Converging findings from diverse levels of analysis provide compelling evidence of cerebellar (CB) abnormalities in autism spectrum disorder (ASD), including decreased Purkinje cell numbers, neurochemical abnormalities, and increased glial cell activation. However, little is known about in vivo CB structure and function, nor the behavioral consequences of CB abnormalities. The proposed research tests a novel theoretical model using cutting-edge brain connectivity approaches to explore pathophysiological mechanisms associated with ASD and explicitly targets the CB, a brain area known to be abnormal in ASD. We will recruit 40 high functioning individuals with ASD and 40 neurotypical controls.
Specific Aim 1 will determine how CB functional and structural abnormalities contribute to documented CB-dependent task-related deficits in the disorder. Specifically, we will determine if CB fMRI activation and CB gray matter volumes predict CB- dependent delay eyeblink conditioning (dEBC) behavioral abnormalities in ASD. Regression analyses will quantify the CB's specific contribution over and above other contributing regions (e.g., middle frontal, temporal & parietal cortices, basal ganglia).
Specific Aim 2 will determine CB task-related (dEBC) effective connectivity and resting state functional connectivity to brain regions with which it has strong neuroanatomical connections, and the extent to which connectivity is disrupted in ASD. Path analysis will be used to determine CB effective connectivity and directionality. Resting state functional connectivity will be quantified using seed- based and ROI-based approaches. These functional analyses will explore CB connectivity and directional influence in the context of a network and rule out models where the deficit is systemic or due to extra-CB areas.
Specific Aim 3 will determine whether core ASD symptom domains correlate with functional connectivity within specific closed-loop CB-cortical circuits. We hypothesize the following with respect to ASD functional connectivity: 1) CB anterior lobe and lobules VII-VIII to somatosensory/motor cortex will be inversely correlated with dEBC timing impairment and with Repetitive Behaviors Scale Revised (RBS-R) scores; 2) Posterior CB (including Crus I/II) to temporal and prefrontal cortex will be positively correlated with the social cognition scale of the Social Responsiveness Scale (SRS); 3) Crus I & II with cortical language regions will be inversely correlated with receptive language processing. The proposed research could identify critical mechanisms underlying ASD by re-shaping ideas about the role of the CB in the disorder's fundamental motor, social, and cognitive deficits. Moreover, these aims are consistent with NIMH priorities including developing an integrative understanding of basic brain-behavior processes that provide the foundation for understanding mental disorders and probing the connectivity of brain networks.
This study will lead to improved understanding of the neural mechanisms underlying autism, which is an extraordinarily debilitating developmental disorder. The resulting knowledge will be especially informative about the role of an understudied region of the human brain called the cerebellum, and may lead to the identification and development of innovative treatments.
