Cerebellum and autism: Regional specialization for social and executive functions - PROJECT SUMMARY Autism spectrum disorder (ASD) is a prevalent neurodevelopmental condition characterized by deficits in social communication and the presence of repetitive and inflexible behaviors. There are currently few biologically- targeted treatment options for ASD, in part because the underlying neurobiology is not well understood. One region of the brain that is consistently implicated in ASD is the cerebellum. However, despite extensive evidence of cerebellar dysfunction in ASD, the exact contribution of the cerebellum to ASD remains unclear. The cerebellum is richly interconnected with other regions of the brain that support motor, cognitive, and affective functions, and our previous work has established functional subregions within the cerebellum, providing a useful framework for understanding how regional differences within the cerebellum might contribute to ASD. Specifically, two cerebellar subregions show structural and functional differences in autism: right cerebellar lobule VII (RVII) and the posterior cerebellar vermis. Based on the different anatomical connectivity of these regions, we hypothesize that RVII and the posterior vermis regulate different core deficits in ASD. Our previous work has shown that grey matter in RVII correlates with social and communication scores in ASD, whereas the volume of the posterior vermis is associated with repetitive behaviors. In a previous R15 award, we determined the impact of non-invasive neuromodulation of cerebellar RVII on social task performance and brain activation patterns. We found that cerebellar neuromodulation changed performance on a social learning task and altered functional connectivity in brain circuits relevant to autism. Further, our collaborators showed that RVII inhibition led to social deficits in mice, while RVII excitation rescued social deficits in a mouse model of autism. These findings suggest that cerebellar neuromodulation could be a novel therapeutic option in ASD. However, the optimal modulation target within the cerebellum has yet to be established, and we hypothesize that this could differ in a symptom-specific way. Here we will combine cerebellar neuromodulation with functional neuroimaging to test our hypothesis that neuromodulation targeting RVII will selectively alter social learning and neural networks supporting social behavior, while neuromodulation targeting the posterior vermis will impact cognitive flexibility and neural networks involved in the allocation of attention. Neurotypical adults and adults with ASD will complete social and cognitive flexibility tasks after excitatory, inhibitory, or sham neuromodulation in a within-subjects design. Some participants will receive neuromodulation targeting RVII and others will receive neuromodulation targeting the posterior vermis. We will acquire functional brain imaging data during and after cerebellar neuromodulation, which will allow us to better understand the mechanisms by which non-invasive modulation might impact behavior in clinical disorders. This work will further contribute to our understanding of the neurobiology of autism, with the broader significance of generating critical proof-of- concept data to evaluate the clinical translational potential of cerebellar neuromodulation.
