self-stimulatory behaviors.
Rett Syndrome is caused by a mutation on the X chromosome at MeCP2. Girls with Rett Syndrome share many features of autism, including delayed or lack of language development, impaired fine motor skills, repetitive behaviors and cognitive disability. MeCP2 activity is also regulated by environmental factors and has been implicated in autism when a genetic cause has not been identified. This fellow will look closely at changes in MeCP2 binding and how it regulates gene expression by isolating different types of neurons at different ages to determine which are critical in the progression of symptoms. The fellow will also employ a sophisticated analysis of machine learning techniques to integrate the data to predict how MeCP2 activity regulates different neuron types at different points in development. This will allow scientists to move closer to providing patients with targeted approaches to interventions.
On the first podcast of 2024, we describe a new paper in the Journal of the American Medical Association or JAMA which uses physiological measurements like heart rate and skin conductance to predict severe and dangerous behaviors, specifically aggression. If aggression can be predicted, it might be able to be prevented. It turns out aggression can be predicted up to 3 minutes before an episode occurs, in the future these measures can be used to possibly redirect aggression. In a separate study, the issue of stigma is addressed. There is an intense debate over “person first” vs. “identity first” language in autism, promoting recommendations of using one over the other because fear that person first language promotes stigma against autism. A new study shows that there is no added prejudice or fear using either person first or identity first language, but the stigma associated with schizophrenia is worse than it is for autism. What contributes to stigma? There is a wide range of experiences and perceptions of autism that need to be addressed. It’s not as simple as the language used.