Over the past decade, the hypothesis that autism spectrum disorder (ASD) is a disorder of reduced long-range and increased local functional connectivity has been gaining traction. To date, however, there is no evidence of increased local functional connectivity in ASD. If, furthermore, ASD is indeed a disorder of functional connectivity, then similar abnormalities ought to manifest in both the social communication (core/defining) and the non-social communication (non-core/non-defining) domains of deficits. Whether this is the case, however, has never been systematically tested in one group of participants. The objectives of the current proposal are to determine the nature of local and long-range functional connectivity abnormalities in ASD, the relationship between them, whether they are manifested similarly in both the core social and non-core non-social domains of ASD deficits, and their correlations with behavioral and structural measures. Our central hypotheses are that ASD is in fact a disorder of connectivity, and that reduced long-range and reduced, not increased, local functional connectivity are distributed, cortex-wide features of ASD, manifested in all domains of deficits. We further hypothesize that local and long-range functional connectivity are reduced proportionally to one another in ASD. These hypotheses will be tested by investigating local and long-range functional connectivity in the social communication (Aim 1) and non-social (Aim 2) domains of deficits of ASD, and their correlation with the ASD phenotype (Aim 3). The proposed studies will take advantage of MEG's high spatial and temporal resolutions to examine functional connectivity in 45 ASD children, ages 8-12, and 45 matched typically developing children, as they perform tasks that tap into core social communication (face perception and speech processing) and non-core (executive control and auditory processing) domains of ASD deficits. The proposed research is conceptually innovative because our hypothesis challenges the prevailing notion that local functional connectivity is increased in ASD, and further proposes a direct correlation between the reductions in local and long-range functional connectivity. Furthermore, it addresses multiple domains of deficits simultaneously in the same participants. The proposed research is analytically innovative because it uses novel analytical tools to study phase-amplitude cross-frequency coupling (a measure of local functional connectivity) non-invasively in cortical space. The proposed research is significant because (a) it will examine the nature of both local and long-range functional connectivity abnormalities in multiple domains of deficits simultaneously, (b) it will determine whether local and long-range functional connectivity abnormalities are directly correlated in ASD, (c) it will provide a novel approach for non-invasively measuring local functional connectivity in cortical space, (d) it will set the stage for developing novel functiona-connectivity based neurophysiological biomarkers for ASD, which have potential applications for treatment and early diagnosis.

Public Health Relevance

The proposed research will elucidate the neurophysiological underpinnings, as manifested through functional connectivity, of autism spectrum disorders (ASD). It will advance the field by elucidating neurophysiological correlates of ASD, in ways that have the potential to impact future treatment research avenues, treatment evaluations, earlier diagnosis through the development of objective neurophysiological biomarkers for ASD.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Child Psychopathology and Developmental Disabilities Study Section (CPDD)
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Kau, Alice S
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Massachusetts General Hospital
United States
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Mamashli, Fahimeh; Khan, Sheraz; Bharadwaj, Hari et al. (2018) Maturational trajectories of local and long-range functional connectivity in autism during face processing. Hum Brain Mapp 39:4094-4104
Khan, Sheraz; Hashmi, Javeria A; Mamashli, Fahimeh et al. (2018) Maturation trajectories of cortical resting-state networks depend on the mediating frequency band. Neuroimage 174:57-68
Mamashli, Fahimeh; Khan, Sheraz; Bharadwaj, Hari et al. (2017) Auditory processing in noise is associated with complex patterns of disrupted functional connectivity in autism spectrum disorder. Autism Res 10:631-647
Ganesan, Santosh; Khan, Sheraz; Garel, Keri-Lee A et al. (2016) Normal Evoked Response to Rapid Sequences of Tactile Pulses in Autism Spectrum Disorders. Front Hum Neurosci 10:433
Khan, Sheraz; Hashmi, Javeria A; Mamashli, Fahimeh et al. (2016) Altered Onset Response Dynamics in Somatosensory Processing in Autism Spectrum Disorder. Front Neurosci 10:255
Kitzbichler, Manfred G; Khan, Sheraz; Ganesan, Santosh et al. (2015) Altered development and multifaceted band-specific abnormalities of resting state networks in autism. Biol Psychiatry 77:794-804
Khan, Sheraz; Michmizos, Konstantinos; Tommerdahl, Mark et al. (2015) Somatosensory cortex functional connectivity abnormalities in autism show opposite trends, depending on direction and spatial scale. Brain 138:1394-409
Khan, Sheraz; Lefèvre, Julien; Baillet, Sylvain et al. (2014) Encoding cortical dynamics in sparse features. Front Hum Neurosci 8:338