CRCNS US-German-Israeli Research Proposal: Multi-Level Neuro-Computational Models of Basal Ganglia Dysfunction in Tourette Syndrome

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Tourette syndrome is a neurological disorder characterized by sudden movements and vocalizations known as tics. The disorder can be highly debilitating with severe clinical and social effects. The overall goal of this work is to combine experimental and computational approaches to better understand the mechanisms leading to tic production. In past work, tic production has been linked to abnormal activity in a variety of brain regions, many of which are in an area called the basal ganglia. Experiments in animals have shown that blocking certain forms of signaling between neurons in the basal ganglia induces tics. This project will use innovative methods to collect data from neurons in the basal ganglia in these tic-producing animal models, which will be used in several ways. Data analysis will identify changes in neural activity that are linked with tic production, providing a detailed view of the neuronal interactions involved. The data will also guide the development of two novel computational model networks, one focused and one large-scale. These models will be used to explore how changes in signaling between neurons within the basal ganglia, as well as between the basal ganglia and major motor command centers in the cortex, can lead to tic production. Results of these computational studies will yield predictions for subsequent experimental testing. For an action to be performed, it must be selected from among the myriad of possible movements that could be made. How this action selection is accomplished is currently not well understood. This project will enhance our understanding of how changes in neuronal activity and signaling lead to tic production, as well as to the selection of actions in general. The results about tic production will have clinical implications for Tourette syndrome by suggesting targets for interventions and providing a framework for testing the impact of potential treatments. Currently, such a framework in the area of Tourette syndrome is lacking, and related computational studies have been quite limited. The models developed will also advance the field by serving as resources for the study of additional questions relating to neuronal activity and to signaling between neurons in movement-related brain areas. Companion projects are being funded by the Federal Ministry of Education and Research, Germany (BMBF), and the US-Israel Binational Science Foundation (BSF).