This is a resubmission of an application that responds to Program Announcement PA-06-392 (Research on Autism and Autism Spectrum Disorders). This PA solicits exploratory/developmental (R21) grant applications to support research into the pathophysiology of autism spectrum disorders. Explicitly included in this funding opportunity are studies, such as the one proposed, that investigate brain mechanisms and the neurobiological basis of ASD, an area of high public health priority. Autism is a serious childhood-onset disorder whose symptoms reflect underlying brain pathology. Overall, the cerebellum and inferior olive are two brain areas consistently shown to be abnormal in neurobiological and post-mortem anatomical studies in autism. The inferior olive (IO), part of the brainstem-cerebellar system, integrates sensory and motor activity before relaying it to the cerebellum. Of particular interest in autism spectrum disorder (ASD) is the fact that the IO is a pacemaker system that may play a global role in brain timing that is important for language functioning. Eyeblink conditioning is an associative learning task and a sensitive measure of brain timing;it is non-invasive and can be performed in a relatively short period of time. Importantly, eyeblink conditioning requires normal functioning of the inferior olive and cerebellum. The present study will test the general hypothesis that children with ASD are impaired in rapid temporal processing and will show deficits in eyeblink conditioning. To do so, subjects will be randomized to one of 2 groups. In the first, subjects will initially undergo 'delay conditioning'followed by 'trace conditioning, and in the second group, subjects will initially undergo 'trace conditioning'followed by 'delay conditioning'. By involving subjects in both delay and trace conditioning, the data can be examined for between and within differences. Also, by counterbalancing delay-trace and trace-delay ordering, the effect of each type of conditioning on learning the other can be examined. The delay and trace conditioning paradigms will differ only in specific CS-US pairing parameters. In all, the study will involve 40 patients with ASD (aged 6 to 18 years) and 40 matched controls. Data obtained from this study will be used to devise larger and more definitive studies in ASD and as a tool to guide mechanistic studies in animals. Such a non-invasive measure could have a number of uses including as a measure for early detection of ASD, as a tool for translational research, and as an outcome measure for treatment studies.
The proposed study will develop an area of research that may be valuable in determining the brain networks that are dysfunctional in ASD. Findings from this line of research may help direct future animal and human studies to better understand the role of brain mechanisms in ASD. This research is translational and will bring together an established basic scientist (John P. Welsh, Ph.D.) and a clinical researcher (Richard P. Malone, M.D.) so that knowledge gained in the basic science laboratory can be used to further investigate causes of symptomology in individuals with ASD.
| Oristaglio, J; Hyman West, S; Ghaffari, M et al. (2013) Children with autism spectrum disorders show abnormal conditioned response timing on delay, but not trace, eyeblink conditioning. Neuroscience 248:708-18 |
