The tics of Tourette syndrome (TS) have a surprising variation in clinical history and response to treatment. In many cases, the tics disappear in adolescence and early adulthood. However, in others, the tics persist and although they often respond to treatment with dopamine antagonists, the effect in individual cases is notoriously difficult to predict. The aim of this proposal is to use physiological tools to probe individual differences in brain organisation that might be responsible for these effects. Our current understanding of the neurobiology of TS suggests that tics arise from a combination of two factors: reduced excitability of GABAergic inhibition in striatum coupled with changes in plasticity of corticostriatal synapses. The former leads to release of unwanted movements by reducing inhibitory output of basal ganglia, whereas the latter may promote long term plastic changes in the strength of synapses that impact on the learning processes responsible for development of complex tics and behaviours. Corticostriatal plasticity is heavily influenced by dopaminerigic projections, which may account for the clinical effect of dopaminergic antagonists in treating tics. It is difficult to study directly the corticostriatal system in awake humans. However work suggests that the postulated abnormalities in these deep circuits may also be reflected in organisation of cortical circuits that are much more amenable to study. In the present project we will employ a range of newly developed non-invasive electrophysiological tests of synaptic plasticity and inhibition in motor cortex of subgroups of patients who show different characteristics of individual history and response to treatment. We hypothesise that these will provide objective biomarkers to quantify and even predict effects of treatment in individual patients. John Rothwell, Ph.D., Eileen Joyce, M.D. & Diane Ruge, M.D. University College London Institute of Neurology, London, United Kingdom Award: $74,959 (2nd Year Funding) Tourette Association of America Inc. – Research Grant Award 2012-2013