This proposal examines how local cortico-cortical connectivity forms a biological basis of autism spectrum disorder (ASD). The incidence of ASD in our society is about 1% but characteristically there is no known singular etiology, or indeed phenotype, of ASD. Deficiencies in long-range brain connectivity have been repeatedly observed in ASD, especially in thalamocortical and association projections associated with auditory and related language systems. However, recent studies have indicated that local cortico-cortical connections may also be disrupted in ASD. Local phase amplitude coupling (PAC) has emerged as a resting-state cortico-cortical mechanism by which low-frequency cortical oscillations gate or modulate higher frequency oscillations such as gamma- band activity. PAC has been observed in multiple brain regions and is thought to be a common mechanistic framework for timing communication between neuronal assemblies, and thus provides a measureable assay of local functional connectivity. PAC can be measured with magnetoencephalography (MEG) and does not rely on task-based trials. This proposal uses PAC to overcome the experimental inefficiencies of task-based MEG by first validating PAC as a sensitive resting-state metric in ASD and then extending measures of local PAC across the brain.
Aim 1 uses the auditory system as a testbed to characterize the contribution of resting-state superior temporal gyrus PAC to previously described developmental irregularities and delays in signal conduction.
Aim 2 extends PAC as a contrast map across the brain and elucidates spatial patterns of cortical dysfunction in ASD.
Aim 3 uses diffusion MR to correlate white matter structure to PAC. We hypothesize that the spatial correlation pattern between structural connectivity and PAC will be degraded in ASD. To accomplish these goals, we will contrast PAC between groups of school-aged (6-15yrs) children with ASD and typically-developing controls. This proposal leverages a large existing cohort which already consists of 53 ASD (mean age 10.42.4yrs) and 39 control children (mean age 11.02.7yrs) who underwent neuropsychological testing, MEG, and MRI with evaluable data across all domains. This multimodal proposal is innovative in both the concept of validating PAC as a sensitive metric of local connectivity and the methods used to extend PAC as a generalizable measure of cortico-cortical connectivity across the brain in ASD. This investigation will provide new insights into how the structure-function relationship develops across the brain, as well informing contemporary theories of ASD as a disorder of connectivity.

Public Health Relevance

Autism spectrum disorder (ASD) is thought to be associated with abnormalities to local cortio-cortical connections. This proposal uses magnetoencephalography to examine local connectivity with measures of phase-amplitude coupling (PAC) to further our understanding of the neural dysfunctions which underlie the symptoms of ASD. This proposal seeks to validate MEG measures of PAC in ASD and then correlate local connectivity with measures of white matter structure.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Developmental Brain Disorders Study Section (DBD)
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Gilotty, Lisa
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Children's Hospital of Philadelphia
United States
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