Autism spectrum disorders (ASD) are increasingly thought to arise from abnormalities in the way different regions of the brain become connected to each other during development. Brain connectivity is under strong genetic control and affects thought and behavior. In ASD, abnormalities in the way the brain is "wired" interfere with the coordination of activity across brain regions and give rise to symptoms. The goal of the present study is to identify genes that affect brain connectivity in ASD and to learn how brain connectivity is related to symptoms. Finding genes that affect brain connectivity will give critical information about the brain mechanisms that underlie symptoms and facilitate the development of treatments for these symptoms in individuals with ASD that carry specific risk genes.
We will investigate brain connectivity in ASD, its relation to specific risk genes and to a core defining feature of ASD -- restricted, repetitive behavior (RRB). Although RRBs are often the most disabling core feature of ASD, effective treatments are lacking. This may reflect that there are different types of RRBs that arise from different underlying mechanisms and therefore require different treatment approaches. By clarifying the different genetic and brain bases of RRBs, the proposed study will guide the development of treatment. Converging lines of evidence, including from our own preliminary studies, link RRBs to the connectivity of a specific brain region, the anterior cingulate cortex (ACC), and to imbalances of a specific chemical that transmits brain signals, the neurotransmitter "serotonin." Based on these findings, we hypothesize that individuals with ASD will show abnormal connectivity of the ACC as characterized by (1) reduced integrity in the wiring of the ACC (i.e., structural connectivity) as measured with diffusion tensor imaging (DTI), a technique that measures the structural integrity of white matter brain connections, and (2) reduced coordination between the ACC and other brain regions (i.e., functional connectivity) as measured by functional connectivity magnetic resonance imaging (fcMRI), which measures the similarity in levels of activity across brain regions over time. We expect that reduced structural and functional connectivity of the ACC will be associated with increased severity of RRBs and variation in a specific set of risk genes that are involved in serotonin neurotransmission.
The primary aim of this study is to discover the brain mechanisms underlying RRBs in ASD and their relation to genes that regulate serotonin.
We will study 40 neurotypical control participants and 80 individuals with ASD, recruited from the Autism Consortium, whose genetic makeup, symptoms, development, and family history have been extensively characterized. The type and severity of RRBs will be quantified using reliable and well-validated instruments. fcMRI and DTI images will be acquired using state-of-the-art sequences that have been tested in children and automatically correct for participant motion during scanning. Data analyses will be conducted to determine whether reduced structural and functional connectivity in ASD is associated with RRBs and with variation in genes that regulate serotonin.
The findings will provide a more thorough understanding of the genetic and brain mechanisms that underlie a core and highly disabling feature of ASD. It will illuminate how the development of brain connectivity from adolescence to young adulthood differs in ASD, how these differences may influence symptoms such as RRB, and whether specific risk genes may be involved. The findings will also provide pilot data for a larger brain imaging and genetics grant application to the National Institute of Mental Health to examine the brain and genetic bases of RRBs. We hope to identify the subset of individuals with ASD whose RRBs would be most likely to benefit from a class of drugs that affect serotonin neurotransmission (SSRIs). Thus, this work will have a direct impact on both research and clinical care.
The proposed study will be the first to utilize state-of-the-art complementary brain imaging techniques with real-time motion correction to test the hypothesis that RRBs are associated with specific reductions in brain functional and structural connectivity in ASD and to identify genetic targets that may point to specific interventions.